Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:16][CH2:15]2)=[CH:10][C:9]=1[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:14]1([C:11]2[CH:10]=[C:9]3[C:8](=[CH:13][CH:12]=2)[NH:7][C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:17]3)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2CC2)cc1CC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(-c2cc3cc(C4CC4)ccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 85.1 %

Procedure:
To a solution of tert-butyl[4-cyclopropyl-2-(2-oxo-2-phenylethyl)phenyl]carbamate (561 mg) in dichloromethane (8 mL) was added dropwise trifluoroacetic acid (1.6 mL) under ice-cooling. The mixture was heated to room temperature, and then stirred for 23 hours. The reaction mixture was concentrated under reduced pressure. To the residue were added ethyl acetate and saturated aqueous sodium hydrogen carbonate solution to separate the organic layer. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (317 mg). 1H-NMR (CDCl3) δ ppm: 0.65-0.75 (2H, m), 0.85-1.00 (2H, m), 1.95-2.10 (1H, m), 6.70-6.80 (1H, m), 6.90-7.00 (1H, m), 7.25-7.50 (5H, m), 7.60-7.70 (2H, m), 8.24 (1H, br s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5](=[O:21])[C@H:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH:7]([CH3:9])[CH3:8].[BH4-].[K+]>CO>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C@H:5]([OH:21])[C@H:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[CH:7]([CH3:9])[CH3:8]
Reactant: COC(=O)CC(=O)[C@H](NC(=O)OCc1ccccc1)C(C)C
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: COC(=O)C[C@H](O)[C@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl ester 11 (2.8 g, 9.15 mmol) in HPLC MeOH (30 mL), cooled to −78° C., potassium borohydride (1.72 g, 32 mmol) was added in portions. The reaction mixture was stirred at −78° C. for 10 min, warmed to −20° C. for 30 min and then to 0° C. for 10 min. The reaction was quenched with acetic acid to pH 7 and extracted with CH2Cl2 (3×50 mL). The organic layer was washed with NaHCO3 (50 mL, sat), NaCl (50 mL, sat), dried (Na2SO4), filtered and evaporated. The alcohol 12 was obtained as a colorless oil (2.7 g, 98%) and used directly in the next step. 1H-NMR (500 MHz, CDCl3): 0.87 (d, J=6.7 Hz, 3H), 0.94 (d, J=6.7 Hz, 3H), 2.10-2.19 (m, 1H), 2.47 (dd, J=16.7 and 9.1 Hz), 2.58 (dd, J=16.7 and 2.9 Hz, 1H), 3.11-3.20 (m, 1H), 3.56-3.63 (m, 1H), 3.68 (s, 3H), 3.90-3.98 (m, 1H), 4.64 (d, J=7.9 Hz, 1H), 5.09 (s, 2H), 7.30-7.39 (m, 5H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([NH2:13])=O)[CH:6]=[CH:7][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.[OH-].[Na+]>C1COCC1>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][NH2:13])[CH:6]=[CH:7][CH:8]=1
Reactant: NC(=O)CCc1cccc(C(F)(F)F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NCCCc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 50.2 %

Procedure:
To a solution of 3-(3-trifluoromethyl-phenyl)-propionamide (12) (3.4 g, 15.7 mmol) in THF (70 mL) was added dropwise a solution of lithium aluminum hydride in THF (1.0 M, 15.7 mL, 15.7 mmol) at room temperature. The reaction mixture was heated to reflux for 4 hours, then cooled to 0° C. Ethyl acetate was added to quench the reaction. Sodium hydroxide (5 N) was added and the mixture was refluxed for 30 min. The reaction was cooled to room temperature. Ethyl acetate was added to extract the product. The organic layer was separated and washed by saturated sodium bicarbonate and brine, then dried over MgSO4. Evaporation gave a crude oil, which purified by chromatography to give compound 13 as a colorless oil (1.6 g, 50.2%).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[Cl:12][CH2:13][CH2:14]O>>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([O:5][CH2:14][CH2:13][Cl:12])=[O:4]
Reactant: O=C(O)C(O)c1ccccc1
Reactant: OCCCl
Product: O=C(OCCCl)C(O)c1ccccc1

Procedure:
2-Chloroethyl 2-hydroxy-2-phenylacetate was prepared from 2-hydroxy-2-phenylacetic acid and excess 2-chloroethanol essentially by the method described in Step 1 of Example 1; however, the distillate solidified after standing at 4° C.: b.p. 119° C./0.35 mm Hg; m.p. 43°-45° C.; 1H NMR γ3.50 (d, 1H, J=6.0 Hz), γ3.58-3.62 (m, 2H), γ4.28-4.46 (m, 2H), γ5.22 (d, 1H, J=5.9 Hz), δ7.3-7.4 (5H); HRMS calcd for C9H7ClO3Tms (M-CH3) 271.0557, obsd 271. 0598.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][C:11]([CH3:13])=O.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OC(C)C)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][CH:11]([CH3:13])[CH3:10])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CC(C)=O
Reactant: Nc1cc(Br)cnc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 102.6 %

Procedure:
5-bromo-2-chloropyridin-3-amine (1.889 g, 9.1 mmol) was dissolved in isopropyl acetate (20 ml) and acetone (0.81 ml, 11 mmol), trifluoroacetic acid (1.40 ml, 18 mmol), and sodium triacetoxyborohydride (2.34 g, 11 mmol) were added. The reaction was stirred under nitrogen at room temperature for almost 4.5 hours and then quenched with 10% sodium hydroxide in water (˜20 ml) to raise the pH to about 9. The layers were separated, and the aqueous phase was extracted with EtOAc. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and dried under high vacuum to afford 5-bromo-2-chloro-N-isopropylpyridin-3-amine (2.33 g, 89% purity, 100% yield). MS (ESI pos. ion) m/z: 249 (MH+, 79Br), 251 (MH+, 81Br). Calculated exact mass for C8H10BrClN2 248 (79Br), 250 (81Br).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[CH:8][N:7]=1)=[O:5])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:25])C=1>>[CH2:1]([NH+:3]([O-:25])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[CH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCNC(=O)c1ccc(C(=O)NCC)nc1
Product: CCNC(=O)c1ccc(C(=O)[NH+]([O-])CC)nc1

Procedure:
From 1 g of N,N'-diethylpyridine-2,5-dicarboxamide and 1.8 g of MCPBA.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:11][N:12](C=O)C.CCN(C(C)C)C(C)C.Cl.CN.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>O>[NH2:1][C:2]1[C:3]([C:8]([NH:12][CH3:11])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccnc1C(=O)O
Reactant: CN(C)C=O
Agent: CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CNC(=O)c1ncccc1N
Reaction time: 3 h
Yield: 35.7 %

Procedure:
A solution of 3-aminopicolinic acid (0.3 g, 2 mmol) in DMF (2.0 mL, 26 mmol) was cooled to 0° C., treated with DIPEA (7.57 mL, 43.4 mmol), methylamine hydrochloride (1.47 g, 21.7 mmol) and TBTU (0.837 g, 2.61 mmol). The flask was sealed and the mixture was allowed to come up to RT stirring for 3 hours. The reaction mixture was poured into water and extracted with EtOAc three times. The combined organic layers were dried over Na2SO4, filtered and concentrated to an oil which was passed through an ion exchange column (SCX). The MeOH/NH3 washes were combined to isolate 108 mg of a brown oil which crystallized upon standing. 1H NMR (400 MHz, DMSO-d6) d 2.76 (d, J=4.80 Hz, 3H), 6.81 (br. s., 2H), 7.13 (dd, J=8.30, 1.50 Hz, 1H), 7.22 (dd, J=8.30, 4.30 Hz, 1H), 7.77 (dd, J=4.17, 1.39 Hz, 1H), 8.52 (d, J=3.79 Hz, 1H). MS (ES+): m/z=152.04 [MH+].
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:8]([Cl:13])=[N:9][CH:10]=[CH:11][CH:12]=1)=O.N(O)=O.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH2:29])=[NH:28])[CH:23]=[CH:24][CH:25]=1.[OH-].[Li+]>CC(O)CC>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:26][C:27]2[N:29]=[C:5]([C:7]3[C:8]([Cl:13])=[N:9][CH:10]=[CH:11][CH:12]=3)[CH:4]=[CH:3][N:28]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: CN(C)C=CC(=O)c1cccnc1Cl
Reactant: COc1cccc(NC(=N)N)c1
Agent: O=NO
Agent: [Li+]
Agent: [OH-]
Solvent: CCC(C)O
Product: COc1cccc(Nc2nccc(-c3cccnc3Cl)n2)c1
Temperature: 25 °C
Yield: 78 %

Procedure:
A mixture of 3-dimethylamino-1-(2-chloro-3-pyridyl)-2-propen-1-one (3.50 g, 16.5 mmol), 3-methoxy-phenyl-guanidine nitrite (3.70 g, 16.2 mmol), lithium hydroxide (412 mg, 16.5 mmol) in 2-butanol (15 mL) is heated to reflux overnight. The reaction mixture is cooled to room temperature, concentrated and water (60 mL) is added. The resultant solid is filtered, washed with water, isopropanol and dried to give N-[3-methoxy-phenyl]-4-(2-chloro-3-pyridyl)-2-pyrimidineamine (3.95 g); ESI-MS (m/z): 313 (M++H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[Br:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].C(=O)(O)[O-].[Na+]>COC(O)C>[Br:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:17]#[N:18])[CH:24]=[CH:25][CH:26]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1[N+](=O)[O-]
Reactant: Nc1cccc(Br)c1
Agent: COC(C)O
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc2ncc(C#N)c(Nc3cccc(Br)c3)c2cc1[N+](=O)[O-]
Yield: 15.3 %

Procedure:
A solution of 5.2 g (19.7 mmol) of 4chloro-7-methoxy-6-nitro-3-quinolinecarbonitrile and 3.7 g (21.7 mmol) of 3-bromo aniline in 130 ml of methoxyethanol was refluxed under nitrogen for 4 hours. The reaction mixture was poured into dilute sodium bicarbonate solution. Solid was collected and washed with water and dried in air. The solid was chromatographed on silica gel eluting with chloroform-ethyl acetate 9:1. Solvent was removed from product fractions giving 1.2 g of 4-[(3-bromophenyl)amino]-7-methoxy-6-nitro-3-quinolinecarbonitrile as a yellow solid: mass spectrum (electrospray, m/e): M+H 399.0, 402.0.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[C:12]1([S-:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+]>CC(O)C.O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([S:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: [S-]c1ccccc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Nc1nc(Sc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 91.2 %

Procedure:
2-amino-3-nitro-6-(phenylmercapto)pyridine was prepared by heating 2-amino-6-chloro-3-nitropyridine (84.0 g, 0.484 mol) and sodium thiophenolate (Fluka) (72.0 g, 0.545 mol) in 2-propanol (1500 mL) under reflux for 2 hours. After cooling to room temperature the suspension was diluted with water (100 ml), the solid was collected by vacuum filtration, washed with water and 2-propanol, and dried at 50° C. under vacuum to give 109.1 g (95% yield) of 2-amino-3-nitro-6-(phenylmercapto)pyridine, m.p. 148-152° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.O.[NH2:10][NH2:11]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:10][NH2:11])[CH:3]=1
Reactant: Fc1cc(Br)ccn1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1cc(Br)ccn1
Temperature: 45 °C
Reaction time: 16 h
Yield: 91.4 %

Procedure:
To a solution of 4-bromo-2-fluoropyridine (23.75 g, 135 mmol) in ethanol (120 mL) was added hydrazine monohydrate (65.5 mL, 1350 mmol). The mixture was stirred at 45° C. for 16 h then concentrated. The resulting solid was triturated with water, collected by filtration, rinsed with water, and dried under vacuum, to give the title compound (23.2 g) as a white solid. LCMS m/z=188.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 4.19 (s, 2H), 6.69 (dd, J=5.3, 1.8 Hz, 1H), 6.92 (d, J=1.7 Hz, 1H), 7.69 (s, 1H), 7.84 (d, J=5.3 Hz, 1H).
Reaction SMILES: C([S:4][CH:5]([CH3:13])[CH:6]([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)C>Cl.C(O)C>[SH:4][CH:5]([CH3:13])[CH:6]([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(C)C(C)SC(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(C)C(C)S
Yield: 52 %

Procedure:
The crude product of Example 1 prior to column chromatography (˜9 g) was refluxed with 10 mL ethanol and several drops of 10M HCl (in ethanol) for 12 hours. Distillation (8.5 T, 75° C.) afforded the free thiol as a clear oil (3.7 g, 52%) and as a mixture of stereoisomers. Odor: at 1 ppm in DPG—guava, mango, exotic fruity note, juicy, sweet, tropical and ripe. GC/MS (EI): m/z (%) 162(34), 134(2), 129(34), 89(52), 74(77), 56(100). 1H NMR (CDCl3); δ 4.08-4.17 (m, 2H), 3.14-3.31 (m, 1H), 2.46-2.58 (m, 1H), 1.67 & 1.50 (2d, J=7.79 Hz, 1H mix of diastereomers), 1.17-1.35 (m, 9H)). 13C NMR (CDCl3) for mix of diastereomers: δ 174.6, 60.9, 60.6, 48.8, 47.7, 37.8, 23.6, 21.9, 14.3, 13.5.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[C:10]([F:16])[CH:9]=2)[CH2:6][CH2:5][N:4]([CH:17]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([F:30])[CH:24]=3)[C:18]2=[O:31])[CH2:3]1.B(Br)(Br)Br>C(Cl)Cl>[F:1][C@@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([F:16])[CH:9]=2)[CH2:6][CH2:5][N:4]([CH:17]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([F:30])[CH:24]=3)[C:18]2=[O:31])[CH2:3]1
Reactant: COc1ccc([C@H]2CCN(C3CCN(Cc4ccc(C)c(F)c4)C3=O)C[C@@H]2F)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc(CN2CCC(N3CC[C@H](c4ccc(O)c(F)c4)[C@@H](F)C3)C2=O)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.3 %

Procedure:
To a stirred solution of 3-((3R,4R)-3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one (diastereomeric pair from step L, 50 mg, 0.12 mmol) in DCM (5 mL) at −78° C. was added boron tribromide (2 mL, 2 mmol, 1 M in DCM) and the resulting mixture was stirred at rt for 3 h. The solvent was evaporated and the residue subjected to preparative HPLC (method D) to yield 20 mg (0.04 mmol, 37%) of 3-((3R,4R)-3-Fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one (diastereomeric pair). LCMS (Method K) RT 1.16 min; m/z 419 (M+H+); 1H NMR (400 MHz, methanol-d4) δ ppm 7.22-7.29 (m, 1H) 6.90-7.09 (m, 5H) 4.88-4.96 (m, 1H) 4.49-4.53 (m, 2H), 4.12-4.25 (m, 1H), 4.35-4.42 (m, 1H) 3.98-4.02 (m, 1H) 3.34-3.48 (m, 4H) 3.14-3.21 (m, 1H) 2.98-3.07 (m, 1H) 2.46-2.56 (m, 1H) 2.20-2.30 (m, 5H) 1.98-2.12 (m, 1H).
Reaction SMILES: Br[CH2:2][CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)[O:4][Si](C)(C)C.[N-:16]=[N+:17]=[N-:18].[Na+]>CS(C)=O>[N:16]([CH2:2][CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)[OH:4])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: C[Si](C)(C)OC(CBr)c1cccc(Br)c1
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC(O)c1cccc(Br)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
[2-Bromo-1-(3-bromo-phenyl)-ethoxy]-trimethyl-silane (5.85 g, 16.6 mmol and tetrabutyl sodium iodide (613 mg, 1.66 mmol) were dissolved in DMSO and sodium azide (2.16 g, 33.2 mmol) was slowly added. The mixture stirred at 80° C. for 4 hours and then at room temperature for 18 hours. The mixture was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The organics were washed with water brine and 1M HCl, then again with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with 5-10% ethyl acetate in hexanes. The title compound was isolated as a yellow oil (3.38 g, 83%). 1H NMR (300 MHz, CDCl3): 7.57 (s, 1H), 7.48 (d, 1H), 7.31-7.29 (m, 2H), 4.87 (m, 1H), 3.49 (d, 2H), 2.45 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[S:24]1[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25]1>>[S:24]1[CH:28]=[CH:27][C:26]([C:29]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:30])=[CH:25]1
Reactant: O=C(Cl)c1ccsc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: O=C(Nc1ccc2[nH]cc(C3CCNCC3)c2n1)c1ccsc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.009 mL (0.062 mMol) 3-thiophenecarbonyl chloride, the title compound was prepared.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31](O)[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH2:37]2)=[CH:24]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31]([O:9][C:8](=[O:10])[C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:14][CH:13]=2)([CH3:12])[CH3:11])[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:45])[CH3:46])[CH2:37]2)=[CH:24]1)([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CC(C)(Oc1ccc(F)cc1)C(=O)O
Product: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](OC(=O)C(C)(C)Oc3ccc(F)cc3)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Yield: 1959.2 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 719 mg of 2-(4-fluorophenoxy)-2-methylpropionic acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give1.26 g of the title compound as a colorless foam.
Reaction SMILES: O.C1O[CH:5]([C:6]2[CH:11]=[CH:10][C:9]([C@H:12]3[CH2:29][C@@:27]4([CH3:28])[C@@H:23]([CH2:24][CH2:25][C@:26]4([C:32]#[CH:33])[O:30]C)[C@H:22]4[C:13]3=[C:14]3[C@@:19](O)([CH2:20][CH2:21]4)[CH2:18][C:17](OC)([O:35]C)[CH2:16][CH2:15]3)=[CH:8][CH:7]=2)[O:4]C1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CC(C)=O>[C:32]([C@:26]1([OH:30])[CH2:25][CH2:24][C@H:23]2[C@H:22]3[C:13]([C@@H:12]([C:9]4[CH:10]=[CH:11][C:6]([CH:5]=[O:4])=[CH:7][CH:8]=4)[CH2:29][C@:27]12[CH3:28])=[C:14]1[C:19](=[CH:18][C:17](=[O:35])[CH2:16][CH2:15]1)[CH2:20][CH2:21]3)#[CH:33]
Reactant: C#C[C@]1(OC)CC[C@H]2[C@@H]3CC[C@@]4(O)CC(OC)(OC)CCC4=C3[C@@H](c3ccc(C4OCCO4)cc3)C[C@@]21C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(C=O)cc3)C[C@@]21C
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.8 %

Procedure:
Water (2 ml) is added to 1.2 g of 4-(3,3-dimethoxy-17α-ethinyl-5α-hydroxy-17β-methoxy-estr-9-en-11β-yl)benzaldehyde ethylene acetal in 20 ml of acetone. After the addition of 300 mg of 4-toluenesulfonic acid, the mixture is stirred for 2 hours at room temperature. The reaction solution is stirred into 300 ml of ice water, a flaky precipitate being obtained. After neutralization with sodium bicarbonate solution and stirring for 30 minutes, the precipitate is filtered off with suction, washed with water and dried under vacuum, 786 mg being obtained as a yellow foam. The crude product is purified by preparative layer chromatography on silica gel PF254+366nm (MERCK AG) with a mixture of 4:1 of toluene:acetone as mobile phase, 430 mg of 4-(17α-ethinyl-17β-hydroxy-3-oxoestra-4,9-diene-11β-yl)benzaldehyde being obtained. The product is recrystallized from boiling t-butyl methyl ether with addition of n-hexane.
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=[C:16](Br)[CH:17]=2)=[N:9][CH:10]=1)([CH3:4])[CH3:3].[C:21]([C:25]1[CH:26]=[C:27]2[C:32](=[C:33]([F:35])[CH:34]=1)[C:31](=[O:36])[N:30]([C:37]1[CH:47]=[CH:46][CH:45]=[C:44](B3OC(C)(C)C(C)(C)O3)[C:38]=1[CH2:39][O:40][C:41](=[O:43])[CH3:42])[N:29]=[CH:28]2)([CH3:24])([CH3:23])[CH3:22].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[NH2:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=[C:16]([C:44]3[CH:45]=[CH:46][CH:47]=[C:37]([N:30]4[N:29]=[CH:28][C:27]5[C:32](=[C:33]([F:35])[CH:34]=[C:25]([C:21]([CH3:23])([CH3:22])[CH3:24])[CH:26]=5)[C:31]4=[O:36])[C:38]=3[CH2:39][O:40][C:41](=[O:43])[CH3:42])[CH:17]=2)=[N:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: Cn1cc(Br)cc(Nc2ccc(C(C)(C)N)cn2)c1=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C(C)(C)N)cn3)c(=O)n(C)c2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 125 °C
Yield: 53.7 %

Procedure:
3-[5-(1-Amino-1-methyl-ethyl)-pyridin-2-ylamino]-5-bromo-1-methyl-1H-pyridin-2-one (160 mg, 0.474 mmol), Acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (235 mg, 0.474 mmol), x-phos (34 mg, 0.0712 mmol), potassium phosphate (252 mg, 1.186 mmol) were dissolved in dioxane (4 ml) and water (1 ml). Finally bis(dibenzylideneacetone)palladium (41 mg, 0.0712 mmol) was added and heated in the microwave to 125° C. for 30 min. The reaction mixture was filtered, washed with dioxane, partially concentrated and dry loaded to a 24 g SiOH column. Purification by chromatography with 0-10% MeOH (contains 1% NH4OH) in DCM for 30 min afforded Acetic acid 2-{5-[5-(1-amino-1-methyl-ethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-benzyl ester (159 mg, 54%) as a yellow solid. MS (H+) 625.2.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=O)=[C:2]=[S:3]>FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(Cl)Cl>[N:1]([C:4]1[CH:5]=[C:6]2[C:13](=[O:14])[O:15][C:8](=[O:10])[C:7]2=[CH:11][CH:12]=1)=[C:2]=[S:3]
Reactant: O=C(O)c1ccc(N=C=S)cc1C(=O)O
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C1OC(=O)c2cc(N=C=S)ccc21
Temperature: 25 °C

Procedure:
The 4-isothiocyanatophthalic acid thus obtained was immediately heated to reflux in a mixture of trifluoroacetic anhydride and methylene chloride for 2 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Recrystallization of the resultant solid from 30 mL of carbon tetrachloride afforded 4-isothiocyanatophthalic anhydride as brownish-purple crystals in a yield of 2.3778 g, (77 percent of theoretical). The title compound melted at 106°-108° C.; 1H NMR (300 MHz, acetone-d6) d, 8.15 (d, J=8.1 Hz, 1H), 8.06 (d, J=1.7 Hz, 1H), 7.97 (dd, J=8.1, 1.7 Hz, 1H); 13C NMR (75 MHz, acetone-d6) d 163.3, 162.6, 139.8, 134.8, 134.6, 130.6, 128.2, 123.5, 111.6; IR (CHCl3) 2010 (br), 1840, 1740 cm-1; MS m/e 205, 161, 133 (base), 74.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11]#[N:12])=[CH:5][CH:4]=1.O.[NH2:15][NH2:16]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([NH2:12])[NH:16][N:15]=2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1ccc(C(=O)CC#N)cc1
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cc(N)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(4-methoxyphenyl)-3-oxopropanenitrile (5.0 g, 28.5 mmol) in ethanol (100 mL) was added hydrazine hydrate (2.8 mL, 57.1 mmol) at room temperature. The mixture was heated to reflux for 8 h, allowed to cool and concentrated under reduced pressure to about ¼ volume (25 mL). The resulting precipitate was allowed to stir overnight at room temperature, filtered and rinsed with ethanol (2 mL). The title product was dried under vacuum. Yield 4.15 g (77%); LCMS m/z 190.1 (M+H)+, ret. time=1.56 min.