Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[NH:12][CH:11]=[CH:10][C:9]2=O)([O-:3])=[O:2].[O:15]1[CH2:20]OCOC1.[ClH:21]>O1CCOCC1>[Cl:21][CH2:9][C:10]1[C:20](=[O:15])[C:8]2[C:13](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=2)[NH:12][CH:11]=1
Reactant: Cl
Reactant: O=c1cc[nH]c2c([N+](=O)[O-])cccc12
Reactant: C1OCOCO1
Solvent: C1COCCO1
Product: O=c1c(CCl)c[nH]c2c([N+](=O)[O-])cccc12
Temperature: 90 °C
Reaction time: 3.5 h

Procedure:
A mixture of 1,4-dihydro-8-nitro-4-oxoquinoline (10 g) and 1,3,5-trioxane (23.7 g) in dioxane (100 ml) and conc. hydrochloric acid (200 ml) was stirred for 3.5 hours at 90° C. and allowed to stand to ambient temperature. To the mixture was added ice water (700 g), and the mixture was stirred for 1 hour. The resulting precipitates were collected by filtration and washed with cold water to give 3-chloromethyl-1,4-dihydro-8-nitro-4-oxoquinoline (6.5 g).
Reaction SMILES: [F:1][C:2]1([F:36])[CH2:8][N:7]([CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[N:18]=[C:19]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=3[O:32][CH3:33])[N:20]=[CH:21][C:5]=2[N:4]([CH3:34])[C:3]1=[O:35].C([N:39](C(C)C)C(C)C)C.[Cl-].[NH4+]>CN(C)C=O>[F:1][C:2]1([F:36])[CH2:8][N:7]([CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]2[N:18]=[C:19]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH2:39])=[O:28])=[CH:25][C:24]=3[O:32][CH3:33])[N:20]=[CH:21][C:5]=2[N:4]([CH3:34])[C:3]1=[O:35]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(CCCc1ccccc1)CC(F)(F)C(=O)N2C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc(C(N)=O)ccc1Nc1ncc2c(n1)N(CCCc1ccccc1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.2 %

Procedure:
To a mixture of 0.05 g (0.10 mmole) of 4-[7,7-difluoro-5-methyl-6-oxo-9-(3-phenyl-propyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-benzoic acid (I-281), 0.07 mL (0.4 mmole) of ethyldiisopropyl amine and 0.011 g (0.20 mmole) of ammonium chloride in 2.0 mL of dimethylformamide was added 0.048 g (0.11 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted three times with dichloromethane. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.011 g of 4-[7,7-difluoro-5-methyl-6-oxo-9-(3-phenyl-propyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-benzamide (I-283) as a white solid.
Reaction SMILES: [CH3:1][C:2]([C@:4]1([OH:26])[C@@:8]2([CH3:25])[CH2:9][CH2:10][C@@H:11]3[C@:22]4([CH3:23])[C:15](=[CH:16][C:17]([C@H:19]5[C@@H:21]4[CH2:20]5)=[O:18])[C:14]([Cl:24])=[CH:13][C@H:12]3[C@@H:7]2[CH2:6][CH2:5]1)=[O:3].CS(C)=[O:29]>>[Cl:24][C:14]1[C:15]2[C@:22]([CH3:23])([C@H:21]3[CH2:20][C@H:19]3[C:17](=[O:18])[CH:16]=2)[C@@H:11]2[C@H:12]([C@H:7]3[C@:8]([CH3:25])([CH2:9][CH2:10]2)[C@@:4]([OH:26])([C:2](=[O:3])[CH3:1])[CH2:5][C@H:6]3[OH:29])[CH:13]=1
Reactant: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3CC[C@@]21C
Reactant: CS(C)=O
Product: CC(=O)[C@@]1(O)C[C@@H](O)[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3CC[C@@]21C
Yield: 36 %

Procedure:
Under the culturing and fermentation conditions of Example 1, a 50-liter fermentor is prepared with 28 l. of a Bacillus megaterium culture and, after a culture period of 12 hours, combined with 6 g. of cyproterone (6-chloro-17-hydroxy-1α,2α-methylene-4,6-pregnadiene-3,20-dione), dissolved in 400 ml. of dimethyl sulfoxide. After a contact period of 60 hours, the content of the fermentor is extracted with methyl isobutyl ketone and worked up as described in Example 1. The thus-obtained crude product is chromatographed over a silica gel column with the use of the solvent gradient methylene chloride-methylene chloride/acetone and recrystallized from acetone/hexane, thus obtaining in a 36% yield pure 6-chloro-15β,17-dihydroxy-1α,2α-methylene-4,6-pregnadiene-3,20-dione, m.p. 251°-253° C.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:10]([O:8][C:7](=[O:9])[C@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[NH2:1])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: CCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCOC(=O)[C@@H](N)CC(C)C
Yield: 97.4 %

Procedure:
L-Leucine (5.0 g, 0.038 mol), 1-octanol (5.0 g, 0.038 mol) and p-toluenesulfonic acid monohydrate (8.0 g, 0.042 mol) were suspended in toluene (200 ml) in a flask equipped with a Dean-Stark trap and refluxed for 20 h. Subsequently, the solvent was removed in vacuo and the remaining white solid was dissolved in CHCl3 (150 ml). This solution was extracted with 10%1/sodium carbonate, water and brine and dried Over MgSO4, Evaporation of the solvent in vacuo yielded a colourless oil (9.0 g, 0.037 mol, 97%). 1H NMR (CDCl3): δ=4.18 (t, 2H, 3J=7.0 Hz), 3.63 (dd, 1H, 3JAB=8.4 Hz, 3JAB=5.9 Hz), 1.85 (m, 1H), 1.74-3.18 (m, 6H), 1.37 (s, 10H, 0.99 (t's, 9H); 13C NMR (CDCl3): δ=176.98, 64.82, 52.79, 44.06, 31.64, 29.04, 28.47, 25.76, 24.66, 22.81, 22.51, 21.77, 13.96
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH3:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:32][CH2:31][C:30]1[CH:33]=[CH:34][C:27]([CH3:26])=[CH:28][CH:29]=1)=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: Cc1ccc(CN)cc1
Solvent: c1ccccc1
Product: Cc1ccc(CNC(=O)C2=C(C(=O)Nc3cc(OC4CCCC4)c(Cl)cc3F)CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (0.700 g, 1.92 mmol), 4-methylbenzylamine (0.330 g, 2.72 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(4-methylbenzyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.741 g, 79.7% yield).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]1.[S-:21][C:22]#[N:23].[NH4+].[NH2:25][C:26]1[C:27](Cl)=[N:28][CH:29]=[CH:30][C:31]=1[O:32][CH3:33]>CC(C)=O>[CH3:33][O:32][C:31]1[CH:30]=[CH:29][N:28]=[C:27]2[S:21][C:22]([NH:23][C:13]([N:10]3[CH2:11][CH2:12][N:7]([CH2:6][C:5]4[CH:16]=[CH:17][CH:18]=[C:3]([C:2]([F:20])([F:19])[F:1])[CH:4]=4)[CH2:8][CH2:9]3)=[O:14])=[N:25][C:26]=12
Reactant: O=C(Cl)N1CCN(Cc2cccc(C(F)(F)F)c2)CC1
Reactant: N#C[S-]
Reactant: COc1ccnc(Cl)c1N
Agent: [NH4+]
Solvent: CC(C)=O
Product: COc1ccnc2sc(NC(=O)N3CCN(Cc4cccc(C(F)(F)F)c4)CC3)nc12
Yield: 5.8 %

Procedure:
A magnetically stirred mixture of 4-(3-Trifluoromethyl-benzyl)-piperazine-1-carbonyl chloride (500 mg, 1.630 mmol) in acetone (20 mL) under a nitrogen atmosphere at 25° C. was treated with ammonium thiocyanate (115 mg, 1.49 mmol). The reaction mixture was stirred at reflux for 30 min. At this time, the reaction was treated with 3-amino-2-chloro-4 methoxypyridine (215 mg, 1.34 mmol). The reaction mixture was refluxed overnight. At this time, the reaction was concentrated in vacuo, poured into water and extracted with ethyl acetate. The organics were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75:25 hexanes/ethyl acetate) afforded 4-(3-Trifluoromethyl-benzyl)-piperazine-1-carboxylic acid (7-methoxy-thiazolo[5,4-b]pyridin-2-yl)-amide (35 mg, 15%) as white solid. LRMS for C20H20F3N5O2S (M+H)+ at m/z=451. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH2:4][CH2:5][CH3:6].Cl[C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=1.O>CN(C=O)C>[CH2:3]([N:7]([C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=1)[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH2:4][CH2:5][CH3:6]
Reactant: Cn1c(Cl)nc2ccccc21
Reactant: CCCCNS(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCN(c1nc2ccccc2n1C)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.029 g, 0.0012 mol, 1.1 equiv) was suspended in DMF (5 mL). N-Butyl-benzenesulfonamide (0.256 g, 0.222 mL, 0.0012 mol. 1.2 equiv) was then added and stirred at room temperature for 10 minutes. To the resulting mixture was then added the 2-chloro-N-methyl benzimidazole, (0.166 g, 0.001 mol). The resulting mixture was heated to 50° C. and stirred overnight (16 hours). The resulting mixture was then poured into water (15 mL) and stirred for 1 hour. The resulting solution was extracted with DCM (20 mL) and the organic layer was separated. The organic layer was washed with 1N NaOH (20 mL), and brine (20 mL), then dried over Na2SO4 and evaporated under reduced pressure. The resulting residue was purified by reverse phase HPLC (eluent 60-80% acetonitrile) to yield the title compound as a yellowish solid. MS 343.4
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:19]2[O:23][CH2:22][CH2:21][O:20]2)[N:5]([CH2:8][C:9]2[C:17]([Cl:18])=[CH:16][C:12]3[O:13][CH2:14][O:15][C:11]=3[CH:10]=2)[C:6]=1Br.[O:24]1CCC[CH2:25]1.C([Mg]Br)C.CN(C)C=O>C(OC(C)C)(C)C>[Br:1][C:2]1[N:3]=[C:4]([CH:19]2[O:23][CH2:22][CH2:21][O:20]2)[N:5]([CH2:8][C:9]2[C:17]([Cl:18])=[CH:16][C:12]3[O:13][CH2:14][O:15][C:11]=3[CH:10]=2)[C:6]=1[CH:25]=[O:24]
Reactant: Clc1cc2c(cc1Cn1c(C3OCCO3)nc(Br)c1Br)OCO2
Reactant: C1CCOC1
Agent: CC[Mg]Br
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: O=Cc1c(Br)nc(C2OCCO2)n1Cc1cc2c(cc1Cl)OCO2
Reaction time: 0.33 h

Procedure:
10 g of the product obtained in Stage 3 above is introduced into 200 ml of anhydrous tetrahydrofuran. 10 ml of ethyl magnesium bromide (3M solution in ethyl ether) is added and the reaction medium is left under agitation for 20 minutes at ambient temperature. Then an excess of anhydrous dimethylformamide is added. After 2 hours at ambient temperature, hydrolysis is carried out with 200 ml of 1N hydrochloric acid and extraction is carried out 3 times with 300 ml of ethyl acetate. The organic phase is washed with saturated sodium chloride then dried and evaporated to dryness. The residue obtained is impasted in isopropyl ether. In this way 7.6 g of expected product is obtained, which is used without purification for the following stage.
Reaction SMILES: [Na].CN(C)[C:4]1[CH2:8][CH2:7][CH2:6][N+:5]=1[CH3:9].COS([O-])(=O)=O.C(OC(=O)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)C.O>C(O)C.C(OCC)C>[CH3:29][O:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9]
Reactant: CCOC(=O)Cc1cccc(OC)c1
Reactant: CN(C)C1=[N+](C)CCC1
Agent: COS(=O)(=O)[O-]
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: COc1cccc(CC2CCCN2C)c1

Procedure:
Add a solution of 8.1 g of sodium in 160 ml of ethanol dropwise at 90°, with stirring, in a stream of nitrogen to 83.4 g of 2-dimethylamino-1-methyl-1-pyrrolinium-methylsulfate and 48.3 g of 3-methoxyphenylacetic acid ethyl ester. Stir the resulting reaction mixture for a further 30 minutes at 90° and then distribute the reaction mixture between 300 ml of water and 300 ml of diethyl ether. Concentrate the ether phase and boil the residue with conc. hydrochloric acid until carbon dioxide ceases to evolve. After cooling, alkalize the boiled residue with 6 N sodium hydroxide solution before extracting it with diethyl ether. Dry the ether extract over sodium sulfate; concentrate it, and reduce the concentrate in methanol with platinum/hydrogen. Separate the catalyst by filtration, concentrate the filtrate and distil to obtain a yield of 23.0 g (45% of theory) of title compound (b.p. 88° at 0.005 mm of Hg).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[O:11][N:10]=2)[CH2:3]1.[O:21]1[CH2:23][C@H:22]1[CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]2[S:33][C:32]([CH3:34])=[N:31][C:30]=2[CH:35]=1>C(O)(CC)(C)C>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:12]1[O:11][N:10]=[C:9]([CH2:8][N:4]2[CH2:5][CH2:6][N:7]([CH2:23][C@@H:22]([OH:21])[CH2:24][O:25][C:26]3[CH:27]=[CH:28][C:29]4[S:33][C:32]([CH3:34])=[N:31][C:30]=4[CH:35]=3)[C@@H:2]([CH3:1])[CH2:3]2)[CH:13]=1
Reactant: C[C@H]1CN(Cc2cc(-c3ccccc3F)on2)CCN1
Reactant: Cc1nc2cc(OC[C@@H]3CO3)ccc2s1
Solvent: CCC(C)(C)O
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(Cc4cc(-c5ccccc5F)on4)C[C@@H]3C)ccc2s1
Temperature: 95 °C
Reaction time: 24 h

Procedure:
To a solution of 3-[((3S)-3-methylpiperazinyl)methyl]-5-(2-fluorophenyl)isoxazole (28 mg, 0.10 mmol) in tert-amyl alcohol (5 mL) was added 5-[((2S)oxiran-2-yl)methoxy]-2-methylbenzothiazole (22 mg, 0.10 mmol). The reaction mixture was stirred at 95° C. for 1 day. It was then cooled, concentrated, and purified by preparative chromatography (1:19 methanol:methylene chloride) to afford (2R)-3-((2S)-4-{[5-(2-fluorophenyl)isoxazol-3-yl]methyl}-2-methylpiperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol (M+1=497.27).
Reaction SMILES: O(CC([NH:11][CH:12]1[C:33](=[O:34])[N:14]2[CH:15]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])[C:16](=[CH2:19])[CH2:17][S:18][C@H:13]12)=O)C1C=CC=CC=1.C(Cl)[Cl:36].N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl>C(O)C(C)C>[ClH:36].[NH2:11][CH:12]1[C:33](=[O:34])[N:14]2[CH:15]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)=[O:21])[C:16](=[CH2:19])[CH2:17][S:18][C@H:13]12
Reactant: C=C1CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: ClCCl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CC(C)CO
Solvent: c1ccncc1
Product: C=C1CS[C@@H]2C(N)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: Cl
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of 965 mg. (2 mmole) of p-nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4-carboxylate in 10 ml. of methylene chloride were added 175 mg of dry pyridine and 460 mg. of phosphorus pentachloride and the mixture was stirred at room temperature for 6 hours. One ml. of isobutanol was added to the mixture which was then stored at 0° C. overnight. The reaction product, p-nitrobenzyl 7-amino-3-methylenecepham-4-carboxylate hydrochloride, which formed as a crystalline precipitate was filtered to yield 430 mg. (58% yield).
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][OH:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:33][C:34]1([Br:50])[CH:36]([C:37]2[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=2)[CH:35]1[CH2:44][C:45]([O:47]CC)=[O:46].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(O)(C(F)(F)F)=O>C1COCC1>[Br:33][C:34]1([Br:50])[CH:36]([C:37]2[CH:42]=[CH:41][C:40]([O:13][CH2:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[CH2:6][CH2:7][CH2:8][NH:9][C:10]=4[N:1]=3)=[CH:39][CH:38]=2)[CH:35]1[CH2:44][C:45]([OH:47])=[O:46]
Reactant: CCOC(=O)CC1C(c2ccc(O)cc2)C1(Br)Br
Reactant: OCCc1ccc2c(n1)NCCC2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(O)CC1C(c2ccc(OCCc3ccc4c(n3)NCCC4)cc2)C1(Br)Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.3 %

Procedure:
To a solution of 2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-1-ethanol (0.17 g, 0.96 mmol) and polymer bound PPh3 (0.32 g, 0.96 mmol) in dry THF (10 mL) was added ethyl [2,2-dibromo-3-(4-hydroxyphenyl)cyclopropyl]acetate (0.18 g, 0.6 mmol) followed by diisopropyl azodicarboxylate (0.2 mL, 1 mmol). The reaction mixture was stirred at room temperature. After 18 hours, polymer was filtered through Celite and washed with excess THF. Filtrate was concentrated. The concentrated residue in 50% acetonitrile in water (4 mL) was added LiOH (0.14 g). The reaction mixture was stirred 3 hours at room temperature. Reaction mixture was acidified by adding TFA and purified by reverse phase HPLC to afford 50 mg (12%) of desired product. 1H NMR (CD3OD) δ 7.59 (d, 1H, J=7.4 Hz), 7.21 (d, 2H, J=8.6 Hz), 6.88 (d, 2H, J=8.7 Hz), 6.73 (d, 1H, J=7.2 Hz), 4.27 (t, 2H, J=6.0 Hz), 3.49 (t, 2H, J=5.9 Hz), 3.14 (t, 2H, J=5.9 Hz), 2.82-2.78 (m, 3H), 2.71-2.59 (m, 2H), 2.25-2.19 (m, 1H), 1.97-1.90 (m, 2H). HRMS calcd for C21H22N2O3 (M+H): 421.1080. found 421.1069.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:17]=1)[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.[CH3:41][NH:42][O:43][CH3:44]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[C:11]([C:12](=[O:14])[N:42]([O:43][CH3:44])[CH3:41])[CH:15]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:17]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)Nc1cc(C(=O)O)cc(S(C)(=O)=O)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc(NC(=O)OC(C)(C)C)cc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
3-Tert-butoxycarbonylamino-5-(methylsulfonyl)-benzoic acid (850 mg; 2.695 mmol) was diluted in 30 ml of THF, 1,1′-carbonyldiimidazole (1.3 g; 8.086 mmol) and triethylamine (0.818 ml; 5.661 mmol) were added. The reaction mixture was stirred at room temperature for 30 min., then, N,O-dimethylhydroxylamine (0.329 g; 0.005 mol) was added. The reaction mixture was refluxed overnight. Then, it was concentrated in vacuo. The crude was diluted with dichloromethane and to washed with a saturated sodium bicarbonate solution. The organic phase was separated, dried on MgSO4 and concentrated in vacuo. The crude was treated with isopropyl ether/ethyl acetate 2/1. The precipitate formed was filtered and dried in vacuo. 460 mg (1.25 mmol; 46% yield) of [3-methanesulfonyl-5-(methoxy-methyl-carbamoyl)-phenyl]-carbamic acid tert-butyl ester were obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH2:20][CH2:19]3)[C:5]2=[N:6][CH:7]=1.[CH2:33]([N:36]=[C:37]=[O:38])[CH2:34][CH3:35]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:19][CH2:20][N:21]([C:24](=[O:32])[CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:37]([NH:36][CH2:33][CH2:34][CH3:35])=[O:38])[CH2:28][CH2:27]4)[CH2:22][CH2:23]3)[C:5]2=[N:6][CH:7]=1
Reactant: CCCN=C=O
Reactant: O=C(CC1CCNCC1)N1CCN(C2c3ccc(Cl)cc3CCc3cc(Br)cnc32)CC1
Solvent: ClCCl
Product: CCCNC(=O)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4CCc4cc(Br)cnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 44 h
Yield: 112.9 %

Procedure:
1-(3-Bromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-4-[(4-piperidinyl)acetyl]piperazine (Preparative Example 10) (490 mg, 0.8 mmoles) was dissolved in anhydrous dichloromethane (5 ml) and n-propyl isocyanate (322.1 mg, 3.2 mmoles) was added. The mixture was stirred under argon at 25° C. for 44 h. The solution was chromatographed on silica gel using 2% (10% concentrated NH4OH in methanol)dichloromethane as the eluant to give 544.8 mg of the title compound (Yield: 95%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH2:28])[C:12]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:15]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:14]=2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[N:32]=[CH:33][N:34]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:28][C:30]1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[N:32]=[CH:33][NH:34]2)[C:12]1[N:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:15]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:14]=2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H](CCOCc1ccccc1)c1nc2ccc(F)cc2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Fc1ccc2nc([C@H](CCOCc3ccccc3)Nc3ncnc4[nH]cnc34)n(-c3ccccc3)c2c1
Temperature: 100 °C
Yield: 83.8 %

Procedure:
A mixture of (S)-3-benzyloxy-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)propylamine (639 mg, 1.7 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (410 mg, 1.7 mmol) and DIPEA (1.5 mL, 8.5 mmol) in n-butanol (6 mL) was heated at 100° C. for 18 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford the title compound as a white solid (703 mg, 84%). LCMS (Method C): RT 3.10 min [M+H]+ 494.3.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16](O)[C:17]([CH3:20])([CH3:19])[CH3:18].N1C(C)=CC=CC=1C>ClCCl>[CH3:16][C:17]([CH3:20])([CH3:19])[CH2:18][O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)CO
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)COS(=O)(=O)C(F)(F)F
Reaction time: 1 h
Yield: 71.7 %

Procedure:
Add trifluoromethanesulphonic anhydride (1.12 mL, 6.8 mmol) to a solution of neopentylalcohol (0.5 g, 5.7 mmol) and 2,6-lutidine (0.7 mL, 6.8 mmol) in dichloromethane (10 mL) at −78° C. and stir for 1 hour. Add water to quench the reaction, separate the organic layer and extract the aqueous layer with dichloromethane. Combine the organic layers, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 1:4 hexane:dichloromethane) to give the desired compound as an oil (0.9 g, 72% yield).
Reaction SMILES: C(O[C:4]([C:6]1[N:10]2[CH2:11][CH2:12][N:13]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:9]2=[N:8][C:7]=1[CH2:23][CH3:24])=[O:5])C.[CH2:25]([Mg]Cl)[CH2:26][CH3:27].[C:30]1(C)[CH:35]=CC=C[CH:31]=1>O1CCCC1>[CH2:23]([C:7]1[N:8]=[C:9]2[N:13]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[CH2:12][CH2:11][N:10]2[C:6]=1[C:4]([OH:5])([CH2:31][CH2:30][CH3:35])[CH2:25][CH2:26][CH3:27])[CH3:24]
Reactant: CCOC(=O)c1c(CC)nc2n1CCN2c1c(C)cc(C)cc1C
Reactant: Cc1ccccc1
Reactant: CCC[Mg]Cl
Solvent: C1CCOC1
Product: CCCC(O)(CCC)c1c(CC)nc2n1CCN2c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
To a 0° C. solution of 2-ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid ethyl ester (1 mL of a 0.14M solution in toluene) in tetrahydrofuran (1 mL) was added n-propylmagnesium chloride (0.84 mL of 1.0M in tetrahydrofuran). The resulting solution was removed from the ice bath and allowed to stir for 15 min. It was then heated at reflux for 14 h. Upon cooling to room temperature, the reaction solution was quenched with saturated aqueous ammonium chloride, and the phases were separated. The aqueous phase was extracted twice with ether, and the combined organic portions were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a yellow semi-solid (0.0448 g, 86%). LC/MS: tR=1.58 min., (MH+)=370.31.