Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH:16]([NH:27][C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[CH:34][CH:33]=2)=[O:29])[C:17]([O:19]CC2C=CC=CC=2)=[O:18])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[C:42]([O:41][C:39]([NH:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][NH:30][C:28](=[O:29])[NH:27][CH:16]([CH2:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=2)[C:17]([OH:19])=[O:18])=[CH:37][CH:36]=1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CNC(=O)NC(Cc2cccc(OCc3ccccc3)c2)C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(CNC(=O)NC(Cc2cccc(O)c2)C(=O)O)cc1
Yield: 97 %

Procedure:
A solution of 174 (410 mg) in MeOH (20 ml) was stirred for 1 h under hydrogen atmosphere in the presence of 10% Pd/C. The resulting mixture was filtered through celite and the filtrate was evaporated under reduced pressure to give 175 as white solid (280 mg, 97%). 1H NMR (DMSO): δ 1.61 (s, 9H), 2.93 (m, 1H), 3.05 (m, 1H), 4.23 (m, 2H), 4.38 (m, 1H), 6.17 (d, 1H, J=8.0 Hz), 6.66 (t, 1H, J=5.9 Hz), 7.16 (t, 1H, J=7.3 Hz), 7.22 (d, 2H, J=7.6 Hz), 7.50 (d, 2H, J=7.6 Hz), 9.38 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([C:29]4([OH:35])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[CH2:25][CH2:24]3)[N:18]2[CH3:21])=[C:14]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[N:13]=1>>[CH3:21][N:18]1[C:17]([CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3([OH:35])[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[CH2:27][CH2:28]2)=[N:16][C:15]2[C:19]1=[N:20][C:12]([N:3]1[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]1[CH3:1])=[N:13][C:14]=2[N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCC(C3(O)CCOCC3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C4(O)CCOCC4)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-methylbenzimidazole and 4-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)-tetrahydro-2H-pyran-4-ol were reacted to give 317. LCMS m/z: 547.3 (MH+)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[CH:10]=[N:9]1.N1C2C=CC=C(N)C=2C=N1.IC1C=C[C:32]([O:35]C)=CC=1>>[CH3:32][O:35][C:6]1[CH:5]=[CH:4][C:3]([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=3[CH:10]=[N:9]2)=[CH:2][CH:7]=1
Reactant: COc1ccc(I)cc1
Reactant: Nc1cccc2c1cnn2-c1ccccc1F
Agent: Nc1cccc2[nH]ncc12
Product: COc1ccc(-n2ncc3c(N)cccc32)cc1

Procedure:
Similarly prepared to Intermediate 1 from 1H-indazol-4-amine and 1-iodo-4-(methyloxy)benzene.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16](NC)=[O:17])(=[O:14])=[O:13]>ClC1C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13]
Reactant: CNC(=O)NS(=O)(=O)c1ccccc1OCCOC
Solvent: Clc1ccccc1
Product: COCCOc1ccccc1S(=O)(=O)N=C=O
Yield: 99.1 %

Procedure:
13.0 g of N-(2-methoxyethoxy-phenylsulfonyl)-N'-methylurea are suspended in 200 ml of chlorobenzene. The solution is dried by azeotropic destillation of about 20 ml of the solvent. 7.0 g of phosgen are introduced into the solution within 45 minutes at a temperature of the reaction mixture to dryness yields 11.5 g of 2-methoxyethoxy-phenylsulfonyl-isocyanate in form of a yellowish oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:18])[CH:5]=[C:6]([CH3:17])[C:7]=1B1OC(C)(C)C(C)(C)O1.[C:19]([O:23][C:24](=[O:45])[NH:25][C:26]([C:28]1[S:29][C:30]([S:43][CH3:44])=[C:31]([S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38](Br)[CH:37]=2)(=[O:35])=[O:34])[CH:32]=1)=[NH:27])([CH3:22])([CH3:21])[CH3:20].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO>[C:19]([O:23][C:24](=[O:45])[NH:25][C:26]([C:28]1[S:29][C:30]([S:43][CH3:44])=[C:31]([S:33]([C:36]2[CH:37]=[C:38]([C:7]3[C:6]([CH3:17])=[CH:5][C:4]([OH:18])=[CH:3][C:2]=3[CH3:1])[CH:39]=[CH:40][CH:41]=2)(=[O:35])=[O:34])[CH:32]=1)=[NH:27])([CH3:22])([CH3:21])[CH3:20]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Reactant: Cc1cc(O)cc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(O)cc2C)c1

Procedure:
Following the same procedure as in Example 1, step c, reaction of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (355 mg, 0.8 mmol, assuming quantitative yield from Example 224, step a), {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (100 mg, 0.2 mmol, as prepared in Example 27, step c), tetrakis(triphenylphosine)palladium(0) (58 mg, 0.05 mmol, Strem Chemicals Inc, Newburyport, Mass.), Na2CO3 (0.8 mL, 2M), and toluene/EtOH mixture (2:1, 2.4 mL) afforded 35 mg (13%) after purification (PTLC) of the title compound as a tan solid. ESI-MS (m/z): Calcd. for C25H28N2O5S3: 532.7; found: 532.8, 477.0, 433.1 (M−Boc).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]1[C:10]([F:11])=[CH:9][C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:7]([CH3:17])[CH:6]=1)[CH3:4].[F:18][C:19]([F:34])([F:33])[C:20]1[N:25]=[C:24]2[O:26][CH2:27][CH:28]([C:30](O)=[O:31])[O:29][C:23]2=[CH:22][CH:21]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])(O)=O.[Na+]>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:11][C:10]1[CH:9]=[C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:7]([CH3:17])=[CH:6][C:5]=1[C@H:3]([NH:2][C:30]([CH:28]1[CH2:27][O:26][C:24]2=[N:25][C:20]([C:19]([F:33])([F:18])[F:34])=[CH:21][CH:22]=[C:23]2[O:29]1)=[O:31])[CH3:4]
Reactant: O=C(O)C1COc2nc(C(F)(F)F)ccc2O1
Reactant: Cc1cc([C@@H](C)N)c(F)cc1NS(C)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc([C@@H](C)NC(=O)C2COc3nc(C(F)(F)F)ccc3O2)c(F)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a solution of N-[4-((R)-1-Aminoethyl)-5-fluoro-2-methylphenyl]methanesulfonamide hydrochloride (25 mg, 0.09 mmol), 6-trifluoromethyl-2,3-dihydro[1,4]dioxino[2,3-b]pyridine-2-carboxylic acid (20 mg, 0.08 mmol), 4-dimethylaminopyridine (0.8 mg, 0.8 mop and N,N-diisopropylethylamine (50 μL, 0.29 mmol) in anhydrous DMF (1 mL) was added HATU (34 mg, 0.09 mmol). The reaction was stirred overnight at room temperature, then poured into saturated NaHCO3 solution (20 mL) and extracted with EtOAc (3×20 mL). The combined organics were washed with brine (3×30 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (0 to 3.5% MeOH in DCM) gave the title compound (24 mg, 60%) as a solid. m/z=478.2 (M+1), r.t.=2.98 mins. 1H NMR (400 MHz; DMSO-d6) 9.20 (1H, dd), 8.82 (1H, dd), 7.51-7.43 (2H, m), 7.27 (0.5H, d), 7.14 (0.5H, d), 7.07 (1H, dd), 5.20-5.17 (1H, m), 5.09 (1H, t), 4.48-4.42 (2H, m), 3.01 (3H, d), 2.27 (1.5H, s), 2.21 (1.5H, s), 1.38 (3H, d).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[CH2:8][N:9]1[C@@H:17]2[C@H:12]([C@H:13]([CH2:20][C:21]3[CH:26]=[C:25]([CH2:27][C@H:28]([OH:33])[C:29]([F:32])([F:31])[F:30])[C:24]([N:34]=[CH:35][N:36]([CH3:38])[CH3:37])=[C:23]([F:39])[CH:22]=3)[CH2:14][S:15](=[O:19])(=[O:18])[CH2:16]2)[O:11][C:10]1=[O:40])([CH3:4])([CH3:3])[CH3:2].CI.[C:46]([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[CH2:8][N:9]1[C@@H:17]2[C@H:12]([C@H:13]([CH2:20][C:21]3[CH:26]=[C:25]([CH2:27][C@H:28]([O:33][CH3:46])[C:29]([F:31])([F:32])[F:30])[C:24]([N:34]=[CH:35][N:36]([CH3:37])[CH3:38])=[C:23]([F:39])[CH:22]=3)[CH2:14][S:15](=[O:18])(=[O:19])[CH2:16]2)[O:11][C:10]1=[O:40])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])O
Reactant: CN(C)C=Nc1c(F)cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc1C[C@H](O)C(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CO[C@@H](Cc1cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc(F)c1N=CN(C)C)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N′-[4-[(3aR*,7S*,7aS*)-3-(3-tert-butyl-benzyl)-2,5,5-trioxo-octahydro-1-oxa-5lambda*6*-thia-3-aza-inden-7-ylmethyl]-2-fluoro-6-((S)-3,3,3-trifluoro-2-hydroxy-propyl)-phenyl]-N,N-dimethyl-formamidine (0.095 g, 0.144 mmol) in anhydrous DMF was added under argon NaH (0.008 g, 0.34 mmol, 95%) and after 20 min stirring methyliodide (0.028 mL, 0.44 mmol). The reaction mixture was stirred for 2 h at 25° C. After addition of saturated aq. NaHCO3 solution the title compound was extracted with EtOAc. The crude compound, a light yellow oil, was used as such in the next step: TLC (EtOAc) Rf=0.47; HPLC RtA=2.06 min; ESIMS [M+H]+=642.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.ClC1C=CC(C(=O)C)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39]Br)=[CH:33][CH:32]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:39][CH2:38][O:37][C:34]2[CH:35]=[CH:36][C:31]([CH3:30])=[CH:32][CH:33]=2)[CH2:5][CH2:4]1
Reactant: NCC1CCNCC1
Reactant: Cc1ccc(OCCBr)cc1
Agent: CC(=O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(OCCN2CCC(CN)CC2)cc1

Procedure:
A mixture of 4-aminomethylpiperidine (3.58 g) and 4'-chloroacetophenone (4.85 g) in toluene (100 ml) was boiled under reflux with a catalytic amount of p-toluenesulphonic acid for 5 hours, removing the water formed by means of a Dean and Stark apparatus, to give a solution. The solution was cooled and 2-bromoethyl 4-methylphenyl ether (6.68 g) was added, followed by triethylamine (4.4 ml). This mixture was boiled under reflux for 6 hours then evaporated to dryness. 6M Hydrochloric acid (50 ml) was added to the residue and the mixture heated on a steam bath for 16 hours. The mixture was evaporated to near dryness, water (50 ml) was added and the mixture was washed with ether. The aqueous layer was basified with 2M sodium hydroxide solution and extracted with dichloromethane to give 4-aminomethyl-1-[2-(4-methylphenoxy)ethyl]piperidine as an oil. The oil was cooled in ice and 98% formic acid (5.0 ml) and formaldehyde (5.0 ml, 38% aqueous solution) were added. The mixture was heated on a steam bath for 4 hours then evaporated to near dryness and the residue treated with 2M hydrochloric acid (50 ml). The solution obtained was washed with dichloromethane, basified with 2M sodium hydroxide solution and extracted with dichloromethane to give an oil which was distilled at 150° C. at 0.13 mbar. This distillate was dissolved in ether and the solution acidified with ethereal hydrogen chloride. The precipitate was collected by filtration, washed with ether and recrystallised from absolute ethanol to give 4-dimethylaminomethyl-1-[2-(4-methylphenoxy)ethyl]piperidine dihydrochloride, m.p. 278°-280° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4](I)[CH:3]=1.C([Mg]Cl)(C)C.[CH2:15]([O:18][CH2:19][C:20](N(OC)C)=[O:21])[CH:16]=[CH2:17].[NH4+].[Cl-]>C1COCC1.O>[CH2:15]([O:18][CH2:19][C:20]([C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[F:8])=[O:21])[CH:16]=[CH2:17]
Reactant: C=CCOCC(=O)N(C)OC
Reactant: Fc1ccc(Br)cc1I
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOCC(=O)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Scheme 1, steps C and D: To 4-bromo-1-fluoro-2-iodobenzene (0.95 equiv.) in THF (4.6 mL/g) at 0° C. is added isopropylmagnesium chloride (1.0 equiv, 20 weight percent in THF). After about 60 minutes at 0° C., a solution of 2-(allyloxy)-N-methoxy-N-methylacetamide (1.0 equiv.) (Volumes for this stage are in mL/g of this compound) in THF (2.2 mL/g) is added over about 60 minutes. The reaction mixture is quenched into a solution of NH4Cl (4.3 equiv.) in water (5.8 mL/g) at 0° C. Heptanes (7.2 mL/g) is added as the mixture is warmed to room temperature, and the layers are separated. The organic layer is washed with water (7.2 mL/g). The organic layer is concentrated while additional heptanes (4 mL/g) is added to remove water and THF. The intermediate, 2-allyloxy-1-(5-bromo-2-fluoro-phenyl)ethanone is obtained as a solution in heptanes (approximately 20-25 weight %).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Br:12]Br.P(Cl)(Cl)Cl>C(OCC)(=O)C>[Br:12][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:1]([OH:11])=[O:10]
Reactant: BrBr
Reactant: CCCCCCCCC(=O)O
Solvent: CCOC(C)=O
Solvent: ClP(Cl)Cl
Product: CCCCCCCC(Br)C(=O)O
Yield: 90.4 %

Procedure:
To a mixture of nonanoic acid (20 g, 126 mmol) and bromine (24.3 g 152 mmol) was added phosphorous trichloride (5.2 g, 38 mmol) slowly over 0.5 hour. The mixture was refluxed for 3 days and then diluted with ethyl acetate (200 mL). The organic phase was washed with aqueous saturated NaHSO3 (3×), separated, dried over anhydrous sodium sulfate, and the solvent removed in vacuo to yield 27.0 g of the title compound as a brown oil. 1H NMR (CDCl3, 60 MHz) δ0.70 (m, 3H), 1.20 (m, 9H), 1.90 (m, 3H), 4.13 (m, 1H), 10.80 (br s, 1H).
Reaction SMILES: C([O:8][CH2:9][CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([NH:21][C:22]1[C:23](=[O:42])[N:24]([C:28]2[CH:29]=[C:30]([CH:37]=[C:38]([F:41])[C:39]=2[CH3:40])[C:31]([NH:33][CH:34]2[CH2:36][CH2:35]2)=[O:32])[CH:25]=[CH:26][N:27]=1)([CH3:20])[CH3:19])C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl>[CH:34]1([NH:33][C:31](=[O:32])[C:30]2[CH:29]=[C:28]([N:24]3[CH:25]=[CH:26][N:27]=[C:22]([NH:21][C:18]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][CH2:10][CH2:9][OH:8])([CH3:20])[CH3:19])[C:23]3=[O:42])[C:39]([CH3:40])=[C:38]([F:41])[CH:37]=2)[CH2:36][CH2:35]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2SCCOCc2ccccc2)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2SCCO)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
3-[3-{[1-(2-{[2-(Benzyloxy)ethyl]sulfanyl}phenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide (Example 320f, 1.2 g) was stirred in DCM (120 mL) and cooled to 0° C. Boron tribromide (0.387 mL of a 1M solution in DCM) was added dropwise at 0° C. and the reaction stirred for 30 min at 0° C. A further 4 eq of boron tribromide solution was added after 1 h and the reaction warmed to room temperature. The reaction mixture was diluted with ice water, and extracted with ethyl acetate. The organic layers were combined and dried (MgSO4), filtered and evaporated in vacuo to afford the crude product. The crude product was purified (SiO2 chromatography eluting with 100% diethyl ether to 100% ethyl acetate) to afford the subtitle compound as a solid (0.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]([F:35])[F:34])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:31])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]([F:35])[F:34])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[C:17]([OH:19])=[O:18])[C:10](=[O:31])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C[C@H]2CCCCO2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(C[C@H]2CCCCO2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1OC(F)F

Procedure:
85 mg (purity 94%, 0.16 mmol) of tert-butyl 2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-[(2R)-tetrahydro-2H-pyran-2-yl]propanoate (mixture of enantiomerically pure diastereomers 1 and 2) were hydrolysed with TFA according to General Method 6A. Yield: 83 mg (purity 85%, 99% of theory)
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1/[C:12](=[N:16]\[OH:17])/[C:13]([NH2:15])=[O:14])(=[O:3])[CH3:2].[C:18](=O)([O-])[O-].[K+].[K+].CC(C)=O.S(OC)(OC)(=O)=O>O>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1/[C:12](=[N:16]\[O:17][CH3:18])/[C:13]([NH2:15])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccccc1/C(=N\O)C(N)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CO/N=C(/C(N)=O)c1ccccc1COC(C)=O
Temperature: 25 °C
Yield: 95.3 %

Procedure:
A mixture of (E)-2-(2-acetoxymethylphenyl)-2-hydroxyiminoacetamide (428 mg), potassium carbonate (301 mg) and acetone (3.6 ml) was stirred at room temperature. To the mixture was added dropwise 95% dimethyl sulfate (0.20 ml). The mixture was stirred at room temperature for 4.5 hours. Water (10 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. Water (30 ml) was added, and the mixture was extracted with ethyl acetate three times. The combined ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave the crude product (440 mg). The crude product was crystallized from ethyl acetate-hexane, the crystallization mother liquor was concentrated and purified by silica gel thin layer chromatography (ethyl acetate:hexane=4:1) to obtain the title compound (432 mg in total, yield 95.6%, colorless crystals).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:48])[N:17]([CH3:47])[C@@H:18]([C:30](=[O:46])[N:31]([CH3:45])[C@@H:32]([C:40]([NH:42][NH:43][CH3:44])=[O:41])[CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:49](OC(=O)C)(=[O:51])[CH3:50].N1C=CC=CC=1>C(Cl)Cl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16](=[O:48])[N:17]([C@@H:18]([C:30](=[O:46])[N:31]([C@H:32]([CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:40]([NH:42][N:43]([C:49](=[O:51])[CH3:50])[CH3:44])=[O:41])[CH3:45])[CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)[CH3:47])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CNNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(C)NC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 110 %

Procedure:
To a solution of N-methyl-N-((1R)-1-(N-methyl-N-[(1R)-1-(N'-methylhydrazinocarbonyl)-2-phenylethyl]carbamoyl)-2-(2-naphthyl)ethyl)carbamic acid ((9H-fluoren-9-yl)methyl) ester (0.18 g, 0.28 mmol) in methylene chloride (2 ml) was added acetic acid anhydride (0.053 ml) and pyridine (0.027 ml) and the mixture was stirred overnight. The mixture was concentrated in vacuo and stripped three times with methylene chloride to give 0.21 g (110%) of N-((1R)-1-(N-[(1R)-2-(N'-acetyl-N'-methylhydrazino)-1-benzyl-2-oxoethyl]-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid ((9H-fluoren-9-yl)methyl) ester as a colourless oil.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C@@H:14]4[C:19]([CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C:6]2=[O:23])=[CH:18][C:17](=[O:22])[CH2:16][CH2:15]4)[CH3:4].C(O)(=O)C>C(O)C>[CH2:3]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C@@H:14]4[C:19]([CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[OH:23])=[CH:18][C:17](=[O:22])[CH2:16][CH2:15]4)[CH3:4]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O

Procedure:
Add sodium borohydride (200 mg.) in ethanol (25 cc.) to 13β-ethyl-gon-4-en-3,17-dione (1 g.) in ethanol (50 cc.) at 8°. After 15 minutes add an excess of acetic acid and evaporate the solution to dryness under reduced pressure. Add water, collect the product in ether, and after this work up in the usual manner, recrystallize from a mixture of ether and pentane to obtain 13β-ethyl-17β-hydroxy-gon-4-en-3-one; ultraviolet absorption peak at 240 mμ (ε15,500); infrared absorption peaks at 2.94, 6.06, 6.23.
Reaction SMILES: ClCCCl.[Cl:5][C:6]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9].[N+:15]([O-])([O-:17])=[O:16].[K+].S(=O)(=O)(O)O>C(Cl)Cl>[Cl:5][C:6]1[CH:13]=[C:12]([F:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:7]=1[CH:8]=[O:9]
Reactant: O=[N+]([O-])[O-]
Reactant: O=Cc1ccc(F)cc1Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Solvent: ClCCCl
Product: O=Cc1cc([N+](=O)[O-])c(F)cc1Cl
Reaction time: 1.33 h
Yield: 64.8 %

Procedure:
To 300 ml of 1,2-dichloroethane that had been cooled to 0° C. was added 31.3 g (0.197 mole) of 2-chloro-4-fluorobenzaldehyde, prepared by the method of Example 2, Steps A and B. Subsequently, 19.96 g (0.197 mole) of potassium nitrate was added to the reaction mixture, and dropwise addition of 300 ml of concentrated sulfuric acid followed while maintaining the temperature between 0° C. and 5° C. The reaction was complete after 80 minutes, and 750 ml of methylene chloride was added to the reaction mixture. The phases were separated, and the sulfuric acid phase was extracted three times with 150 ml of methylene chloride. The extracts were combined with the organic phase before being washed three times with 450 ml of water. The extracts were dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure, leaving an amber oil weighing 32.5 g as a residue. This oil was passed through a column of silica gel, eluting with ethyl acetate/heptane (1/4). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure, leaving 26.0 g of 2-chloro-4-fluoro-5-nitrobenzaldehyde as an amber oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:10][C:11]1[CH:28]=[CH:27][C:26]2[C@@H:25]3[C@H:16]([C@H:17]4[C@@:21]([CH2:23][CH2:24]3)([CH3:22])[CH:20]=[CH:19][CH2:18]4)[CH2:15][C:14](=[O:29])[C:13]=2[CH:12]=1)(=O)C>C1COCC1>[CH3:22][C@:21]12[CH2:23][CH2:24][C@H:25]3[C@@H:16]([CH2:15][CH:14]([OH:29])[C:13]4[CH:12]=[C:11]([OH:10])[CH:28]=[CH:27][C:26]=43)[C@@H:17]1[CH2:18][CH:19]=[CH:20]2
Reactant: CC(=O)Oc1ccc2c(c1)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C=CC[C@@H]12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@]12C=CC[C@H]1[C@@H]1CC(O)c3cc(O)ccc3[C@H]1CC2
Yield: 10 %

Procedure:
To a suspension of lithium aluminum hydride (LAH, 95%, 46.9 mg, 1.17 mmol) in 5 mL of anhydrous THF was added estra-1,3,5(10),16-tetraen-6-one-3-yl acetate, 6 (422.9 mg, 1.360 mmol) in 5 mL of anhydrous THF dropwise, with stirring. See FIG. 13. The reaction was stirred 50 min., after which further LAH (46.5 mg, 1.16 mmol) was added and the reaction stirred 22 h. After refluxing 4 h TLC still showed starting material. The reaction was quenched with 0.5 mL of water+0.5 mL of 20% (w/w) sulfuric acid and concentrated under reduced pressure. The residue was extracted four times with 10 mL portions of hot ethyl acetate and filtered through Celite. The combined filtrates were concentrated and purified twice by flash chromatography to give solid product (0.05 g, 0.2 mmol, 10%), m.p. 150-157° C.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][C:11]([OH:16])=[C:12]([CH2:13][CH2:14][CH3:15])[C:7]=2[O:6][N:5]=1.[Br:19][CH2:20][CH2:21][CH2:22]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:18][C:2]([CH3:17])([CH3:1])[CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][C:11]([O:16][CH2:22][CH2:21][CH2:20][Br:19])=[C:12]([CH2:13][CH2:14][CH3:15])[C:7]=2[O:6][N:5]=1
Reactant: CCCc1c(O)ccc2c(CC(C)(C)C)noc12
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCBr)ccc2c(CC(C)(C)C)noc12
Reaction time: 8 h

Procedure:
A solution of 3-(2,2-dimethylpropyl)-6-hydroxy-7-propylbenz[4,5]isoxazole (2.000 grams; 8.090 mmol) in dry DMF (20 mL) was treated with 1,3-dibromopropane (4.29 mL; 42.263 mmol). Cesium carbonate (2.900 grams; 8.901 mmol) was added and the mixture stirred at 20° for 8 hours. The reaction mixture was partitioned between isopropyl acetate and pH 4 buffer. The organic was washed with water, then dried over magnesium sulfate. Filtration and evaporation afforded an oil which was chromatographed over silica gel, giving the title compound.