Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16]/[C:17](=[N:28]\[O:29][CH2:30][CH:31]=[CH2:32])/[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C([C@@H]1C2[C@](C)(CCC(=[O:53])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[CH2:30]([O:29]/[N:28]=[C:17]1\[CH2:16][C@@H:15]2[C@@H:25]([C@:23]3([CH3:24])[CH:18]\1[CH2:19][C:20](=[O:53])[CH2:21][CH2:22]3)[CH2:26][CH2:27][C@@:4]1([CH3:5])[C@H:6]2[CH2:7][CH2:8][C:3]1=[O:2])[CH:31]=[CH2:32]
Reactant: C=CCO/N=C1\C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C=CCO/N=C1\C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Yield: 70 %

Procedure:
The title compound II-aw was prepared in 70% yield from 3,3:17,17-bis(ethylendioxy)-6(E)-allyloxyiminoandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 5.99 (1H, m), 5.25 (1H, m), 5.14 (1H, m), 4.52 (2H, m), 4.42 (1H, dd), 2.68-1.15 (19H, m), 1.01 (3H, s), 0.88 (3H, s).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=1>>[C:12]([C:11]1[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[C:16]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:15]=1)(=[O:13])[NH2:14]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(C(N)=O)cc1
Product: COc1ccc(C(N)=O)cc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 92.8 %

Procedure:
To 1733 g of chlorosulfonic acid was added in small portions 150 g of 4-methoxybenzamide under ice-cooling with stirring during 15 minutes, and the mixture was stirred at room temperature for 14 hours. After being stirred at 50° C. for additional 1.5 hours, the reaction mixture was dropped into 7 kg of ice. The precipitate was collected by filtration, washed with water and hexane to give 230 g of 5-carbamoyl-2-methoxybenzenesulfonyl chloride.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[C:5]([O:13][CH3:14])=[CH:4][N:3]=1.[F-:15].[Cs+]>CS(C)=O.CCOC(C)=O>[F:15][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[C:5]([O:13][CH3:14])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)c2ccc(F)cc12
Reactant: [F-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cnc(F)c2ccc(F)cc12
Temperature: 140 °C
Yield: 67 %

Procedure:
To a solution of 1-chloro-6-fluoro-4-methoxyisoquinoline (115 mg, 0.543 mmol) in DMSO (5 mL), was added CsF (165 mg, 1.087 mmol) and the reaction was heated to 140° C. for 2 h. The reaction was diluted with EtOAc and washed with water, and brine. The organic phase was collected, dried over sodium sulfate, and concentrated under vacuum to give the crude product which was purified by silica gel chromatography using 20-40% DCM in hexanes. The product fractions were collected and the solvent was removed under vacuum to give 1,6-difluoro-4-methoxyisoquinoline (71 mg, 67% yield). MS m/z 196.1 (M++1).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].[OH-].[Na+].[I:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13]>O.O1CCCC1>[I:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](=[O:13])[NH:2][CH2:3][C:4]([NH2:6])=[O:5]
Reactant: O=C(Cl)c1ccccc1I
Reactant: NCC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)CNC(=O)c1ccccc1I
Reaction time: 0.03 h
Yield: 21.9 %

Procedure:
A solution of 5.0 g of glycinamide hydrochloride in 10 ml of water was cooled in an ice bath during the addition of 30 ml of 6 N sodium hydroxide. To the resulting mixture was added a solution of 8.0 g o-iodobenzoyl chloride in 20 ml of tetrahydrofuran and the mixture was shaken vigorously for 2 minutes. The mixture was then stirred for 21/2 hours. The tan solid which formed was filtered by suction and washed with water until the washings were neutral. The residue was then dried on a rotary evaporator for 5 hours at 60° and 80 mm Hg. There was thus obtained a crude product which was recrystallized from ethanol to yield 2.0 g of o-iodohippuramide as buff colored crystals, m.p. 183°-185°, Rf 0.64.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[CH:22][C:21]([C:24]2[N:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[N:25]=2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Ca+2].CN(C)C=O>C(OCC)(=O)C>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:16][C:18]4[CH:19]=[CH:20][C:21]([C:24]5[N:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[N:25]=5)=[CH:22][N:23]=4)[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: COc1cc(OC)nc(-c2ccc(Cl)nc2)n1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(OC)nc(-c2ccc(Oc3ccc4c(c3)CCN(C3CCC3)CC4)nc2)n1

Procedure:
3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (125 mg, 0.58 mmol), 2-(6-chloro-pyridin-3-yl)-4,6-dimethoxy-pyrimidine (145 mg, 0.58 mmol), calcium carbonate (720 mg, 2.2 mmol) and dimethylformamide (4 ml) were heated in a microwave reactor at 180° C. for 900 seconds at 300 W. The mixture was diluted with ethyl acetate, washed with water, then brine and dried over sodium sulphate. The residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.2:1.8:98) to afford the title product. MS (ES+) m/e 433 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([N+:19]([O-])=O)[CH:13]=1.[H][H]>C(O)C.O1CCCC1.[C].[Pd]>[CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([NH2:19])[CH:13]=1
Reactant: Cc1ccn2c(C)c(-c3ccc(O)c([N+](=O)[O-])c3)nc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccn2c(C)c(-c3ccc(O)c(N)c3)nc2c1
Yield: 53.8 %

Procedure:
A solution of 3,7-dimethyl-2-(4-hydroxy-3-nitrophenyl)imidazo[1,2-a]pyridine (2.6 g) in a mixture of ethanol (200 ml) and tetrahydrofuran (100 ml) was hydrogenated over 10% palladium-carbon (wet. 2.0 g) under an atomospheric pressure of hydrogen at ambient temperature for 3 hours. The catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and tetrahydrofuran to give 3,7-dimethyl-2-(3-amino-4-hydro-xyphenyl)imidazo[1,2-a]pyridine (1.25 g). mp. 251°-253° C.
Reaction SMILES: COC1C=CC(N2C[C@H](C[N:15]3[CH2:20][CH2:19][CH:18]([S:21][C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)OC2=O)=CC=1>CS(C)=O>[CH3:28][C:25]1[CH:24]=[CH:23][C:22]([S:21][CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)=[CH:27][CH:26]=1
Reactant: COc1ccc(N2C[C@H](CN3CCC(Sc4ccc(C)cc4)CC3)OC2=O)cc1
Solvent: CS(C)=O
Product: Cc1ccc(SC2CCNCC2)cc1

Procedure:
3-p-methoxyphenyl-5(S)-[(4-p-methylphenylthiopiperidino)methyl]-2-oxazolidinone (hydrochloride), m.p. 226°-229°; [α]D =-33.6° (DMSO);
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Cl:9][C:10]1[C:11]([F:36])=[C:12]([N:16]2[C:23](=[O:24])[C:22]3[CH:21]=[CH:20][N:19]([CH:25]([CH3:27])[CH3:26])[C:18]=3[CH:17]2[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[CH3:35])[CH:13]=[CH:14][CH:15]=1>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[Br:8][C:20]1[N:19]([CH:25]([CH3:27])[CH3:26])[C:18]2[CH:17]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[CH3:35])[N:16]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[C:11]=3[F:36])[C:23](=[O:24])[C:22]=2[CH:21]=1
Reactant: Cc1cc(Cl)ccc1C1c2c(ccn2C(C)C)C(=O)N1c1cccc(Cl)c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(Cl)ccc1C1c2c(cc(Br)n2C(C)C)C(=O)N1c1cccc(Cl)c1F
Reaction time: 1.5 h

Procedure:
NBS (1.926 mmol) was added to a mixture of 5-(3-chloro-2-fluoro-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Step A1) (1.965 mmol) in CCl4 (65 mL). After 1.5 h, the reaction mixture was diluted with EtOAc and successively washed with a saturated aqueous solution of NaHCO3, water and brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a white solid. tR: 5.69 min (HPLC 1); ESI-MS: tR=1.39 min, [M+H]+ 495/497/499 (LC-MS 1); TLC: Rf=0.12 (CH2Cl2).
Reaction SMILES: [Si:1]([O:18][C@@H:19]1[C@H:24]([CH3:25])[C@H:23]([OH:26])[CH2:22][C@H:21]([C:27]([O:29][CH3:30])=[O:28])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:1]([O:18][C@@H:19]1[C@@H:24]([CH3:25])[C@H:23]([O:26][S:37]([C:34]2[CH:35]=[CH:36][C:31]([CH3:41])=[CH:32][CH:33]=2)(=[O:39])=[O:38])[CH2:22][C@@H:21]([C:27]([O:29][CH3:30])=[O:28])[CH2:20]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@H]1C[C@@H](O)[C@@H](C)[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](C)[C@H](OS(=O)(=O)c2ccc(C)cc2)C1

Procedure:
To a mixture of 2.2.c (R=Me, P=TBDMS, A=COOCH3) (279 mg, 0.828 mmol), p-toluenesulfonyl chloride (323 mg, 1.69 mmol, 98%), DMAP (5.1 mg, 0.042 mmol) in 10 ml of dry CH2Cl2 at 0° C. (ice bath) was added Et3N (308 μL, 2.54 mmol). The mixture was refluxed for three days; then p-toluenesulfonyl chloride (320 mg, 1.69 mmol, 98%), DMAP (5.1 mg, 0.042 mmol) and Et3N (500 μL) were added. The resulting solution was refluxed for two days, p-toluenesulfonyl chloride (320 mg, 1.69 mmol, 98%), DMAP (5.1 mg, 0.042 mmol) and Et3N (500 μL) were added again and reflux was continued for another day. The resulting mixture was diluted with 20 ml of CH2Cl2, washed with brine and the aqueous phase was extracted with EtOAc (4×50 ml). The combined organic phases were dried over MgSO4. Filtration of the solvent, concentration and flash chromatography on silica (isooctane/EtOAc: 9:1), afforded 2.3.c (R=Me, P=TBDPS, L=OTos, A=COOCH3) (316 mg, 83.5%) as a light yellow oil.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[NH:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>N1C=CC=CC=1>[N:12]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCCNCC1
Reactant: O=C1CCc2cc(F)ccc21
Solvent: c1ccncc1
Product: O=C1CCc2cc(N3CCCCCC3)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Fluoroindan-1-one (5 g, 33.3 mmol) and azepane (9.92 g, 100 mmol) were dissolved in pyridine (20 ml) and heated at reflux for 3 hours, stirred at ambient temperature for 16 hours, and then heated at reflux for an additional 6 hours. The solvent was removed under vacuum and the residue partitioned between methylene chloride and water. The organic layer was washed with 1N aqueous sodium hydroxide, dried with magnesium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was filtered through a pad of silica gel with 1:1 ethyl acetate:hexanes, and the solvent evaporated under vacuum to provide the title compound which was used without further purification. 1H NMR (CDCl3) δ 1.56 (m, 4H), 1.81 (m, 4H), 2.62 (m, 2H), 3.02 (m, 2H), 3.55 (t, 4H), 6.59 (d, 1H), 6.68 (dd, 1H), 7.61 (d, 1H); MS (DCI) 230(M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([NH:26][OH:27])=[O:25])=[CH:20][CH:19]=3)=[O:16])[CH2:14][CH2:13][CH2:12]C[CH2:10]2)=[CH:5][CH:4]=1>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([NH:26][OH:27])=[O:25])=[CH:20][CH:19]=3)=[O:16])[CH2:10][CH2:12][CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(C(=O)Oc3ccc(C(=O)NO)cc3)CCCCC2)cc1
Solvent: C1COCCO1
Product: COc1ccc(C2(C(=O)Oc3ccc(C(=O)NO)cc3)CCCC2)cc1
Yield: 78 %

Procedure:
The title compound was obtained from 4-{(benzyloxy)[(benzyloxy)imino] methyl}phenyl 1-(4-methoxyphenyl)-cyclopentanecarboxylate (26) by a method analogous to that described for 4-[(Hydroxyamino)carbonyl]phenyl 1-(4-methoxyphenyl) -cyclohexanecarboxylate (PX118478), using dioxane as a solvent. After filtration of the catalyst and evaporation of the solvent the crude product was washed with diethyl ether to give the title compound in 78% yield as crystals, m.p. 143-144° C. 1H NMR (DMSO-d6, HMDSO) δ: 1.61-1.86 (4H, m); 1.86-2.08 (2H, m); 2.54-2.74 (2H, m); 3.75 (3H, s); 6.95 (2H, d, J=8.7 Hz); 7.01 (2H, d, J=8.5 Hz); 7.38 (2H, d, J=8.7 Hz); 7.75 (2H, d, J=8.5 Hz); 9.04 (1H, s); 11.22 (1H, s). HPLC analysis on Alltima C18 column: impurities 2% (column size 4.6×150 mm; mobile phase acetonitrile−0.1M phosphate buffer (pH 2.5), 50:50; detector UV 230 nm; sample concentration 1.0 mg/ml; flow rate 1.5 ml/min). Anal. Calcd for C20H21NO5*0.1 EtOAc, %: C, 67.28; H, 6.03; N, 3.85. Found, %: C, 67.00; H, 5.96; N, 3.78.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:15]([F:18])([F:17])[F:16])[CH2:13][OH:14])=[CH:8][CH:7]=1)[CH3:4].[Br:19][C:20]1[CH:34]=[CH:33][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH2:28]Br)=[CH:22][CH:21]=1>C1COCC1>[Br:19][C:20]1[CH:34]=[CH:33][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH2:28][O:14][CH2:13][CH:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:3][CH3:4])=[CH:11][CH:10]=2)[C:15]([F:16])([F:17])[F:18])=[CH:22][CH:21]=1
Reactant: CCOc1ccc(C(CO)C(F)(F)F)cc1
Reactant: BrCc1cccc(Oc2ccc(Br)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc(C(COCc2cccc(Oc3ccc(Br)cc3)c2)C(F)(F)F)cc1
Temperature: 25 °C
Yield: 30.8 %

Procedure:
Under a nitrogen atmosphere, 171 mg of sodium hydride (60% oil dispersion) was added to 20 ml of dry THF. A solution of 1.0 g of 2-(4-ethoxyphenyl)-3,3,3-trifluoropropanol and 1.30 g of 3-(4-bromophenoxy)benzyl bromide in 30 ml of dry THF was then added with ice-cooling, and the reaction solution was stirred with ice-cooling for 1 hour and at room temperature for 12 hours. Thereafter, the reaction mixture was poured into dilute HCl-ice water and extracted twice with diethyl ether. The ether layers were combined, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure, and the residue was subjected to column chromatography on silica gel [eluted with n-hexane/ethyl acetate (50:1) mixture] to obtain 0.58 g of the desired compound.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[OH:9][CH2:10][C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([C:20]#[N:21])=[CH:15][CH:14]=2>CCO>[OH:3][NH:2][C:20]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH2:10][OH:9])=[CH:19]2)=[NH:21]
Reactant: N#Cc1ccc2[nH]c(CO)cc2c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N=C(NO)c1ccc2[nH]c(CO)cc2c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 83.9 %

Procedure:
Hydroxylamine hydrochloride (243 mg) and sodium bicarbonate (586 mg) was added to a solution of 2-(hydroxymethyl)-1H-indole-5-carbonitrile (D24) (300 mg) in EtOH (20 mL), in that sequence. The reaction mixture was heated to 50° C. and stirred for 24 hours at that temperature. Another portion of hydroxylamine hydrochloride (100 mg) was added, followed by addition of sodium bicarbonate (220 mg). The resulting suspension was stirred at 50° C. for 7 hours. The inorganics was filtered off. The filtrate was concentrated to afford a pale yellow oil. Trituration of the residue provided N-hydroxy-2-(hydroxymethyl)-1H-indole-5-carboximidamide (D25) (300 mg) as a pale yellow solid. MS (ES): C10H11N3O2 requires 205; found 206.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>COCCOC>[CH2:15]([N:6]1[C:5](=[O:8])[CH:4]=[CH:3][C:2]([Cl:1])=[N:7]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=c1ccc(Cl)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: O=c1ccc(Cl)nn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6-chloro-2H-pyridazine-3-one (3.50 g) was dissolved in DME (130 mL). To this solution, cesium carbonate (17.5 g) was added and the mixture was stirred at room temperature for 15 min in an argon atmosphere. Subsequently, benzyl bromide (4.00 mL) was added and the mixture was stirred at room temperature for 3.5 hours. The insoluble inorganic residue was removed by filtration and the filtrate was concentrated. Water was then added to the residue and the mixture was extracted with ethyl acetate, washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated and the resulting crystals were recrystallized from ethyl acetate/petroleum ether to afford the title compound as a pale yellow powder (4.94 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH:9][C:10](=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:4][C:3]=1[CH:24]1[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]1.FC(F)(F)C(O)=O>ClCCl>[F:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:4][C:5]=1[NH:9][C:10](=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22]
Reactant: COc1ccccc1CCCCC(=O)Nc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)c(F)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1CCCCC(=O)Nc1cc(C2CCNCC2)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.3 %

Procedure:
Into a solution of tert-butyl 4(2,4-difluoro-5-{[5-(2-methoxyphenyl)pentanoyl]amino}phenyl)-1-piperidinecarboxylate (310 mg, 0.620 mmol) in dichloromethane (5.00 mL) at 0° C. was slowly added trifluoroacetic acid (707 mg, 6.20 mmol). The reaction mixture was stirred at room temperature for 10 min and concentrated in vacuo. The residue was dissolved in i-PrOH/CHCl3 (1:3, 10 mL) and basified to pH 11 with 10% KOH solution, washed with H2O, followed by brine. The organic layer was separated, dried over MgSO4 and concentrated in vacuo to afford the desired product (108 mg, 43.3%). 1H NMR (400 MHz, CDCl3) δ 7.59 (t, 1H, J=8.2 Hz), 7.10-6.96 (m, 2H), 6.90-6.68 (m, 3H), 3.67 (s, 3H), 3.09 (d, 2H, J=12.4 Hz), 2.89 (tt, 1H, J=11.8 Hz), 2.69 (dt, 2H, J=2.6, 12.4 Hz), 2.54 (t, 2H, J=7.2 Hz), 2.33 (t, 2H, J=7.2 Hz), 1.76-1.48 (m, 8H); ESMS m/e: 403.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]2[CH2:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[C:5]([N+:21]([O-:23])=[O:22])[CH:4]=[N:3]1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][N:2]1[C:6]([N:7]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[C:5]([N+:21]([O-:23])=[O:22])[CH:4]=[N:3]1
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1ncc([N+](=O)[O-])c1N1CCCNCC1
Yield: 64 %

Procedure:
A solution of tert-butyl 4-(2-methyl-4-nitro-pyrazol-3-yl)-1,4-diazepane-1-carboxylate (200 mg, 0.61 mmol) in DCM (4 mL) and TFA (4 mL) was stirred at room temperature for 1 h. The solvent was removed under reduced pressure, basified with saturated NaHCO3, and extracted with ethyl acetate (3×). The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure and the residue purified via silica gel column chromatography (0-10% methanol/DCM) to gave 1-(2-methyl-4-nitro-pyrazol-3-yl)-1,4-diazepane (88 mg, 64%). This was dissolved in acetonitrile (3 mL). tert-Butyl 3-iodoazetidine-1-carboxylate (221 mg, 0.78 mmol) and DIPEA (5 eq) were added and the mixture was heated at 75° C. for 7 days, with additional iodide and DIPEA added on days 2 and 3. The reaction mixture was cooled to room temperature, water (20 ml) was added and the mixture was extracted with DCM (50 mL). The organic layer was washed with water (20 mL), separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-10% methanol/DCM) to gave tert-butyl 3-[4-(2-methyl-4-nitro-pyrazol-3-yl)-1,4-diazepan-1-yl]azetidine-1-carboxylate (144 mg, 97%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]([CH3:11])=[CH:9][S:10][C:3]=12.[C:12]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[N:22]=[C:23]([NH:26][C:27]3[N:32]=[CH:31][C:30]([S:33]CCC(OC)=O)=[CH:29][C:28]=3[O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[S:24][CH:25]=2)[CH2:17][CH2:16]1)(=[O:14])[CH3:13].CC([O-])(C)C.[K+]>CS(C)=O>[CH3:11][C:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([S:33][C:30]3[CH:29]=[C:28]([O:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:27]([NH:26][C:23]4[S:24][CH:25]=[C:21]([CH:18]5[CH2:19][CH2:20][N:15]([C:12](=[O:14])[CH3:13])[CH2:16][CH2:17]5)[N:22]=4)=[N:32][CH:31]=3)=[C:3]2[S:10][CH:9]=1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C3CCN(C(C)=O)CC3)cs2)c(Oc2ccccc2)c1
Reactant: Cc1csc2c(Cl)ccnc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)N1CCC(c2csc(Nc3ncc(Sc4ccnc5c(C)csc45)cc3Oc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
7-chloro-3-methylthieno[3,2-b]pyridine (0.072 g, 0.39 mmol) and methyl 3-(6-(4-(1-acetylpiperidin-4-yl)thiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate (0.20 g, 0.39 mmol) were dissolved in DMSO (3 mL). The solution was degassed for 15 minutes under nitrogen. KOtBu (0.13 g, 1.2 mmol) was added and the reaction stirred at room temperature for two hours. The solution was quenched with water, extracted with dichloromethane, dried, and concentrated. Flash chromatography gave the title compound (0.100 g, 44% yield). 1H NMR (400 MHz, CDCl3) δ 1.60-1.72 (m, 2H), 2.03-2.09 (m, 2H), 2.11 (s, 3H), 2.51 (s, 3H), 2.66-2.73 (m, 1H), 2.83-2.90 (m, 1H), 3.15-3.22 (m, 1H), 3.88-3.94 (m, 1H), 4.70-4.73 (m, 1H), 6.51 (s, 1H), 6.75 (d, 1H), 7.05 (d, 2H), 7.17-7.25 (m, 2H), 7.36-7.40 (m, 3H), 8.30 (d, 1H), 8.48 (d, 1H), 8.84 (bs, 1H).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[CH:7].[C:10]([C:14]1([CH2:18]O)[CH2:17][O:16][CH2:15]1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]12[CH2:15][O:16][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[CH:7])([O:9][CH2:18]1)[O:8][CH2:17]2)([CH3:13])([CH3:12])[CH3:11]
Reactant: C#CCCCCC(=O)O
Reactant: CC(C)(C)C1(CO)COC1
Product: C#CCCCCC12OCC(C(C)(C)C)(CO1)CO2

Procedure:
Using the procedure described in stage (vi) of Example I and starting from hept-6-ynoic acid and 3-t-butyl-3-hydroxymethyloxetane (2-t-butyl-2-hyddroxymethylpropan-1,3-diol was prepared by the method of Y. Ozoe and M. Eto Agric.Biol. Chem, 1982, 46, 411), 4-t-butyl-1-(hex-5-ynyl)-2,6,7-trioxabicyclo[2.2.2]octane was prepared.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][C@H:10]([OH:12])[C@@H:9]([NH:13][C:14](=[O:29])[CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:12][C@H:10]1[CH2:11][N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:8][C@@H:9]1[NH:13][C:14](=[O:29])[CH2:15][NH:16][C:17](=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@H]1CN(C2CCCCC2)C[C@@H]1O
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@H]1CN(C2CCCCC2)C[C@@H]1OCc1ccccc1

Procedure:
The title compound was prepared by alkylation of compound of Example 1 with benzyl bromide following the procedure described in Example 2. MS calculated (M+H)+ 504. found 504.