Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:31]=[CH:30][C:21]2[C:22]3[CH:23]=[CH:24][O:25][C:26]=3[CH2:27][CH2:28][O:29][C:20]=2[C:19]=1[C:32]([O:34]C)=[O:33])(=[O:16])=[O:15])[CH3:2].O.[OH-].[Li+]>O.O1CCOCC1>[CH2:36]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:31]=[CH:30][C:21]2[C:22]3[CH:23]=[CH:24][O:25][C:26]=3[CH2:27][CH2:28][O:29][C:20]=2[C:19]=1[C:32]([OH:34])=[O:33])(=[O:15])=[O:16])[CH3:37]
Reactant: CCN(CC)CCCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCCc1occc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCN(CC)CCCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCCc1occc1-2
Yield: 27.6 %

Procedure:
A mixture of methyl 8-[2-(3-diethylaminopropyl)-4-fluorobenzenesulfonylamino]-4,5-dihydro-3,6-dioxabenzo[e]azulene-7-carboxylate (Intermediate 50, 0.134 g) and lithium hydroxide monohydrate (0.159 g) in water (3.8 mL) and dioxane (3.8 mL) was sealed in a microwave vial and irradiated in the microwave at 130° C. for 30 minutes. The mixture was concentrated in vacuo, water was added and it was acidified to pH3 with formic acid. This was extracted into ethyl acetate, dried (MgSO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM, with a gradient of 2.5-10%. The resultant product was recrystallised from a mixture of DCM and ethyl acetate to give 8-[2-(3-diethylaminopropyl)-4-fluorobenzenesulfonylamino]-4,5-dihydro-3,6-dioxabenzo[e]azulene-7-carboxylic acid (0.036 g) as a white solid.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[NH2:11][CH2:12][C:13]1[N:14]2[CH:21]=[N:20][CH:19]=[C:15]2[S:16][C:17]=1[CH3:18].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH:1]([NH:11][CH2:12][C:13]1[N:14]2[CH:21]=[N:20][CH:19]=[C:15]2[S:16][C:17]=1[CH3:18])=[O:3]
Reactant: Cc1sc2cncn2c1CN
Reactant: O=CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: Cc1sc2cncn2c1CNC=O
Reaction time: 1 h

Procedure:
A mixture of 0.94 ml of formic acid and 0.47 ml of acetic anhydride which had been beforehand reacted with each other at 50° C. for 30 minutes was added at room temperature to 5 ml of a dry dichloromethane solution containing 167 mg of 3-aminomethyl-2-methylimidazo[5,1-b]thiazole, and the mixture was then stirred at the same temperature for 1 hour. Then, an aqueous potassium carbonate solution was added to the reaction solution to alkalify the same. The organic layer was separated, and the aqueous layer was further extracted five times with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate and then filtered, and the solvent was evaporated under reduced pressure to obtain 117 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([SH:10])[CH:5]=1.Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.C[O-].[Na+].C(OCC)(=O)C>O1CCCC1.CO>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(S)c1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(Sc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
To a solution of 3-mercaptobenzoic acid methyl ester (504 mg, 3 mmol) and 1-chloro-4-nitrobenzene (473 mg, 3 mmol) in tetrahydrofuran (4 mL) was added at 0° C., in a dropwise manner, a solution of sodium methoxide in methanol (3.3 mL, 1M). The mixture was heated at reflux for 2 hours with stirring, then cooled to room temperature. Ethyl acetate (25 mL) was added and the mixture was washed consecutively with saturated aqueous sodium hydrogen carbonate (10 mL), distilled water (2×10 mL), and brine (10 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a solid that was recrystallised from ethanol to give the title compound (518 mg, 60%) as a solid, mp 98-100° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([I:26])C(=O)C1>CC#N.O>[CH2:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([I:26])=[C:13]([C:15]([F:17])([F:18])[F:16])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: FC(F)(F)c1c[nH]c(COCc2ccccc2)n1
Solvent: O
Solvent: CC#N
Product: FC(F)(F)c1nc(COCc2ccccc2)[nH]c1I
Reaction time: 15 h
Yield: 31.3 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 2-((benzyloxy)methyl)-4-(trifluoromethyl)-1H-imidazole (compound 219.1, 1.5 g, 5.85 mmol) in CH3CN (18 mL). NIS (1.6 g, 7.02 mmol) was added to the reaction. The reaction mixture was stirred for 15 h at 85. The reaction mixture was diluted with 30 mL of H2O. The aqueous phase was extracted with 2×30 mL of ethyl acetate. The combined organic layers were washed with 2×20 mL of Na2S2O3(sat.) and 2×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:100-1:2) as eluent to furnish 0.7 g (31%) of the title compound as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][Cl:7])([O-:3])=[O:2].[NH2:12][C:13]([NH2:15])=[S:14]>ClCCCC>[ClH:7].[C:13]([S:14][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])(=[NH:12])[NH2:15]
Reactant: NC(N)=S
Reactant: O=[N+]([O-])c1ccccc1CCl
Solvent: CCCCCl
Product: Cl
Product: N=C(N)SCc1ccccc1[N+](=O)[O-]
Yield: 77 %

Procedure:
A solution of 34.3 g of o-nitrobenzyl chloride and 15.2 g of thiourea in 250 ml of #2B alcohol was refluxed for 11/2 hours. The solution was cooled to 60° and 250 ml of 1-chlorobutane added. Further cooling to 20° yielded a precipitate which was filtered, washed with 1-chlorobutane and dried at 65° to give 38.1 g of 2-nitrophenylmethyl carbamimidothioate hydrochloride, m.p. 190°-192°.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:10]([F:13])([F:12])[CH:9]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][N:15]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[N:3]=1.[H-].[Na+].[CH2:32](Br)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].O>CN(C=O)C>[CH2:32]([O:20][C:17]1[CH:18]=[CH:19][C:14]([CH:9]2[C:10]([F:12])([F:13])[C:11]3[C:2]([F:1])=[N:3][C:4]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:5][C:6]=3[CH2:7][CH2:8]2)=[N:15][CH:16]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCOc1cc2c(c(F)n1)C(F)(F)C(c1ccc(O)cn1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCOc1ccc(C2CCc3cc(OCCCCCCCC)nc(F)c3C2(F)F)nc1
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
10 mmol of 1,8,8-trifluoro-7-(5-hydroxypyridin-2-yl)-3-octyloxy-5,6,7,8-tetrahydroisoquinoline are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1-octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo and the residue is chromatographed on silica gel, giving 7.55 mmol of 7-[5-(octyloxy)pyridin-2-yl]-1,8,8-trifluoro-3-octyloxy-5,6,7,8-tetrahydroisoquinoline.
Reaction SMILES: [CH:1]1([N:4]([CH:30]2[CH2:32][CH2:31]2)[C:5]([C:7]2[N:27]([CH2:28][CH3:29])[C:10]3=[N:11][C:12]([NH:19]/[C:20](/SC)=[CH:21]/[C:22](=O)[CH3:23])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:33][N:34](C(OCCCC)=O)[NH2:35].C(O)=O>C(O)(=O)C>[CH:1]1([N:4]([CH:30]2[CH2:31][CH2:32]2)[C:5]([C:7]2[N:27]([CH2:28][CH3:29])[C:10]3=[N:11][C:12]([NH:19][C:20]4[CH:21]=[C:22]([CH3:23])[N:34]([CH3:33])[N:35]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N/C(=C/C(C)=O)SC)nc21
Reactant: CCCCOC(=O)N(C)N
Solvent: O=CO
Solvent: CC(=O)O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3cc(C)n(C)n3)nc21
Temperature: 35 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
A mixture of (Z)-N,N-dicyclopropyl-6-ethyl-1-methyl-4-(1-(methylthio)-3-oxobut-1-enylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 72B, 70 mg, 0.155 mmol) and tent-butyl 1-methylhydrazinecarboxylate (0.046 mL, 0.309 mmol) in acetic acid (1 mL) wan stirred at 35° C. for 4 h (monitored by LC/MS until no starting material left). Formic acid (0.5 mL) was added and stirred at 60° C. for 6 h. Solvent was evaporated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (12 g column, eluting with 2-10% methanol/dichloromethane). The impure product was further purified by preparative HPLC to give N,N-dicyclopropyl-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (45 mg, 63.9% yield) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][C:19]([S:25](Cl)(=[O:27])=[O:26])=[CH:20]3)=[C:11]([O:29][CH3:30])[CH:10]=1>>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][C:19]([S:25]([NH:7][C:4]2[CH:3]=[C:2]([CH3:1])[O:6][N:5]=2)(=[O:26])=[O:27])=[CH:20]3)=[C:11]([O:29][CH3:30])[CH:10]=1
Reactant: Cc1cc(N)no1
Reactant: COc1cc(Cl)ccc1-c1cccc2cc(S(=O)(=O)Cl)ccc12
Product: COc1cc(Cl)ccc1-c1cccc2cc(S(=O)(=O)Nc3cc(C)on3)ccc12
Yield: 31862.7 %

Procedure:
This product was prepared as described in Example 43, employing 5-methylisoxazol-3-amine (48.0 mg, 0.49 mmol) and 5-(4-chloro-2-methoxyphenyl)naphthalene-2-sulfonyl chloride (0.498 μl, 0.408 μmol) to provide 5-(4-chloro-2-methoxyphenyl)-N-(5-methylisoxazol-3-yl)naphthalene-2-sulfonamide (55.8 mg, 0.13 mmol) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.27 (s, 3H), 3.67 (s, 3H), 6.19 (s, 1H), 7.12-7.21 (m, 1H), 7.23-7.31 (m, 2H), 7.53-7.64 (m, 2H), 7.69-7.81 (m, 2H), 8.21 (d, J=8.30 Hz, 1H), 8.59 (d, J=1.78 Hz, 1H), 11.55 (br. s., 1H); m/z (ESI, +ve ion) 429.9 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[N:19]2[CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[N:22]=[C:18]2[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]=1>O>[CH2:1]([NH:8][C:10]1[N:19]2[CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[N:22]=[C:18]2[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccccc1-c1cn2c(Cl)nc3c(c2n1)CCCC3
Reactant: NCc1ccccc1
Solvent: O
Product: Fc1ccccc1-c1cn2c(NCc3ccccc3)nc3c(c2n1)CCCC3
Temperature: 100 °C

Procedure:
To 5 mL of benzylamine was added 5-Chloro-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (150 mg) and the resulting mixture heated at 100° C. for 20 min. After 10 mL of water was added to the mixture, it was cooled and the solid that precipitated was collected. The solid was recrystallized from ethanol/water to yield 5-(N-benzylamino)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (Compound 31), m.p. 144°-145° C.
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6]1([CH3:17])[C@H:11]2[C@@H:7]1[C@H:8]([C:13](Cl)([Cl:15])[Cl:14])[O:9][C:10]2=[O:12]>CCOCC.O.[Zn]>[Cl:14][C:13]([Cl:15])=[CH:8][C@H:7]1[C@@H:11]([C:10]([OH:12])=[O:9])[C:6]1([CH3:5])[CH3:17]
Reactant: CC1(C)[C@H]2[C@H](C(Cl)(Cl)Cl)OC(=O)[C@H]21
Agent: [Zn]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)[C@H](C(=O)O)[C@@H]1C=C(Cl)Cl
Yield: 17.7 %

Procedure:
To a suspension of finely divided zinc dust (0.81 g, 1.23 mmole) in acetic acid (0.99 g, 1.64 mmole) and 4 ml of ether was added, under nitrogen, a solution of (1R,4R,5S)-6,6-dimethyl-2-oxo-4-trichloromethyl-3-oxabicyclo[3.1.0]hexane (0.50 g, 1.84 mmole) from Example IA.8.(a) in 4 ml of ether. The reaction was monitored by glpc. When the glpc results indicated almost complete conversion, the reaction mixture was diluted with additional ether and water, filtered through Celite filter aid, and the organic layer was separated, dried, and evaporated to a yellow oil which was chromatographed on two 20×20 cm preparative tlc plates with CH2Cl2 as eluent. The slow running acid band was removed, extracted with CH2Cl2, and the extract was filtered and evaporated to afford (1R,3R)-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid (68 mg, 18% isolated yield). The optical rotation of the acid prepared in a second identical run was measured; [α]D31 =+6.2 (hexane).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[CH:19]=1)=[CH:16][C:15]([C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)=[CH:14][CH:13]=3)=[O:6].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[I-].[K+]>O1CCCC1>[N:26]1([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[NH:11][C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20](=[O:25])[CH2:21][CH2:22][CH2:23][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:14][CH:13]=4)=[O:6])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(CCCCl)c1ccc2[nH]c3ccc(C(=O)CCCCl)cc3c2c1
Reactant: C1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(CCCN1CCCCC1)c1ccc2[nH]c3ccc(C(=O)CCCN4CCCCC4)cc3c2c1

Procedure:
A solution of 15.0 g (0.04 mole) of 3,6-bis(4-chlorobutyryl)carbazole, 85.0 g (1.0 mole) of piperidine and 2.0 g of potassium iodide in 15 ml of tetrahydrofuran was heated at 110°C in a reaction bomb for 24 hours with stirring. Upon cooling the reaction mixture was filtered and diluted with 700 ml of ice water. The resulting solid was washed with water, dried over magnesium sulfate and recrystallized from chloroformpetroleum ether (75°-90°C) and then from acetone to give the desired product. M.P. 171°-173°C, λmaxEtOH 259, E1cm1% 894.
Reaction SMILES: Cl[C:2](Cl)=[CH:3][CH:4]1[C:6]([CH3:8])(C)[CH:5]1[C:9]([O:11][C:12]([CH:14]1[C:16]([CH3:18])([CH3:17])[CH:15]1[CH:19]=[C:20]([Cl:22])[Cl:21])=[O:13])=O.[O:24](C1C=C(C=CC=1)C=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[C-:39]#[N:40].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:22][C:20]([Cl:21])=[CH:19][CH:15]1[C:16]([CH3:17])([CH3:18])[CH:14]1[C:12]([O:11][CH:9]([C:39]#[N:40])[C:5]1[CH:4]=[CH:3][CH:2]=[C:8]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=1)=[O:13]
Reactant: [C-]#N
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)OC(=O)C1C(C=C(Cl)Cl)C1(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1

Procedure:
A 100-ml round-bottomed flask equipped with a magnetic stirrer was charged with 2-(2,2-dichlorovinyl)-3,3-dimethylcyclopropanecarboxylic anhydride (10 mmol), prepared as described above, 3-phenoxybenzaldehyde (10 mmol) and a mixture of alkanes (25 ml) having a boiling range of from 60° C. to 80° C. A solution of sodium cyanide (12 mmol) and tetrabutylammonium bromide (0.006 mmol) in water (3 ml) was added to the mixture in the flask at a temperature of 20° C. and stirring was continued. After 100 minutes stirring, the reaction had come to a standstill at a conversion of 3-phenoxybenzaldehyde of 98.5% and at a yield of the title ester of 98%. The mixture obtained was allowed to settle into an organic and an aqueous layer, the aqueous layer was extracted with toluene (15 ml), the extract phase obtained was added to the organic layer obtained by settling of the reaction mixture, the organic liquid thus formed, was washed with water (25 ml), the washed liquid was dried and the solvent was evaporated from the dried liquid, leaving a residue containing the title ester. The yield of this ester was 96%.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[NH2:6].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.[OH-].[Na+]>N1C=CC=CC=1>[C:15]([NH:6][C:5]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
A mixture of 3-(trifluoromethyl)-4-nitroaniline (1.00 g, 4.85 mmol) and benzoyl chloride (0.62 ml, 5.34 mmol) were heated in pyridine (20 ml) at reflux for 3 hours under an inert atmosphere. The reaction was allowed to cool to ambient temperature, poured into water (200 ml) and basified by addition of 2.0 N aqueous sodium hydroxide solution. An oily liquid separated out which crystallised on standing at 4° C. overnight. The solid was collected by suction filtration, washed with water (3×20 ml) and then purified by flash chromatography on silica gel, eluting with dichloromethane. This yielded N-benzoyl 3-(trifluoromethyl)-4-nitroaniline (1.01 g, 67% yield) as a white solid:
Reaction SMILES: Cl[C:2]([F:7])([F:6])C([O-])=O.[Na+].[Cl:9][C:10]1[CH:11]=[CH:12][N:13]=[C:14]2[C:19]=1[N:18]=[CH:17][C:16]([OH:20])=[CH:15]2.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>CO.ClCCl>[Cl:9][C:10]1[CH:11]=[CH:12][N:13]=[C:14]2[C:19]=1[N:18]=[CH:17][C:16]([O:20][CH:2]([F:6])[F:7])=[CH:15]2
Reactant: Oc1cnc2c(Cl)ccnc2c1
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: FC(F)Oc1cnc2c(Cl)ccnc2c1
Reaction time: 3 h
Yield: 55.8 %

Procedure:
A round bottom flask under nitrogen atmosphere was charged with sodium 2-chloro-2,2-difluoroacetate (0.49 g, 3.2 mmol), 8-chloro-1,5-naphthyridin-3-ol (0.25 g, 1.4 mmol), cesium carbonate (1.4 g, 4.2 mmol), and DMF (2.8 mL, 0.5M). This was then placed in a 100° C. preheated oil bath and stirred at this temperature for 3 hours. Reaction mixture diluted with 10% Methanol/Dichloromethane and filtered over celite. Filtrate concentrated and purified by ISCO silica gel chromatography (40 g) in 1% MeOH/DCM to afford pure 8-chloro-3-(difluoromethoxy)-1,5-naphthyridine (0.18 g, 56% yield) as white solid. MS [M+H]=231.2. Calc'd for C9H5ClF2N2O=230.60.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:29]=[CH:28][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20]C(=O)OC(C)(C)C)=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:30][N:31]1[C:35]([CH3:36])=[C:34]([CH:37]=O)[C:33]([CH3:39])=[N:32]1>>[NH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:7]([CH:4]2[CH2:5][CH2:6][N:1]([CH2:37][C:34]3[C:33]([CH3:39])=[N:32][N:31]([CH3:30])[C:35]=3[CH3:36])[CH2:2][CH2:3]2)=[CH:29][CH:28]=1
Reactant: Cc1nn(C)c(C)c1C=O
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2CCNCC2)cc1
Product: Cc1nn(C)c(C)c1CN1CCC(c2ccc(C(=O)Nc3ccccc3N)cc2)CC1
Yield: 32.9 %

Procedure:
Using an analogous procedure to that described in Example 5, tert-butyl 2-[(4-piperidin-4-ylbenzoyl)amino]phenylcarbamate (prepared as described in Method 1 below; 200 mg, 0.51 mmol) was reacted with 1,3,5-trimethyl-1H-pyrazole-4-carbaldehyde (83.5 mg, 0.60 mmol) to give the title compound (70 mg, 56%); NMR Spectrum: (DMSO d6) δ 1.65 (m, 2H), 1.77 (m, 2H), 1.98 (m, 2H), 2.09 (s, 3H), 2.18 (s, 3H), 2.57 (m, 1H), 2.92 (m, 2H), 3.24 (s, 2H), 3.63 (s, 3H), 4.86 (br s, 2H), 6.60 (m, 1H), 6.78 (d, 1H), 6.97 (m, 1H), 7.17 (d, 1H), 7.37 (d, 2H), 7.91 (d, 2H), 9.55 (s, 1H); Mass Spectrum: M+H+ 418.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:13]([OH:16])[CH2:14][CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[C:10](=[O:12])[O:16][C@H:13]1[CH2:14][CH3:15])([CH3:2])([CH3:3])[CH3:4].[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[C:10](=[O:12])[O:16][C@H:13]1[CH2:14][CH3:15])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(O)C(NC(=O)OC(C)(C)C)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H]1OC(=O)[C@@H]1NC(=O)OC(C)(C)C
Product: CC[C@@H]1OC(=O)[C@H]1NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 24 %
Yield: 6 %

Procedure:
To a stirred solution of 2-(tert-butoxycarbonylamino)-3-hydroxy-pentanoic acid (0.173 mg, 0.74 mmol) in dry CH2Cl2 (17 mL), Et3N (0.255 g, 2.3 mmol) and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (0.463 mg, 0.89 mmol) were added at rt and the reaction stirred overnight. Solvent was evaporated and the crude product purified by typical silica gel column chromatography, eluting with petroleum ether/AcOEt (90:10) to give a mixture of diastereoisomers (anti:sin=8:2) (0.081 g) as a white solid. The diastereomeric mixture was further purified by typical silica gel column chromatography, eluting with petroleum ether/TBME (from 100:0 to 80:20) to give pure diastereoisomers, tert-butyl-N-[(2S*,3R*)-2-ethyl-4-oxo-oxetan-3-yl]-carbamate (0.0095 g, 6%) and tert-butyl-N-[(2S*,3S*)-2-ethyl-4-oxo-oxetan-3-yl]-carbamate (0.0382 g, 24%), as white solids.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:23])[CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[C:25](OC(=O)C)(=[O:27])[CH3:26].O>N1C=CC=CC=1>[C:25]([O:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:23])[CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1)(=[O:27])[CH3:26]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C1
Reaction time: 8 h

Procedure:
A solution of 3α-hydroxy-5α-pregnane-11,20-dione (1 g) in pyridine (ca 5 ml) was treated with acetic anhydride (2.5 ml) and allowed to stand overnight. The reaction mixture was poured into water and the solid collected by filtration and dried to give the title compound m.p. 150°-151°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:12])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14]>O1CCOCC1>[O:9]1[C:5]2[CH:4]=[C:3]3[NH:12][C:13](=[O:14])[NH:1][C:2]3=[CH:11][C:6]=2[NH:7][C:8]1=[O:10]
Reactant: Nc1cc2[nH]c(=O)oc2cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: O=c1[nH]c2cc3[nH]c(=O)oc3cc2[nH]1
Temperature: 25 °C
Yield: 65 %

Procedure:
3.3 g. (0.02 mole) 5,6-diaminobenzoxazolin-2-one and 5.5 g. (0.034 mole) 1,1'-carbonyldiimidazole are dissolved in 150 ml. dioxan and heated to the boil for 3 hours. After cooling to ambient temperature, the brownish crystalline substance obtained is filtered off with suction, boiled with dimethylformamide, filtered with suction and washed with methanol. There is obtained a yield of 65% of theory of the desired compound; m.p. >360° C.