Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]1[CH:14]=[CH:15][C:16]([C:18]([OH:20])=[O:19])=[CH:17][N:8]1[C:7]2=[O:21])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH3:28][N:29]([CH3:32])C=O>>[N:29]1[CH:32]=[CH:1][CH:2]=[C:4]([CH2:13][CH2:12][CH2:11][O:19][C:18]([C:16]2[CH:15]=[CH:14][C:9]3[N:8]([CH:17]=2)[C:7](=[O:21])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([CH:2]([CH3:1])[CH3:3])[CH:5]=2)[N:10]=3)=[O:20])[CH:28]=1
Reactant: CN(C)C=O
Reactant: CC(C)c1ccc2nc3ccc(C(=O)O)cn3c(=O)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)c1ccc2nc3ccc(C(=O)OCCCc4cccnc4)cn3c(=O)c2c1
Temperature: 70 °C
Yield: 38 %

Procedure:
A mixture of 5.0 g of 2-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid, 5.2 g of 3-(3-pyridine)propylbromide hydrobromide, and 5.2 g of potassium carbonate in 200 ml of dimethylformamide was heated to a bath temperature of 70° C. for 45 minutes. The reaction mixture was partitioned between water (100 ml) and dichloromethane (100 ml) and the aqueous layer was extracted with 3×100 ml of dichloromethane. The combined extracts were washed with 100 ml portions of 10% sodium hydroxide and water, were dried over potassium carbonate and evaporated to 6.3 g of an oil which was purified by preparative liquid chromatography over silica gel eluting with 3:1 ethyl acetate-hexane. The major fraction contained 4.6 g of a orange oil which was crystallized from ethyl acetate-hexane to give 2.7 g (38%) of 2-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid 3-(3-pyridyl)propyl ester, mp 108°-109° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12]([CH:14]=[C:15](OCC)[NH:16][C:17]#[C:18][CH3:19])#[N:13].C(N)C#C.C(C=C(OC)OC)#N>>[C:12]([CH:14]=[C:15]([NH:16][CH2:17][C:18]#[CH:19])[NH:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])#[N:13]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CC#CNC(=CC#N)OCC
Agent: C#CCN
Agent: COC(=CC#N)OC
Product: C#CCNC(=CC#N)NCCSCc1[nH]cnc1C

Procedure:
When 2-[(4-methyl-1H-imidazol-5-yl)methylthio] ethylamine [prepared according to the procedure described in U.S. Pat. No. 3,950,353] is reacted with 1-cyano-2-ethoxy-2-propynylaminoethylene [prepared by the reaction of propargylamine with 1-cyano-2,2-bis(methoxy)ethylene, itself prepared by the procedure described in J. Am. Chem. Soc., 71, 47 (1949)], the title product is produced.
Reaction SMILES: CO[C:3](=O)[NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:7][CH:6]=1.[Al+3].[H-].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1>[CH3:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:7][CH:6]=1
Reactant: CCCCCCCCCCCCCCCc1ccc(NC(=O)OC)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCc1ccc(NC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
Compound 7 (3.9 g) was dissolved in tetrahydrofuran (55 mL). Lithium hydride aluminum (620 mg) was carefully added thereto and the reaction solution was refluexed with heating for 2 hours. After cooling the reaction solution to room temperature, 2N aqueous sodium hydroxide solution (3 mL) was added carefully, further tetrahydrofuran and anhydrous magnesium sulfate were added, followed by stirring for 1 hour. The reaction solution was filtered with Celite (brand name) and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to obtain the title compound (3.4 g) having the following physical property values.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:25]([C:27]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:28]=1CO)[CH3:26]>C1COCC1>[CH3:26][O:25][C:27]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:28]=1[CH2:1][Br:5]
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(OC)c(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(OC)c(CBr)c1
Reaction time: 2 h

Procedure:
Carbon tetrabromide (0.47 g, 1.25 mmol) and triphenylphosphine (0.47 g, 1.25 mmol) were added to a solution of 2,5-dimethoxylbenzylalcohol (0.2 g, 1.19 mmol) in THF (10 ml) at room temperature. The mixture was stirred for two hours to form a precipitate which the preciptate was filtered off. The filtrate was evaprated and the crude product was chromatographed (ethyl acetate and hexane 7:3). The desired compound was isolated as a white solid (0.25 g, 93%).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:16][CH2:17][CH3:18])(=[O:15])[CH3:14].[Br:19][C:20]1[C:25]2[N:26]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[O:28][C:29](=O)[C:24]=2[CH:23]=[N:22][CH:21]=1.[OH-].[Na+]>[Cl-].[Na+].O.C1COCC1>[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]2[C:25]=1[NH:26][C:27]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:40])[F:39])[CH:32]=1)=[C:14]([C:13]([O:16][CH2:17][CH3:18])=[O:15])[C:29]2=[O:28]
Reactant: O=c1oc(-c2cccc(C(F)(F)F)c2)nc2c(Br)cncc12
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2cccc(C(F)(F)F)c2)[nH]c2c(Br)cncc2c1=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 77.2 %

Procedure:
A mixture of THF (15 mL) and diisopropylamine (1.40 mL, 10.0 mmol) was cooled to −78° C., and n-BuLi (4.0 mL, 2.5 M in hexanes, 10.0 mmol) was added. After stirring at −78° C. for 20 min, ethyl acetate (1.0 L, 10.2 mmol) was added and stirring was continued for 5 min. 8-bromo-2-(3-(trifluoromethyl)phenyl)-4H-pyrido[4,3-d][1,3]oxazin-4-one 47 (990 mg, 2.67 mmol) was added. After 1 h, the reaction mixture was gradually warmed to room temperature. 1N NaOH (15 mL) was added and the reaction mixture was stirred for 24 h. The mixture was poured into brine (50 mL), extracted with ethyl acetate (2×50 mL), dried (MgSO4), and concentrated in vacuo. The resulting solid was purified by MPLC to give 48 (910 mg, 77% yield).
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH2:9]1[CH2:15][S:12](=[O:14])(=[O:13])[O:11][CH2:10]1>C1COCC1>[OH:8][CH2:7][C@@H:2]([NH:1][CH2:10][CH2:9][CH2:15][S:12]([OH:14])(=[O:13])=[O:11])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: O=S1(=O)CCCO1
Reactant: CC(C)C[C@H](N)CO
Solvent: C1CCOC1
Product: CC(C)C[C@@H](CO)NCCCS(=O)(=O)O
Temperature: 25 °C
Yield: 62.7 %

Procedure:
To a solution of L-(+)-leucinol (5.0 g, 42.8 mmol) in THF (65 mL) was slowly added 1,3-propanesultone (4.85 g, 40.7 mmol in THF (10 mL)). The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration and washed with acetone (2×50 mL). The solid was dissolved in 50% water/EtOH (400 mL). Dowex Marathon C ion exchange resin (strongly acidic) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated under reduced pressure. The solid was suspended in acetone (150 mL), filtered and dried in the vacuum oven (50° C.), affording the title compound (6.11 g, 63%). 1H NMR (D2O, 500 MHz) δ ppm 3.77 (m, 1H), 3.59 (m, 1H), 3.23 (m, 1H), 3.13 (m, 2H), 2.90 (m, 2H), 2.02 (m, 2H), 1.53 (m, 2H), 1.35 (m, 1H), 0.81 (d, 3H, J=16.1 Hz). 13C (D2O, 125 MHz) δ ppm 58.72, 58.00, 48.17, 43.54, 35.96, 24.34, 22.53, 21.62, 20.89. [α]D=+16.6° (c=0.0022 in water), ES-MS 240 (M+1).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:16](Br)=[C:17]2[C:22](=[CH:23][C:24]=1[CH3:25])[N:21]=[C:20]([CH3:26])[CH:19]=[CH:18]2)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[C:1]([O:7][CH2:8][C@@H:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:15]1[C:16]([C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)=[C:17]2[C:22](=[CH:23][C:24]=1[CH3:25])[N:21]=[C:20]([CH3:26])[CH:19]=[CH:18]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1ccc2c(Br)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(C)cc2n1
Reactant: OB(O)c1ccc(Cl)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: COCCOC
Product: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(C)cc2n1
Temperature: 110 °C
Yield: 72.9 %

Procedure:
Pd(PPh3)4 (69 mg, 0.06 mmol) was added to a mixture (S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyethyl pivalate (5E) (325 mg, 0.75 mmol), 4-chlorophenylboronic acid (175 mg, 1.1 mmol), K2CO3 (1.3 mL 2 M in water, 2.6 mmol) in 1,2-dimethoxyethane (10 mL). The reaction mixture was flushed with nitrogen, heated at 110° C. for 30 min under microwave, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product (256 mg, 73%). LCMS-ESI+ (m/z): 468.3, 469.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:40]=[C:39]([CH3:41])[C:5]([C:6]([NH:8][CH2:9][CH2:10][CH:11]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C@H:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:21][N:22]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:15][CH2:14]2)[CH3:12])=[O:7])=[C:4]([CH3:42])[N:3]=1.O.NN>CCO>[NH2:22][CH2:21][C@H:20]([NH:19][CH:16]1[CH2:17][CH2:18][N:13]([CH:11]([CH3:12])[CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]2[C:39]([CH3:41])=[CH:40][C:2]([Cl:1])=[N:3][C:4]=2[CH3:42])[CH2:14][CH2:15]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Cc1cc(Cl)nc(C)c1C(=O)NCCC(C)N1CCC(N[C@@H](CN2C(=O)c3ccccc3C2=O)c2ccccc2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(Cl)nc(C)c1C(=O)NCCC(C)N1CCC(N[C@@H](CN)c2ccccc2)CC1
Yield: 67.5 %

Procedure:
Following general procedure D: a solution of 6-chloro-N-(3-{4-[(R)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1-phenyl-ethylamino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide (194 mg, 0.33 mmol), hydrazine hydrate (0.05 ml ml, 0.1 mmol) in EtOH (2 ml) was stirred at rt overnight. Purification of the crude product by chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 100:10:2) afforded N-{3-[4-((R)-2-Amino-1-phenyl-ethylamino)-piperidin-1-yl]-butyl}-6-chloro-2,4-dimethyl-nicotinamide (102 mg, 67%).
Reaction SMILES: N[C@H](C(O)=[O:8])CC(C)C.CC1(C)S[C@@H]2[C@H](N[C:20]([C@H:22](N)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=O)C(=O)N2[C@H]1C(O)=O.O=C[C@H]([C@@H]([C@@H](CO)O)O)O>>[C:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:8])[CH3:20]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Product: CC(=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
A gene encoding leucine dehydrogenase from B. stearothermophilus is subjected to mutagenesis by error-prone PCR according to the method of May, et al. The error-prone PCR is performed in a 100 mL reaction mixture containing 0.25 ng of plasmid DNA as template dissolved in PCR buffer containing 0.2 mM of each dNTP, 50 pmol of each primer and 2.5 units of Taq polymerase. Conditions for carrying out the PCR are as follows: 2 minutes at 94° C.; 30 cycles of 30 sec 94° C., 30 sec 55° C.; 2 minutes at 72° C. The PCR product is double digest with Nco I and Bgl II and subcloned into pBAD/HisA vector which has been digested with the same restriction enzymes. The resulting leucine dehydrogenase mutant library is transformed into an E. coli host strain LMG194 and plated on LB agar supplied with 100 μg/mL ampicillin. Individual transformants are inoculated into master plates containing 0.2 mL LB Broth with 100 μg/mL ampicillin, and growth is allowed to take place for 8–16 hours at 37° C. with shaking at 200 rpm. Each well in each master plate is then re-inoculated by a replica plating technique into a new second stage 96-well plate pre-loaded with the same growth media plus 2 g/L of arabinose, and growth is allowed to continue for 5–10 hours at 37° C. with shaking at 200 rpm. The second stage plates are then centrifuged at 14,000 rpm for 20 minutes, and the supernatant is decanted. The cell pellet in each well is washed with 200 mL of water. The washed cell pellet is suspended in 30 mL of B-Per. After mixing, the suspension of cells in B-Per reagent is allowed to stand for 10 minutes at room temperature, and a solution having the following composition is then added to each well in the plate:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:41](Cl)(=[O:43])[CH3:42]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([N:26]([S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:41](=[O:43])[CH3:42])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: CC(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)N(C(C)=O)c1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F

Procedure:
The title compound was prepared according to the procedure as described in Example 3 using N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.2 g, 0.41 mmol), triethylamine (1 mL) and acetyl chloride (116 μL, 1.64 mmol) in 1,4-dioxane (10 mL). The title compound was obtained as a white solid (69 mg, 31.8%). The title compound was characterized by LCMS and 1H NMR as shown below:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11]([Mg]Br)[CH2:12][CH:13]=[CH2:14]>C1COCC1>[F:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]([OH:5])[CH2:14][CH2:13][CH:12]=[CH2:11]
Reactant: O=Cc1cc(I)ccc1F
Reactant: C=CCC[Mg]Br
Solvent: C1CCOC1
Product: C=CCCC(O)c1cc(I)ccc1F
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A stirred solution of 2-fluoro-5-iodo-benzaldehyde (0.714 g, 2.86 mmol) in dry THF at −78° C. under nitrogen was treated over 10 min with 0.5 M 3-butenyl magnesium bromide in THF (6.85 mL, 3.43 mmol), stirred for 0.5 h, allowed to warm to −30° C. over 1 h, quenched with saturated ammonium chloride, diluted with water and extracted with ethyl acetate. The extracts were combined, dried over MgSO4 and concentrated in vacuo. Purification of the resultant residue by flash chromatography (5% to 10% ethyl acetate/petroleum ether) gave 1-(2-fluoro-5-iodo-phenyl)pent-4-en-1-ol as a clear oil, 565 mg (65% yield). A portion of this oil (0.25 g, 0.82 mmol) was dissolved in dry methylene chloride, cooled to 0° C., treated with boron triflouride etherate (0.1 mL, 0.81 mmol), stirred for 15 minutes under a nitrogen atmosphere, warmed to room temperature for 1 h, and quenched with saturated sodium bicarbonate. The reaction mixture was partitioned between methylene chloride and H2O; and the aqueous phase was extracted with methylene chloride. The organic phase and the extracts were combined, washed with brine, dried over MgSO4 and concentrated in vacuo to give 1-fluoro-4-iodo-2-pent-4-en-1-ylbenzene as a clear oil, 0.18 g (76% yield).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C@@H:33]([NH2:36])[C@H:32]([F:37])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(C(C)C)CC)(C)C>CC(O)C>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C@@H:33]([NH:36][C:18]2[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)[C@H:32]([F:37])[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](F)C1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)[C@H](F)C1
Temperature: 25 °C
Yield: 86.7 %

Procedure:
A stirred solution of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (173 mg, 0.513 mmol), trans-4-Amino-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester (112 mg, 0.513 mmol), diisopropylethylamine (211 μl, 1.16 mmol) in propan-2-ol (2 ml) were stirred at 82° C. overnight then cooled to room temperature. The precipitated solid was then collected by filtration to yield 231 mg (87%) of trans-4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester that was used without further purification. LCMS (Method F): RT=1.22 min, m+H=520.0; 1H NMR (400 MHz, DMSO) 6=8.91 (s, 2H), 8.13 (d, J=7.4, 2H), 7.86-7.83 (m, 1H), 7.81-7.72 (m, 1H), 7.65 (s, 2H), 7.20-7.15 (m, 1H), 4.88-4.69 (m, 1H), 4.57-4.41 (m, 1H), 4.33 (d, J=4.2, 1H), 4.23-4.02 (m, 1H), 3.26-3.02 (m, 2H), 2.08-1.96 (m, 1H), 1.81-1.69 (m, 1H), 1.42 (s, 9H).
Reaction SMILES: [CH:1]([C:3]1[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])=[O:2].Cl>[OH-].[Na+]>[CH:1]([C:3]1[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:2]
Reactant: CCOC(=O)CCCCOc1cccc(O)c1C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=Cc1c(O)cccc1OCCCCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 5-(2-formyl-3-hydroxyphenoxy)pentanoate (Example 13) (0.5 g, 0.00188 M) was dissolved in 2 N sodium hydroxide solution (10 ml) and stirred at room temperature (30 minutes). The yellow solution was cooled and acidified with concentrated hydrochloric acid and the precipitated solid filtered off and washed well with water to give 5-(2-formyl-3-hydroxyphenoxy)pentanoic acid, m.p. 98°-99° C. from benzene/petrol, identical (NMR spectrum, melting point and mixed melting point) with the end product of Example 4).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19](=[O:24])[CH2:20][C:21](=[O:23])[CH3:22].FC(F)(F)C(O)=O.S(Cl)(Cl)=O>>[C:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[CH:18][C:19](=[O:24])[CH2:20][C:21](=[O:23])[CH3:22])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(OCCc2ccccc2)cc1
Reactant: CC(=O)CC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O=S(Cl)Cl
Product: CC(=O)CC(=O)C=Cc1ccc(OCCc2ccccc2)cc1

Procedure:
The procedure described in example 8 was repeated by using 5.9 g of 4-(2-phenylethoxy)benzaldehyde, 3.9 ml of 2,4-pentanedione, 26 ml of trifluoroacetic acid and 2.1 ml of thionyl chloride. Yield 4.7 91 an viscous oil.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][CH:29]([C:36]2([CH3:42])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.Cl>CC#N>[F:1][C:2]1[C:3]([NH:28][CH:29]([C:36]2([CH3:42])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)CC(Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C1(C)CCCCC1
Agent: Cl
Solvent: CC#N
Product: CCOC(=O)CC(Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F)C1(C)CCCCC1
Temperature: 70 °C

Procedure:
To a solution of ethyl 3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4ylamino)-3-(1-methylcyclohexyl)propanoate, 207a, (0.49 mg, 0.81 mmol) in CH3CN (3 mL) was added HCl (2.0 mL of 4M solution in dioxane, 8.1 mmol). The solution was heated at 70° C. for 3 hours and then cooled to room temperature. The solvent was removed under reduced pressure and the product was neutralized with aqueous saturated NaHCO3 solution. The precipitate was extracted with EtOAc (3×10 mL). The solvent was dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-70% EtOAc/Hexanes gradient) to afford 230 mg of the desired product as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 9.55 (s, 1H), 8.58 (dd, J=9.3, 2.5 Hz, 1H), 8.18 (s, 2H), 8.00 (d, J=2.7 Hz, 1H), 5.13 (brs, 1H), 4.95 (t, J=8.2 Hz, 1H), 3.84 (m, 2H), 2.72 (m, 1H), 2.38 (m, 1H), 1.67-1.15 (m, 10H), 0.94 (m, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.77 minutes (M+H) 444.36.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH3:22])([CH3:21])[C:13]2=[O:23])[CH2:8][CH2:7]1)=[O:5].C(N(CC)CC)C.[N+:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[S:48](Cl)(=[O:50])=[O:49])([O-:41])=[O:40].O>ClCCl.C(OCC)(=O)C>[CH3:21][C:14]1([CH3:22])[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:12]([CH:9]2[CH2:8][CH2:7][N:6]([C:4](=[O:5])[C@@H:3]([NH:2][S:48]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[N+:39]([O-:41])=[O:40])(=[O:49])=[O:50])[CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:11][CH2:10]2)[C:13]1=[O:23]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC1(C)C(=O)N(C2CCN(C(=O)[C@@H](N)CCc3ccccc3)CC2)c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1(C)C(=O)N(C2CCN(C(=O)[C@H](CCc3ccccc3)NS(=O)(=O)c3ccccc3[N+](=O)[O-])CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.4 %

Procedure:
To a solution of (S)-1-(1-(2-amino-4-phenylbutanoyl)piperidin-4-yl)-3,3-dimethylindolin-2-one hydrochloride (1.00 g, 2.26 mmol, EXAMPLE 1, Step 4) in dichloromethane (10 mL) was added triethylamine (954 microL, 6.79 mmol) and 2-nitrobenzenesulfonyl chloride (501 mg, 2.26 mmol) at 0° C. After stirring for 20 min at room temperature, water and ethyl acetate were added to the mixture. The organic layer was washed with sodium hydrogen carbonate aqueous solution, 1 mol/L hydrochloric acid and brine, dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate, gradient) to give the title compound (1.26 g, 94%) as an amorphous solid.
Reaction SMILES: Cl[C@@H:2]1[C@H:19]2[O:20][C@:18]32[C@:13]([CH3:22])([CH2:14][CH2:15][C@H:16]([OH:21])[CH2:17]3)[C@@H:12]2[C@@H:3]1[C@H:4]1[C@@:8]([CH2:10][CH2:11]2)([CH3:9])[C:7](=[O:23])[C@H:6]2[CH2:24][C@@H:5]12.O1CCCC1>C(O)(=O)C.[Zn]>[OH:21][C@H:16]1[CH2:15][CH2:14][C@@:13]2([CH3:22])[C@:18]([OH:20])([CH:19]=[CH:2][C@@H:3]3[C@@H:12]2[CH2:11][CH2:10][C@@:8]2([CH3:9])[C@H:4]3[C@@H:5]3[CH2:24][C@@H:6]3[C:7]2=[O:23])[CH2:17]1
Reactant: C[C@]12CC[C@H]3[C@@H]([C@H](Cl)[C@H]4O[C@]45C[C@@H](O)CC[C@]35C)[C@@H]1[C@@H]1C[C@@H]1C2=O
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H](C=C[C@]4(O)C[C@@H](O)CC[C@]34C)[C@@H]1[C@@H]1C[C@@H]1C2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.4 %

Procedure:
107.5 g of 7α-chloro-5,6β-epoxy-3β-hydroxy-15β,16β-methylene-5β-androstan-17-one is dissolved in 500 ml of acetic acid and 500 ml of tetrahydrofuran and, after the addition of 324 g of zinc dust in three portions, stirred at room temperature for 16 hours. The zinc is then filtered off, the filtrate is diluted with methylene chloride, and washed with sodium bicarbonate solution and water. After drying over sodium sulfate, the product is concentrated under vacuum. By trituration of the thus-obtained solid with ethyl acetate, 91.5 g of 3β,5-dihydroxy-15β,16β-methylene-5β-androst-6-en-17-one is produced, mp 196° C.