Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.N1C=CC=CC=1>O>[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([O:6][C:5]2[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=2[O:8][CH3:9])[CH:2]=[O:1])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: COc1ccc(C=O)cc1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C=O)cc1OS(=O)(=O)c1ccc(C)cc1
Temperature: 75 °C
Reaction time: 0.08 h
Yield: 98 %

Procedure:
A mixture of 3-hydroxy-4-methoxybenzaldehyde 12 (5.0 g, 32 mmol) and p-toluenesulfonyl chloride (10.0 g, 52.5 mmol) was dissolved in pyridine (12.5 mL, 154 mmol). The reaction mixture stirred for 5 min and maintained at 70-80° C. The clear reaction mixture becomes turbid and becomes slurry. The stirring was continued for a period of 2 h at 70-80° C. The reaction completion was determined by TLC and the contents of the flask were cooled to room temperature and poured in to cold water. The white crystalline solid formed was filtered, washed successively with 5 mL 1:1 HCl:H2O, 5 mL of 5% NaOH solution and water till the filtrate is free from pyridine, dried to constant weight to get the desired product 21. Yield: 98%; white solid mp 148-151° C. 1H NMR: δ 2.40 (s, 3H, CH3), 3.71 (S, 3H, OCH3), 6.91-7.83 (m, 7H, Ar—H), 9.83 (s, 1H, CHO). Anal. Calcd for C15H14O5S: C, 58.81, H, 4.61. Found: C, 58.79, H, 4.59.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:18][CH:17]([CH:19]([OH:23])[CH:20]([CH3:22])[CH3:21])[CH2:16]1)=O)(C)(C)C>ClCCl>[NH:15]1[CH2:18][CH:17]([CH:19]([OH:23])[CH:20]([CH3:22])[CH3:21])[CH2:16]1
Reactant: CC(C)C(O)C1CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(O)C1CNC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 88.8 %

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of 3-(1-hydroxy-2-methylpropyl)azetidine-1-carboxylic acid tert-butyl ester (0.84 g, 3.66 mmol) in dichloromethane (12 mL). The resulting reaction mixture was stirred at RT for 40 min. The solvents were reduced in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge (5 g). The cartridge was washed with DCM/MeOH, the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM. The solvents were reduced in vacuo to afford 1-Azetidin-3-yl-2-methylpropan-1-ol as a white solid (0.42 g, 88%). 1H NMR (400 MHz, CDCl3): δ 3.63-3.62 (3H, m), 3.53-3.51 (2H, m), 2.88-2.87 (1H, m), 1.62-1.62 (1H, m), 0.89 (6H, dd, J=6.84, 4.72 Hz)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].C([O-])([O-])=O.[K+].[K+].[Br:18][CH2:19][CH2:20][CH2:21]Br>C(#N)C>[Br:18][CH2:19][CH2:20][CH2:21][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: BrCCCBr
Reactant: COc1cc(C#N)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C#N)ccc1OCCCBr
Reaction time: 8 h

Procedure:
A mixture of 4-hydroxy-3-methoxybenzonitrile (7.5 g, 50 mmol), K2CO3 (12.5 g), and 1,3-dibromopropane (15 g, 75 mmol) in acetonitrile (100 ml) was heated at reflux for 3 hours and left standing at room temperature overnight. The solvent of the reaction was removed on a rotary evaporator, and the crude solid was extracted into methylene chloride (500 ml). The insolubles were filtered off. The dichloromethane solution was concentrated and the material was purified on a flash chromatography column (SiO2, 105 g; eluted with 2:3 dichloromethane:hexane, and then with dichloromethane). The desired product thus purified weighed 7.74 g (52%). Recrystallization twice from ethanol gave analytically pure 4-(3-bromopropoxy)-3-methoxybenzonitrile, m.p.=99°-101° C.
Reaction SMILES: O.[O:2]=[C:3]1[CH2:8][CH2:7][CH2:6][C:5](=O)[CH:4]1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].S(Cl)([Cl:18])=O>C(Cl)Cl>[Cl:18][C:5]1[CH2:6][CH2:7][CH2:8][C:3](=[O:2])[C:4]=1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC1C(=O)CCCC1=O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CC1=C(Cl)CCCC1=O

Procedure:
A slurry of ethyl α-(2,6-dioxocyclohexyl)acetate hydrate (1.53 kg) in methylene chloride (7.7L) is brought to reflux and then thionyl chloride (1.80 kg) is added dropwise over a period of 1.75 hours. The solution is refluxed for 3 hours and then evaporated in vacuo to yield an oil which is distilled to give ethyl α-(2-chloro-6-oxocyclohex-1-enyl)acetate as a yellow oil, bp 115°-125°/0.2 mm.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](OS(C)(=O)=O)([CH3:18])[CH2:15]1)([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.[NH3:24]>C(Cl)Cl.CO>[CH:1]([N:14]1[CH2:17][C:16]([NH2:24])([CH3:18])[CH2:15]1)([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: N
Reactant: CC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CO
Solvent: ClCCl
Product: CC1(N)CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 3 h
Yield: 58 %

Procedure:
To a solution of methanesulfonic acid 1-benzhydryl-3-methyl-azetidin-3-yl ester (12 g, 36.3 mmol) in DCM (100 mL) was added a saturated solution of ammonia in MeOH (200 mL) and the mixture was stirred for 3 h. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (eluting with 0-100% EtOAc in petroleum ether) to give 1-benzhydryl-3-methyl-azetidin-3-ylamine (5.31 g, 58%), which was used directly in step F. Alternatively, 1-benzhydryl-3-methyl-azetidin-3-ylamine can be prepared via steps D and E. TLC (eluting with 20% EtOAc/heptane) Rf=0.2.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[Cl-].[CH3:38][C:39]1[S:40][CH:41]=[C:42]([CH2:44][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:43]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:44]\[C:42]4[N:43]=[C:39]([CH3:38])[S:40][CH:41]=4)=[CH:22][N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: Cc1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C\c2csc(C)n2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 34.5 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.80 g), [(2-methyl-1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (0.98 g), potassium carbonate (0.33 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (2:3, v/v) to give 2-(2-furyl)-4-({2-methoxy-4-[({4-[(Z)-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazole as colorless crystals (0.33 g, yield 35%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 164-165° C.
Reaction SMILES: Cl.C(OC1C=C(C=CC=1C)N[C:10]1[C:19]2[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=O)C.Cl[CH2:28][C:29]1[C:30]([CH3:35])=[N:31][O:32][C:33]=1[CH3:34]>[I-].[K+]>[CH3:35][C:30]1[C:29]([CH2:28][O:22][C:16]2[CH:15]=[C:14]3[C:19]([CH:10]=[N:11][CH:12]=[N:13]3)=[CH:18][C:17]=2[O:20][CH3:21])=[C:33]([CH3:34])[O:32][N:31]=1
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1O
Reactant: Cc1noc(C)c1CCl
Agent: Cl
Agent: [I-]
Agent: [K+]
Product: COc1cc2cncnc2cc1OCc1c(C)noc1C
Yield: 112.6 %

Procedure:
Using an analogouls procedure to that described for the starting material in Example 1, 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (400 mg) was reacted in the presence of potassium iodide (16 mg) with 4-chloromethyl-3,5-dimethylisoxazole (177 mg) to give 4-(3-acetoxy)-4-methylanilino)-7-(3,5-dimethylisoxazol-4-ylmethoxy)-6-methoxyquinazoline (342 mg, 72%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:25]([N:27]2C=N[CH:29]=[CH:28]2)=[O:26])C=1.[N:32]1[CH:37]=[CH:36][C:35]([O:38][C:39]2[CH:44]=CC(N)=[CH:41][CH:40]=2)=[CH:34][CH:33]=1>ClCCCl>[C:1]([C:5]1[CH:6]=[C:7]([NH:19][C:25]([NH:27][C:28]2[CH:29]=[CH:44][C:39]([O:38][C:35]3[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=3)=[CH:40][CH:41]=2)=[O:26])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: Nc1ccc(Oc2ccncc2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a solution of 5-tert-butyl-2-(4-nitrophenyl)-2H-pyrazol-3-ylamine (5.0 g, 19.2 mmol) in anhydrous DCE (2 mL) was added CDI (3.5 g, 21.1 mmol), and the reaction was stirred under N2 at room temperature for 18 h. 4-(Pyridin-4-yloxy)phenylamine (3.3 g, 17.7 mmol, Dumas et al., U.S. pat. appl. US2002065296 (2002)) in DCE (12 mL) was added to the reaction, and the solution was stirred under N2 at room temperature for 7 h. The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated at reduced pressure. The crude residue was purified by MPLC (1:1 hexanes/EtOAc) to give 5.6 g (68%) of the desired product. 1H-NMR (DMSO-d6) δ 9.21 (s, 1H), 8.68 (s, 1H), 8.43 (d, J=6.3 Hz, 2H), 8.36 (d, J=7.2 Hz, 2H), 7.90 (d, J=6.9 Hz, 2H), 7.50 (d, J=6.9 Hz, 2H), 7.09 (d, J=6.6 Hz, 2H), 6.86 (d, J=5.7 Hz, 2H), 6.44 (s, 1H), 1.29 (s, 9H); MS LC-MS [M+H]+=473, RT=2.60 min.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]=1.C=O.Cl.[CH2:15]([NH2:18])[CH2:16][CH3:17].[C:19](O)(=O)[CH3:20]>>[CH2:15]([N:18]1[CH2:5][CH2:6][C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:20][C:19]=3[CH2:4][CH2:3][C:2]=2[CH2:1]1)[CH2:16][CH3:17]
Reactant: CC(=O)O
Reactant: CCCN
Reactant: CC1=CCCc2ccccc21
Agent: C=O
Agent: Cl
Product: CCCN1CCC2=C(CCc3ccccc32)C1

Procedure:
Following the procedure of Example 1, step 3, 1.04 g (7.19 mmol) of 1-methyl-3,4-dihydronaphthalene in 7 ml of acetic acid was reacted with 2.33 ml of 37% formaldehyde solution and 1.58 g of propylamine hydrochloride. Work up gave 1.98 g of crude 1,2,3,4,5,6-hexahydro-3-propyl-benz[f]isoquinoline. Following the procedure of Example 2, this was reacted with 0.435 g of lithium wire in 250 ml of liquid ammonia, 40 ml of anhydrous THF and 1 ml of aniline. Chromatography on flash silica, eluting with 5-10% methanol/dichloromethane, then on alumina, eluting with 2-5% ethyl acetate/petroleum ether, gave 0.497 g (30%) of the title product as a colourless oil. The hydrochloride salt was made using ethereal hydrogen chloride. Upon evaporation of the solvent, the title product hydrochloride was obtained as a white solid, m.p. 257°-259° C. (dec). NMR δ(D2O) 1.00 (3H, t, J=7.4 Hz), 1.57 (1H, m), 1.68-1.92 (5H, m), 2.66-2.76 (2H, m), 2.87-2.95 (3H, m), 3.12-3.16 (3H, m), 3.63 (1H, m), 3.77 (1H, m), 7.22-7.31 (3H, m), 7.35-7.38 (1H, m). m/z (CI+, NH3) 230 (M+H)+, 200 (M-CH2CH3)+. Analysis calcd. for C16H24ClN: C, 72.29; H, 9.10; N, 5.27%. Found: C, 72.07; H, 9.01; N, 5.19%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:11]([O:13][C@H:14]1[CH2:51][N:17]3[C:18](=[O:50])[C@@H:19]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][C@@H:27]4[CH2:32][C@@:28]4([C:33](=[O:41])[NH:34][S:35]([CH:38]4[CH2:40][CH2:39]4)(=[O:37])=[O:36])[NH:29][C:30](=[O:31])[C@@H:16]3[CH2:15]1)=[O:12])[CH2:6]2.[H][H].O.S([O-])(O)(=O)=O.[K+]>C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:11]([O:13][C@H:14]1[CH2:51][N:17]3[C:18](=[O:50])[C@@H:19]([NH:42][C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C@@H:27]4[CH2:32][C@@:28]4([C:33](=[O:41])[NH:34][S:35]([CH:38]4[CH2:40][CH2:39]4)(=[O:36])=[O:37])[NH:29][C:30](=[O:31])[C@@H:16]3[CH2:15]1)=[O:12])[CH2:6]2
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCCCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Agent: CC(C)(C)OC(=O)N[C@H]1COCCC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1COCCCCC[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Reaction time: 16 h
Yield: 53.6 %

Procedure:
(2R,6S,13aS,14aR,16aS,Z)-6-(tert-butoxycarbonylamino)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2,3,5,6,7,9,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(i)pyrrolo[1,2-e][1,5,8]oxadiazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate (0.028 g, 0.038 mmol) and Rh/Al (5%) (0.0079 g, 0.0038 mmol) in Ethyl acetate (5 mL) was charged with 1 atmosphere of hydrogen and stirred for 16 hrs. Water (3 mL) and saturated potassium hydrogen sulfate (3 mL) was added and stirred for 10 minutes. The organic phase was separated and aqueous phase extracted with ethyl acetate (10 mL), washed with brine and dried over sodium sulfate. After removal of solvent, the residue was purified by chromatography (Hexane:Ethyl acetate=1:4) to give (2R,6S,13aR,14aR,16aS)-6-(tert-butoxycarbonylamino)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxohexadecahydro-1H-cyclopropa(i)pyrrolo[1,2-e][1,5,8]oxadiazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate as white solid (0.015 g, 53%). MS: Calcd.: 735; Found: [M+H]+ 736. 1H NMR (400 MHz, CD2Cl2) δ9.65 (s, 1H), 7.22-7.28 (m, 2H), 6.96-7.08 (m, 2H), 5.55 (m, 1H), 5.39 (m, 1H), 4.74 & 4.69 (s, 4H), 4.54 (m, 1H), 3.97 (m, 1H), 3.84 (m, 1H), 3.77 (m, 1H), 3.67 (m, 1H), 3.55 (m, 1H), 3.47 (m, 1H), 2.92 (m, 1H), 2.65 (m, 1H), 2.35 (m, 1H), 1.06-1.68 (m, 25H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:9])[CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Fc1cccc(C2CO2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=Cc1ccc(OCC(O)c2cccc(F)c2)cc1
Temperature: 78 °C
Yield: 16.9 %

Procedure:
To a stirring solution of 2-(3-fluorophenyl)oxirane (5.60 g, 40.5 mmol) in toluene (65 ml) was added 4-hydroxybenzaldehyde (7.40 g, 61.0 mmol), 1M NaOH (65 ml) and PEG4000 (polyethylene glycol, 0.85 g) and the stirring mixture was heated at 78° C. overnight. The reaction mixture was allowed to cool to RT and then extracted with EtOAc (2×150 ml). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting light brown oil was chromatographed eluting with 30-40% EtOAc/hexanes. There are 2 major spots. Fractions containing the higher Rf spot were combined and evaporated in vacuo to give 1.78 g (17%) of the title compound as a white solid. Fractions containing the lower Rf spot were combined and evaporated in vacuo to give 0.90 g (9%) of the regioisomer as a nearly colorless oil.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[N:16]=[N:17][C:18](Cl)=[CH:19][CH:20]=1.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[Cl:14][C:15]1[N:16]=[N:17][C:18]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ccc(Cl)nn1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)nn2)CC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
In a microwave vial were mixed: 1,1-dimethylethyl 1-piperazinecarboxylate (135 mg, 0.725 mmol, available from Fluke), 3,6-dichloropyridazine (90 mg, 0.604 mmol, available from Alfa Aesar) and DIPEA (0.137 mL, 0.785 mmol) in Tert-Butanol (2 mL). The reaction was stirred and heated in an Emrys Optimizer microwave at 100° C. for 20 mins then for 30 mins at 150° C. The reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL) and the organic layer washed with brine (20 mL) before being dried through an hydrophobic frit and concentrated. The residue was dissolved in DCM and purified by SP4 on a 12+M silica cartridge using a gradient of 10-50% EtOAc in cyclohexane. The appropriate fractions were collected and concentrated to yield the desired product as a white solid, 1,1-dimethylethyl 4-(6-chloro-3-pyridazinyl)-1-piperazinecarboxylate (114.2 mg). LCMS (Method C): Rt=0.85, MH+=299
Reaction SMILES: Cl.[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][CH3:15])[CH2:10][CH2:9]1.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[S:24](Cl)(=[O:26])=[O:25]>>[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([N:14]([CH3:15])[S:24]([C:18]2[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=2[F:16])(=[O:26])=[O:25])[CH2:12][CH2:13]1
Reactant: CN[C@H]1CC[C@H](OCCCCBr)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Agent: Cl
Product: CN([C@H]1CC[C@H](OCCCCBr)CC1)S(=O)(=O)c1ccc(F)cc1F

Procedure:
In analogy to example 11.9, trans-[4-(4-Bromo-butoxy)-cyclohexyl]-methyl-amine hydrochloride and 2,4-difluoro-benzenesulfonyl chloride (with 2.1 eq N,N-diisopropylethylamine) were reacted to yield trans-N-[4-(4-Bromo-butoxy)-cyclohexyl]-2,4-difluoro-N-methyl-benzenesulfonamide which was used directly in the next steps see Example 12.57-12.58 and 12.65 and 12.66.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][Cl:14])=[C:6]([O:15][CH3:16])[CH:5]=1.C(OC(=O)C)(=O)C.[N+:25]([O-])([OH:27])=[O:26]>C(O)(=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:5]=[C:6]([O:15][CH3:16])[C:7]([O:10][CH2:11][CH2:12][CH2:13][Cl:14])=[CH:8][C:9]=1[N+:25]([O-:27])=[O:26]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(OCCCCl)c(OC)c1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC)c(OCCCCl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.21 h
Yield: 94 %

Procedure:
The intermediate from Step 1 (26.4 g, 102 mmol) was taken in acetic acid (185 mL) and acetic anhydride (15 mL) was added. The solution was cooled to 0° C. and 90% nitric acid (15 mL) was added. The reaction mixture was stirred for 10-15 minutes at ambient temperature, then heated to 50° C. for 3 hours. Completion of the reaction was monitored by LCMS. The reaction mixture was cooled and was diluted with ethyl acetate. The ethyl acetate layer was washed with aq. sodium bicarbonate, and concentrated to afford the pure compound 4-(3-chloro-propoxy)-5-methoxy-2-nitro-benzoic acid methyl ester (29.14 g, 94%) yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 7.68 (s, 1H), 7.33 (s, 1H), 4.24 (t, 2H), 3.92 (s, 3H), 3.82 (s, 3H), 3.77 (t, 2H), 2.21 (q, 2H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][N:10]1[C:14]([C:15]2[CH:16]=[C:17]([NH:29]C(=O)C)[CH:18]=[CH:19][C:20]=2[O:21][CH2:22][C:23]([CH3:28])([N+:25]([O-:27])=[O:26])[CH3:24])=[CH:13][CH:12]=[N:11]1.[OH-].[Na+].O>CO>[Br:1][C:13]1[CH:12]=[N:11][N:10]([CH3:9])[C:14]=1[C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]([CH3:28])([N+:25]([O-:27])=[O:26])[CH3:24])[NH2:29]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Nc1ccc(OCC(C)(C)[N+](=O)[O-])c(-c2ccnn2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1ncc(Br)c1-c1cc(N)ccc1OCC(C)(C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61 %

Procedure:
N-Bromosuccinimide (0.931 g, 5.23 mmol) was added to a suspension of N-(3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)phenyl)acetamide (1.58 g, 4.75 mmol) in 10 mL of methanol, and the mixture was stirred at room temperature. A clear solution was obtained within minutes. After 20 min, a solution of sodium hydroxide (1.14 g, 28.5 mmol) in water (1.00 mL, 55.5 mmol) was added, and the solution was heated to 160° C. for 0.5 hr under microwave irradiation in a heavy walled sealed tube. The solvent was evaporated under reduced pressure, and the residue was taken up in saturated sodium bicarbonate and extracted twice with dichloromethane. The extracts were combined, dried with sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by flash chromatography (ethyl acetate-hexanes 1:2, then 1:1) to afford the title compound as an off-white solid (1.07 g, 61%). LCMS m/z (%)=371.0 (M+H 81Br 36%), 369.1 (M+H 79Br 30%). 1H NMR (400 MHz, CDCl3) δ ppm 1.44 (s, 3 H), 1.50 (s, 3 H), 3.63 (s, 3 H), 3.81 (d, J=9.85 Hz, 1 H), 4.34 (d, J=9.85 Hz, 1 H), 6.72 (d, J=1.52 Hz, 1 H), 6.87-6.93 (m, 2 H), 7.51 (s, 1 H).
Reaction SMILES: [OH:1][NH2:2].[O:3]([C@H:10]1[CH2:15][C@H:14]([C:16](OC)=[O:17])[C@@H:13]([C:20]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)=[O:21])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O>CO>[OH:1][NH:2][C:16]([C@H:14]1[CH2:15][C@H:10]([O:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:11][CH2:12][C@@H:13]1[C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1)=[O:21])=[O:17]
Reactant: COC(=O)[C@H]1C[C@H](Oc2ccccc2)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Reactant: NO
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(NO)[C@H]1C[C@H](Oc2ccccc2)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of hydroxyamine in MeOH (1.5 M, 0.75 ml) was added to methyl(1S,2S,5R)-5-phenoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexane-carboxylate (0.29 mmol, 0.00029 mol) in MeOH (0.5 mL) at RT. The resulting mixture was stirred at RT for 2 hrs, and was adjusted to PH=2.0 with TFA, and then was purified by Prep-HPLC to give the desired product. LCMS: (M+H)+=424.2.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH:21][C:22](=[O:26])[CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Reactant: CCCC(=O)Cl
Product: CCCC(=O)Nc1ccc(OCc2c(-c3ccccc3)noc2C)nn1
Yield: 62 %

Procedure:
As described for example 18, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (200 mg, 0.7 mmol) was converted, using butyryl chloride instead of methoxyacetyl chloride, to the title compound (155 mg, 62%) which was obtained as a white solid. MS: m/e=353.3 [M+H]−.