Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH3:22])[O:5][C:6]1[C:7]([N+:19]([O-])=O)=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1.O>C(O)(=O)C.[Zn]>[CH3:1][O:2][CH2:3][CH:4]([CH3:22])[O:5][C:6]1[C:7]([NH2:19])=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1
Reactant: COCC(C)Oc1cc(Oc2ccccc2)cnc1[N+](=O)[O-]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: COCC(C)Oc1cc(Oc2ccccc2)cnc1N
Temperature: 100 °C
Yield: 64 %

Procedure:
3-(2-Methoxy-1-methyl-ethoxy)-2-nitro-5-phenoxy-pyridine (0.4 mmol) is dissolved in acetic acid (1.5 ml). After addition of water (1.5 ml), zinc powder (6 eq.) is added and the reaction suspension is heated to 100° C. for 90 minutes. The reaction suspension is cooled to room temperature and filtrated. The filtrate is pored into 3.5% NaOH (30 ml) and extracted with dichloromethane. The combined organic layers are extracted with brine, dried over MgSO4 and the solvent is removed in vacuo. 3-(2-Methoxy-1-methyl-ethoxy)-5-phenoxy-pyridine-2-ylamine is obtained as yellow powder in a yield of 64%. HPLC (method C): 1.51 min, LC-MS (method A): 0.923 min, 275.15 (MH+).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:8][CH2:7][CH2:6]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:45]I>ClCCl.CCOCC>[I:45][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:8][CH2:7][CH2:6]2
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCc2cc(CO)ccc21
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NC1CCCc2cc(CI)ccc21
Reaction time: 0.33 h

Procedure:
To a solution of (R)-tert-butyl 6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate (415.5 mg, 1.5 mmol) in dichloromethane/ether (1:1, 30 mL) at room temperature were added triphenylphosphine (590 mg, 2.25 mmol) and imidazole (153 mg, 2.25 mmol). To this stirred solution was then added iodine (571 mg, 2.25 mmol). After stirring for 20 min, the reaction was quenched with 10% Na2S2O3 (15 mL) until it became a clear two-phase solution. The aqueous phase was extracted with ether. The combined organic phase was dried over Na2SO4, filtered, and evaporated to dryness. Flash chromatography (SiO2, hexane/CH2Cl2=3:1 to pure CH2Cl2) afforded the title compound as a white solid. B. Preparation of (R)-tert-butyl 6-(2-(1,3-dithian-2-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[C@H:10]([CH2:12][CH:13]([CH3:15])[CH3:14])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]1[CH2:23][S:20](=[O:22])(=[O:21])[O:19][CH2:18]1>O1CCCC1.O1CCOCC1.CO>[CH2:1]([O:8][C:9]([C@@H:10]([NH:11][CH2:18][CH2:17][CH2:23][S:20]([OH:22])(=[O:21])=[O:19])[CH2:12][CH:13]([CH3:14])[CH3:15])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCCO1
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)C[C@H](NCCCS(=O)(=O)O)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 47.3 %

Procedure:
To a solution of L-Leucine benzylester (2.81 g, 12.7 mmol) in tetrahydrofuran (6 mL), 1,4-dioxane (6 mL) and MeOH (6 mL) was added 1,3-propane sultone (1.40 g, 11.5 mmol). The solution was stirred at reflux for 2.5 hours. The reaction mixture was cooled to room temperature. The solid was filtered and washed with acetone (2×20 mL). The filtrate was evaporated under reduced pressure. The residue was dissolved in acetone (20 mL). The product was precipitated with Et2O (200 mL). The solid material was filtered. Both solids were combined and dissolved in 50% EtOH/water (200 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 and lyophilized, affording the title compound (1.87 g, 47%). 1H NMR (DMSO, 500 MHz) δ ppm 9.34 (s (broad), 1H), 7.39 (m, 5H), 5.25 (s, 2H), 4.10 (m, 1H), 3.09 (m, 2H), 2.60 (m, 2H), 1.95 (m, 2H), 1.64 (m, 3H), 0.86 (m, 6H). 13C (DMSO, 125 MHz) δ ppm 168.90, 134.91, 128.53, 128.50, 128.41, 67.38, 57.37, 49.17, 45.79, 38.06, 24.07, 22.79, 21.78, 21.33. [α]D=+1.8° (c=0.0017 in water), ES-MS 344 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]([CH3:14])([C:11]([OH:13])=[O:12])[CH3:10])=[C:6]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:4][CH:3]=1.[CH3:18]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].IC>O>[CH3:18][O:12][C:11](=[O:13])[C:9]([CH3:10])([CH3:14])[NH:8][C:7]1[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=1[N+:15]([O-:17])=[O:16]
Reactant: CC(C)(Nc1c(Cl)cccc1[N+](=O)[O-])C(=O)O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COC(=O)C(C)(C)Nc1c(Cl)cccc1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
A mixture of N-(6-chloro-2-nitrophenyl)-2-methylalanine (X, EXAMPLE 14, 11.4 g), DMF (130 ml), potassium carbonate (18.2 g) and iodomethane (13.8 ml) is stirred at 20°-25° for 16 hr, diluted with water, extracted several times with ether. The ether phases are combined and are washed with water and saline, dried over magnesium sulfate and concentrated to give the title compound, IR (mineral oil) 3369, 2990, 2951, 1738, 1598, 1534, 1492, 1451, 1386, 1337, 1277, 1188, 1145, 1103 and 749 cm-1 ; NMR (CDCl3) 7.97, 7.55, 6.94, 6.89, 3.78 and 1.53 δ; MS (m/z) 272 and 213.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1)[CH3:3].C(O)C.C([O-])([O-])=O.[K+].[K+].[I-].C[N+]1(C)[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1>O>[N:6]1[CH:5]=[C:4]([CH:2]([N:1]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[CH3:3])[CH:9]=[N:8][CH:7]=1
Reactant: C[N+]1(C)CCC(=O)CC1
Reactant: CC(N)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(c1cncnc1)N1CCC(=O)CC1
Yield: 26.2 %

Procedure:
To a stirred mixture of 1.1 g of 5-(1-aminoethyl)pyrimidine (O. Cervinska and P. Malon, Coll. Czechoslov. Chem. Commun. 1977, 42, 3464-72.), 17 mL of ethanol and 1.36 g of K2CO3 heated to reflux was added dropwise over 30 min, a solution of 4 g of 1,1-dimethyl-4 -oxopiperidinium iodide in 70 mL of water. When the addition was complete, the mixture was heated under reflux for an additional 2 h, cooled, basified to pH 9 with K2CO3 and extracted with 5 times with 50 mL portions of methylene chloride. The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. Chromatography over silica gel, eluting with 90:10 CH3CN:MeOH gave 0.48 g of 1-(1-(5-pyrimidinyl)-ethyl)-4-oxopiperidine as an oil: 1H NMR (400 MHz, CDCl3) 9.14 (s, 1H), 8.78 (s, 2H), 3.8 (q, J=7 Hz, 1H), 2.7-2.9 (m, 4H), 2.45 (m, 4H), 1.5 (d, J=7 Hz, 3H).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:22])[C:4]1[CH:21]=[CH:20][C:7]2[CH2:8][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:11][O:12][C:6]=2[CH:5]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH:34]([CH3:36])[CH3:35])[C:27](O)=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CCOC(C)=O.O>[Cl:23][C:24]1[CH:25]=[C:26]([C:27]2[O:1][N:2]=[C:3]([C:4]3[CH:21]=[CH:20][C:7]4[CH2:8][N:9]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:10][CH2:11][O:12][C:6]=4[CH:5]=3)[N:22]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH:34]([CH3:35])[CH3:36]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(C(=N)NO)ccc2C1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)OCCN(C(=O)OC(C)(C)C)C4)no2)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.8 %

Procedure:
A mixture of 1,1-dimethylethyl 8-[(hydroxyamino)(imino)methyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 33) (0.195 g, 0.634 mmol), 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (Preparation 6) (0.136 g, 0.634 mmol), EDC (0.146 g, 0.761 mmol) and HOBT (0.107 g, 0.698 mmol) DMF (4 ml) was stirred at room temperature for 20 minutes then heated at 100° C. for 17 hours. The cooled reaction mixture was diluted with EtOAc/water (40 ml of each) and the organics collected, dried (magnesium sulphate), evaporated and purified by biotage chromatography in 1:4 EtOAc/iso-hexane to give the title compound (172 mgs) as a white solid. MS (ES) C25H2835ClN3O5 requires 485; found 486 [M+H]+; C25H2837ClN3O5 requires 487; found 488 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[N:22]([C:24](Br)=[C:25]([CH3:27])[N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:36](B1OB(C=C)OB(C=C)O1)=[CH2:37].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[N:22]([C:24]([CH:36]=[CH2:37])=[C:25]([CH3:27])[N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn2c1Br
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: C=Cc1c(C)nc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn12
Reaction time: 0.5 h

Procedure:
200 mg (0.375 mmol) {1-[4-(3-Bromo-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, intermediate example Int-2-3, 90.3 mg (0.375 mmol) 2,4,6-trivinyl-cyclotriboroxane, 43 mg (0.038 mmol) tetrakis triphenylphosphine palladium(0) and 51.8 mg (0.375 mmol) potassium carbonate in 2.9 mL dimethoxyethane and 1 mL water were heated in a microwave vial at 110° C. for 16 hours. The reaction mixture was poured on water/saturated ammonium chloride/dichloromethane and vigorously stirred for 30 minutes. The organic phase was separated and the aqueous phase extracted once more with dichloromethane. The combined organic extracts were washed twice with brine, dried, and the solvent was removed. The crude product (244 mg) was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:14])([C:10]([O:12][CH3:13])=[O:11])[C:3]([F:9])([F:8])[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:16][CH2:17][OH:18].CS(C)=O.[H-].[Na+]>CCOCC.O>[CH3:7][O:6][C:4]1([C:3]([F:9])([F:8])[C:2]([F:14])([F:1])[C:10]([O:12][CH3:13])=[O:11])[O:18][CH2:17][CH2:16][O:5]1
Reactant: COC(=O)C(F)(F)C(F)(F)C(=O)OC
Reactant: OCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C(F)(F)C(F)(F)C1(OC)OCCO1
Yield: 44.1 %

Procedure:
A mixture of 43.6 g (0.20 mol) of dimethyl tetrafluorosuccinate, 16.1 g (0.20 mol) of 2-chloroethanol, and 100 mL of DMSO was stirred and maintained at 25°-35° while 9.6 g (0.20 mol) of 50% NaH in mineral oil were added portionwise. The resulting mixture was stirred overnight, and then poured into 500 mL of cold water. Ether (300 mL) was added, and the resulting mixture was shaken. After mixture separated into layers, the ether layer was separated, washed with 100 mL of water, dried over CaSO4, filtered and distilled to give 23.1 g (44%) of 2-methoxy-2-(2-methoxycarbonyltetrafluoroethyl)-1,3-dioxolane, b.p. 72°-72.5° at 13 Pa (0.1 mm). IR (neat) and NMR (CCl4) spectra of the product were consistent with the assigned structure.
Reaction SMILES: [CH:1]1([CH2:9]O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].[BrH:16]>>[CH:1]1([CH2:9][Br:16])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CCCCCCC1
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: BrCC1CCCCCCC1
Temperature: 130 °C

Procedure:
Cyclooctylmethanol (8.16 g) was dissolved in 47% HBr-solution (70 ml) and refluxed for 1 hour at 130° C. The reaction mixture was poured onto icewater (500 ml) and saturated sodium hydrogencarbonate solution (500 ml) was added. The aqueous solution was extracted with dichloromethane. The combined organic phases were washed with water, brine and dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel in toluene as eluent. The fractions containing cyclo-octylmethyl bromide were pooled and evaporated. Yield: 9.85 g. TLC: Rf=0.95, silica gel, toluene
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.[I-].[Na+]>[Cl:23][C:21]1[CH:20]=[CH:19][C:18]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:17]([CH2:16][N:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)[CH:22]=1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: Clc1ccc(OCc2ccccc2)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnn(Cc2cc(Cl)ccc2OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of 4-nitropyrazole (Manchester organics; 0.503 g, 4.45 mmol) in DMF (10 ml) was added potassium carbonate (1.24 g, 9.0 mmol), sodium iodide (24 mg, 0.160 mmol) and then 2-(bromomethyl)-4-chloro-1-[(phenylmethyl)oxy]benzene (synthesised according to WO2006066968; 1.23 g, 3.95 mmol). The reaction was stirred at ambient temperature overnight. A further amount of 2-(bromomethyl)-4-chloro-1-[(phenylmethyl)oxy]benzene (156 mg) was added and the reaction was stirred at ambient temperature for a further 30 min. The reaction mixture was concentrated in vacuo and treated with water (60 ml). The aqueous solution was extracted with ethyl acetate (3×60 ml). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The sample was loaded in dichloromethane and purified on silica (50 g) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound (1.17 g) as a white solid; LCMS (System 1): MH+=344, tRET=3.58 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][C@H:13]1[C:26]([OH:28])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2[CH:40]=[CH:41][CH:42]=[N:43][C:38]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCC1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:14][C@H:13]1[C:26]([N:43]1[CH2:42][CH2:41][CH2:40][CH2:38]1)=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](C(=O)O)C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](C(=O)N2CCCC2)C1
Yield: 71.1 %

Procedure:
To a solution of (1R,2S,5R)-2-benzyloxycarbonylamino-5-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (240 mg, 0.6 mmol) in DMF (15 mL) at rt was added HATU (278 mg, 0.73 mmol), pyrrolidine (0.06 mL, 0.73 mmol), and iPr2NEt (0.13 mL, 0.73 mmol). The mixture was stirred at rt for 16 h before water and EtOAc were added. The organic layer was separated and re-washed twice before it was collected, dried over Na2SO4, and concentrated to provide (1S,2R,4R)-[4-tert-butoxycarbonylamino-2-(pyrrolidine-1-carbonyl)-cyclohexyl]-carbamic acid benzyl ester as a glassy solid (190 mg, 69%). MS found: (M+H)+=446.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[O:14][CH3:15])[C:2]#[CH:3].S(Cl)([Cl:18])=O>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:18])=[O:10])=[CH:7][C:6]=1[O:14][CH3:15])[C:2]#[CH:3]
Reactant: C#CCOc1ccc(C(=O)O)cc1OC
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C#CCOc1ccc(C(=O)Cl)cc1OC
Yield: 84.1 %

Procedure:
To 100 ml of toluene were added 12.0 g of 4-(2-propynyloxy)-3-methoxybenzoic acid, 9.0 g of thionyl chloride and 50 mg of DMF, and the mixture obtained was heated under reflux for 3 hours. Then, the reaction mixture was concentrated. The solid obtained was washed with hexane to obtain 11.0 g of 4-(2-propynyloxy)-3-methoxybenzoyl chloride represented by the formula.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:8]([N+:19]([O-])=O)=[C:9]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:10]([O:12][CH3:13])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[NH2:19][C:8]1[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[C:16]([O:17][CH3:18])[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1ccc(OC)c(OC2CCCC2)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(OC)c(OC2CCCC2)c1N
Temperature: 23 °C
Reaction time: 21 h

Procedure:
A mixture of methyl 3-(cyclopentyloxy)-4-methoxy-2-nitrobenzoate (750 mg, 2.54 mmol), 10% Pd/C (50% H2O, 500 mg, 0.23 mmol Pd), and methanol (10 mL) was stirred vigorously at 23° C. under an atmosphere of H2. After 21 h, the mixture was filtered through Celite and concentrated to give methyl 2-amino-3-(cyclopentyloxy)-4-methoxybenzoate: MS (ESI): 266.5.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][C@@H:5]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH:25]([F:27])[F:26])[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][C:11]=2[CH3:33])=[O:9])[C@H:4]([F:34])[CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:30]1([CH2:29][O:28][C:20]2[CH:21]=[CH:22][C:23]([CH:25]([F:27])[F:26])=[CH:24][C:19]=2[C:18]2[C:13]3[NH:12][C:11]([CH3:33])=[C:10]([C:8]([NH:7][C@@H:5]4[CH2:6][C@@H:2]([NH:1][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:3][C@H:4]4[F:34])=[O:9])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:31][CH2:32]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1C[C@@H](N)C[C@H]1F
Product: COCC(=O)N[C@H]1C[C@@H](F)[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C1

Procedure:
Starting from N-[(1R*,2R*,4R*)-4-amino-2-fluorocyclopentyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f71) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[F:14][CH:15]([F:26])[O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH2:25])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[BH4-].[Na+].Cl>CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:25][CH2:24][CH2:23][C:20]2[CH:19]=[CH:18][C:17]([O:16][CH:15]([F:14])[F:26])=[CH:22][CH:21]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1ccc(OC(F)F)cc1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2ccc(OC(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
1.12 ml of 4-tert-butylbenzaldehyde (6.71 mmol), 1 g of 2-(4-difluoromethoxy-phenyl)-ethylamine hydrochloride (4.47 mmol) and 618 mg of potassium carbonate (4.47 mmol) were suspended in 13 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2 h. After cooling down to rt, 254 mg (6.71 mmol) sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was then refluxed for 2.5 h. After cooling down to rt, the reaction mixture was treated with 1.2 ml 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:4) to give 1.19 g light yellow oil (80%). MS (ISP) 334.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[C:5]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: c1ccc(-c2ccccc2)cc1
Temperature: 100 °C
Yield: 170.2 %

Procedure:
To a solution of 4.75 g (12.7 mmol) of N-(2R-(t-Butoxycarbonyl)methyl-4-pentenoyl)-4S-phenylmethyl-2-oxazolidinone, 3.73 g (16.0 mmol) of 4-bromobiphenyl, 0.234 g (0.77 mmol) of tri-o-tolylphosphine, and 2.22 mL (1.62 g, 16.0 mmol) of triethylamine in 10 mL of anhydrous DMF under argon was added 0.086 g (0.385 mmol) of palladium(II) acetate. The solution was heated at 100° C. for 4 h, cooled to room temperature, diluted with ethyl acetate. The precipitate was removed by filtration, and the filtrate was partitioned between 150 mL of 2:1 ethyl acetate:hexane and 50 mL of pH 7 phosphate buffer (0.5 M) containing a little sodium sulfite. The organic layer was washed with 0.2 N aq. sodium bisulfate and brine/pH 7 phosphate buffer, dried over sodium sulfate, and concentrated. The residue was dissolved in 50 mL of ethyl acetate, diluted with 250 mL of isooctane, and seeded with a few crystals of the product. The solid was removed by filtration, and recrystallized from 250 mL of 4:1 isooctane:ethyl acetate to give 4.20 g (63%) of the product, N-(2R-(t-Butoxycarbonyl)methyl-(5-(biphen-4-yl)-4-pentenoyl)-4S-phenylmethyl-2-oxazolidinone, as fine white needles: mp 118-119° C.; 1H NMR (300 MHz, CDCl3) 7.25-7.60 (m, 14H), 6.47 (d, 1H, J=16 Hz), 6.25 (dt, 1H, J=16 and 8 Hz), 4.65-4.70 (m, 1H), 4.34-4.44 (m, 1H), 4.11 (dd, 1H, J=9 and 2 Hz), 4.01 (t, 1H, J=8 Hz), 3.33 (dd, 1H, J=14 and 3 Hz), 2.89 (dd, 1H, J=17 and 11 Hz), 2.76 (dd, 1H, J=14 and 10 Hz), 2.40-2.57 (m, 3H), 1.43 (s, 9H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]1([O:10][C@H:11]2[CH2:16][CH2:15][C@H:14]3[C@H:17]4[C@H:27]([CH2:28][CH2:29][C@:12]23[CH3:13])[C@:25]2([CH3:26])[C:20](=[CH:21][C:22](=[O:30])[CH2:23][CH2:24]2)[CH2:19][CH2:18]4)[CH2:9][CH2:8]1.C([O:34][N+:35]([O-])=[O:36])(C)C.C(O)(=O)C>C(O)(C)(C)C.[Cl-].[Na+].O.C(Cl)Cl>[CH:7]1([O:10][C@H:11]2[CH2:16][CH2:15][C@H:14]3[C@H:17]4[C@H:27]([CH2:28][CH2:29][C@:12]23[CH3:13])[C@:25]2([CH3:26])[C:20](=[C:21]([N+:35]([O-:36])=[O:34])[C:22](=[O:30])[CH2:23][CH2:24]2)[CH2:19][CH2:18]4)[CH2:8][CH2:9]1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1
Reactant: CC(C)O[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=C([N+](=O)[O-])C(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.6 %

Procedure:
Potassium tert-butoxide (109 g, 0.97 mol, 2.1 molar equivalents) is added to a stirred solution of 17β-(cyclopropyloxy)-androst-4-en-3-one (150 g, 0.46 mol) in tert-butanol (2 L) over 10 minutes at room temperature and under nitrogen. Continue stirring at room temperature for 18 hours, then add isopropylnitrate (48.2 g, 0.46 mol, 1.0 mol. equiv.) in tert-butanol (50 mL) over 30 minutes at room temperature. After an additional day of continuous stirring at room temperature, glacial acetic acid (130 mL) is added over 25 minutes and stirring is continued for an additional 18 hours. Subsequently, methylene chloride (1.5 L) and brine (saturated NaCl, 800 mL) is added and the solution is stirred an additional 10 minutes. The organic phase is then seperated and dried over magnesium sulfate. The resulting slurry is filered and the filtrate concentrated (35° C./40 Torr) to give a dark red oil. Purify by flash chromatography (SiO2, elution: EtOAc/hexane 5:95, EtOAc/hexane 1:9 and EtOAc/hexane 15:85). Combine and concentrate the fractions containing the desired product (30° C./40 Torr) to give a solid residue which is stirred under hexane (350 mL). Filter and dry the solids to give the title compound (68 g, 40%) as a yellow solid. Additional compound is obtained from the filtrate after concentration and rechromatography as above (8 g, 5%). mp 133°-134° C.