Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=C(C=CC=1)C([O:9][C@@H:10]1[CH2:14][C@@H:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][C@@H:11]1[CH3:23])=O)([O-])=O.CO>C1COCC1.O>[CH2:16]([O:15][C@@H:13]1[CH2:14][C@@H:10]([OH:9])[C@@H:11]([CH3:23])[CH2:12]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@H]1C[C@H](OCc2ccccc2)C[C@H]1OC(=O)c1cccc([N+](=O)[O-])c1
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H]1C[C@H](OCc2ccccc2)C[C@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of (1R*,2S*,4S*)-4-(benzyloxy)-2-methylcyclopentyl 3-nitrobenzoate (example 25; 11.5 g; 32.5 mmol) in THF (80.0 mL) and MeOH (40.0 mL) LiOH (1.17 g; 48.7 mmol) dissolved in water (40.0 mL) is added. The reaction mixture is stirred at ambient temperature for one hour and concentrated under reduced pressure. The residue is diluted with water and extracted with dichloromethane. The organic layer is dried over MgSO4, and concentrated under reduced pressure. The residue is chromatographed on silica gel (cyclohexane/tert-BuOMe—80:20 to 50:50) to yield 5.9 g of the title compound as pale yellow oil.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([C:21]3[N:22]=[C:23]4[C:29]([C:30](O)=[O:31])=[CH:28][N:27]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:24]4=[N:25][CH:26]=3)=[N:16][N:17]2[CH3:20])=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[NH2:72][C@H:73]([CH2:81][CH2:82][CH3:83])[C:74]([N:76]1[CH2:79][CH:78]([F:80])[CH2:77]1)=[O:75]>CN(C=O)C>[F:80][CH:78]1[CH2:77][N:76]([C:74]([C@H:73]([NH:72][C:30]([C:29]2[C:23]3[C:24](=[N:25][CH:26]=[C:21]([C:15]4[C:14]5[C:18](=[CH:19][C:11]([F:10])=[CH:12][CH:13]=5)[N:17]([CH3:20])[N:16]=4)[N:22]=3)[N:27]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:38])[CH3:39])[CH:28]=2)=[O:31])[CH2:81][CH2:82][CH3:83])=[O:75])[CH2:79]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: CCC[C@@H](N)C(=O)N1CC(F)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCC[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(=O)N1CC(F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
In a round-bottomed flask, (R)-2-amino-1-(3-fluoro-azetidin-1-yl)-pentan-1-one trifluoroacetate (crude from Step 2) was dissolved in DMF (1.5 ml) and N,N-diisopropylethylamine (0.60 ml, 3.44 mmol) was added. Then 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (110 mg, 0.25 mmol) and HATU (104 mg, 0.27 mmol) were added. The yellow reaction mixture was stirred at room temperature overnight then quenched with water and diluted with petroleum ether. The resulting suspension was filtered. The filter cake was washed with water and petroleum ether then dried under high vacuum to afford 128 mg (86%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(3-fluoro-azetidine-1-carbonyl)-butyl]-amide as an off-white powder.
Reaction SMILES: Cl.[CH:2]1([NH+:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>O>[CH:2]1([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C1CCC([NH+]2CCCC2)CC1
Agent: Cl
Solvent: O
Product: C1CCC(N2CCCC2)CC1

Procedure:
In some instances when some unreacted cyclohexanone is still in the reaction mixture, the product after hydrogenation was purified by adding 3M HCl solution to the mixture (after filtering out the palladium/carbon catalyst) and left to stir for 15-20 minutes. The resulting mixture was then extracted with diethyl ether to remove the cyclohexanone from the mixture and leaving behind the cyclohexylpyrrolidinium hydrochloride salt. The water layer containing cyclohexylpyrrolidinium hydrochloride salt is separated and then neutralized with NaOH solution to a pH of 9-10. The free cyclohexylpyrrolidine is extracted with ethyl acetate, dried over MgSO4 and concentrated on a rotary evaporator at reduced pressure to give the desired product free from any impurities.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[N:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=1>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([N:1]=[CH:31][C:28]3[CH:27]=[CH:26][C:25]([O:24][C:19]4[N:18]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:30][CH:29]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: O=Cc1ccc(Oc2ncccn2)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N=Cc1ccc(Oc2ncccn2)cc1

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was suspended in EtOH and 4-(2-pyrimidinyloxy)benzenecarbaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain B64 as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[C:4]([O:12][CH:13]([CH:16]2[CH2:18][CH2:17]2)[C:14]#[CH:15])[CH:3]=1.C(N(CC)C1C=CC=CC=1)C.Cl>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[C:4]2[C:3]=1[CH:15]=[CH:14][CH:13]([CH:16]1[CH2:18][CH2:17]1)[O:12]2
Reactant: C#CC(Oc1cc(Br)ccc1OC(F)F)C1CC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)c1ccccc1
Product: FC(F)Oc1ccc(Br)c2c1OC(C1CC1)C=C2
Temperature: 200 °C
Reaction time: 2 h
Yield: 62.9 %

Procedure:
To 545 mg (1.7 mmol) of 4-bromo-2-(1-cyclopropyl-2-propynyloxy)-1-difluoromethoxybenzene obtained in Reference example 14-(b) was added 5 ml of N,N-diethylaniline, and the mixture was stirred at 200° C. for 2 hours. After completion of the reaction, water was added to the reaction mixture, and then, a pH of the mixture was adjusted to 1 with conc. hydrochloric acid, and the mixture was extracted with diethyl ether. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 339 mg of the title compound as yellowish liquid. (Yield: 63%)
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:10]([CH2:12][CH:13]1[O:18][CH2:17][CH2:16][N:15](CC2C=CC=CC=2)[CH2:14]1)C)C1C=CC=CC=1.C(O)C>[C].[Pd].O>[OH2:18].[ClH:1].[ClH:1].[CH3:3][NH:10][CH2:12][CH:13]1[O:18][CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CN(Cc1ccccc1)CC1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CNCC1CNCCO1

Procedure:
A mixture of 58 g of 2-chloromethyl-4-benzylmorpholine, 62.3 g of N-benzyl-N-methylamine and 38.6 g of sodium iodide in 220 ml of dimethylformamide is refluxed under stirring at 140° C. for 6 hours. After completion of the reaction, the dimethylformamide is distilled off under reduced pressure, water is added to the residue and the mixture is subjected to extraction with ethyl acetate. After washing with water, the resultant mixture is dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is treated in 37% hydrochloric acid-ethanol to give 2-(N-benzyl-N-methylaminomethyl)-4-benzylmorpholine dihydrochloride as white crystals. The obtained hydrochloride compound (29.7 g) is subjected to catalytic reduction with 50 ml of ethanol, 80 ml of water and 3 g of 10% palladium-carbon. After absorbing the theoretical volume of the hydrogen, the catalyst is filtered off and the solvent of the filtrate is distilled off to give 2-(methylaminomethyl)morpholine dihydrochloride monohydrate as white crystals, melting at 122°-124° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:9][CH:10]=1)=[O:5])[CH3:2].[Cl:17]N1C(=O)CCC1=O>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:9][C:10]=1[Cl:17])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1csc(-c2ccccc2)c1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccccc2)sc1Cl
Reaction time: 8 h
Yield: 76.7 %

Procedure:
Ethyl-2-phenylthiophen-4-carboxylate (0.5 g, 2.15 mmol) was dissolved in acetic acid (5 mL). N-chlorosuccinimide (2.17 mmol) was added and the reaction stirred overnight. The reaction was concentrated under vacuum and purified by flash chromatography on silica, eluting with 0%-50% ethyl acetate in cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.44 g). 1H NMR (400 MHz, CHCl3-d): δ 7.5 (d, 2H), 7.4-7.25 (m, 4H), 4.4 (q, 2H), 1.4 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:21]Br)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.O>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:21][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of 500 mg of 4-bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester in 5 mL of acetonitrile was added 190 mg of potassium carbonate and 110.5 mg of morpholine. The resulting mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient of dichloromethane/methanol from 100/0 to 50/50) followed by washing of the collected solid with diisopropyl ether to give 355 mg of 4-morpholin-4-ylmethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]([OH:26])[C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:18][CH:19]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[O:26]1[CH2:12][CH:13]1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:23])([F:24])[F:25])=[N:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(O)c2ccc(OCC(F)(F)F)nc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: FC(F)(F)COc1ccc(C2CO2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
A mixture of 2-hydroxy-2-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl 4-methylbenzenesulfonate (1.66 g, 4.25 mmol, Step-4, single enantiomer) and potassium carbonate (1.76 g, 12.8 mmol) in methanol (43 mL) is stirred at room temperature for 2 hours. White precipitate is filtrated and filtrate is concentrated in vacuo. The residue is poured into water, extracted with ethyl acetate and dried over sodium sulfate and concentrated in vacuo to give 0.89 g (95% yield) of the title compound as colorless oil. This material is used for the next reaction (Step-6) without further purification.
Reaction SMILES: C([Li])CCC.[Br-].[F:7][C:8]1[CH:9]=[CH:10][C:11]([OH:34])=[C:12]([CH:33]=1)[CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:35]([CH:37]([CH2:50][CH2:51][C:52]1[CH:61]=[CH:60][C:55]([C:56]([O:58][CH3:59])=[O:57])=[CH:54][CH:53]=1)[CH2:38][CH2:39][C:40]1[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=1)=O.[Cl-].[NH4+]>CCCCCC.C1COCC1.O.C(OCC)(=O)C>[F:7][C:8]1[CH:9]=[CH:10][C:11]([OH:34])=[C:12](/[CH:13]=[CH:35]/[CH:37]([CH2:38][CH2:39][C:40]2[CH:41]=[CH:42][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:48][CH:49]=2)[CH2:50][CH2:51][C:52]2[CH:61]=[CH:60][C:55]([C:56]([O:58][CH3:59])=[O:57])=[CH:54][CH:53]=2)[CH:33]=1
Reactant: Oc1ccc(F)cc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(CCC(C=O)CCc2ccc(C(=O)OC)cc2)cc1
Agent: [Br-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCC(/C=C/c2cc(F)ccc2O)CCc2ccc(C(=O)OC)cc2)cc1
Reaction time: 0.75 h

Procedure:
At 0° C., 2.95 ml (7.39 mmol) of a 2.5 M solution of n-butyllithium in hexane are slowly added dropwise to a solution of 1479 mg (3.2 mmol) of (5-fluoro-2-hydroxybenzyl)-(triphenyl)phosphonium bromide in 40 ml of THF. The reaction mixture is stirred at this temperature for another 45 min. At 0° C., 1080 mg (2.64 mmol) of dimethyl 4,4′-(3-formylpentane-1,5-diyl)dibenzoate in 10 ml of THF are then slowly metered in. The reaction solution is stirred at 0° C. for 5 h, saturated ammonium chloride solution is then added and the mixture is diluted with water and ethyl acetate. The organic phase is separated off, and the aqueous phase is extracted two more times with ethyl acetate. The combined organic phases are dried over sodium sulfate and filtered, and the solvent is removed to dryness. The crude product obtained is purified by flash chromatography on silica gel (mobile phase:cyclohexane/ethyl acetate 4:1). This gives 529 mg (1.11 mmol, 42% of theory) of a colorless oil.
Reaction SMILES: N#N.[F:3][C:4]([F:18])([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:10][CH:11]=[C:12]([C:14](Cl)=[O:15])[N:13]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>CC(C)=O.O>[F:3][C:4]([F:18])([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:10][CH:11]=[C:12]([C:14]([N:19]=[N+:20]=[N-:21])=[O:15])[N:13]=1
Reactant: CC(F)(F)CCCCc1nc(C(=O)Cl)co1
Reactant: [N-]=[N+]=[N-]
Agent: N#N
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(F)(F)CCCCc1nc(C(=O)N=[N+]=[N-])co1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of this crude 2-(5,5-difluoro-hexyl)-oxazole-4-carbonyl chloride was dissolved in dry acetone (12.0 mL). The solution was cooled to 0° C. and a solution of sodium azide (196 mg, 2.98 mmol) in H2O (1.4 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 45 min. The mixture was concentrated under reduced pressure, and the residue was dissolved in CH2Cl2 and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a brown solid. LC-MS-conditions 02: tR=0.98 min, [M+H]+=259.09.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1.[Si](C=[N+]=[N-])(C)(C)[CH3:12].CO>C(OCC)C>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH3:12])=[O:9])[CH2:3]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C1CCCC(C(=O)O)C1
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C1CCCC(=O)C1
Temperature: 25 °C

Procedure:
To a solution of 3-oxocyclohexanecarboxylic acid (1.0 g, 7.0 mmol) in diethyl ether (28 mL) was added dropwise TMS-diazomethane (3.5 mL, 7.0 mmol, 2.0 mL in diethyl ether). MeOH (30 mL) was added and the mixture was maintained at ambient temperature for 30 minutes. The mixture was concentrated in vacuo, and the residue was purified by MPLC on silica gel (using a gradient elution of 0-45% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([C:35]6[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=6)[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Clc1nc2c(-c3ccccc3)cccc2s1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5c(-c6ccccc6)cccc5s4)cc3CC[C@@H]12
Yield: 61.5 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4-phenyl-benzothiazole (113 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (4×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 110 mg (61%) of the title compound as an amorphous foam. FDMS: m/e=470. α[D]589 =+53.51 (c=0.66, chloroform).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:9][C:10]([CH3:11])=[C:5]2[CH2:4][CH2:3]1.[Br:20]N1C(C)(C)C(=O)N(Br)C1=O>C(Cl)(Cl)Cl>[Br:20][C:9]1[C:10]([CH3:11])=[C:5]2[CH2:4][CH2:3][N:2]([CH3:1])[C:6]2=[N:7][C:8]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CCCCCCCCc1cc(C)c2c(n1)N(C)CC2
Solvent: ClC(Cl)Cl
Product: CCCCCCCCc1nc2c(c(C)c1Br)CCN2C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution containing 402 mg (1.54 mmol) of 1,4-Dimethyl-6-octyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine in 6 mL of chloroform was added 220 mg (0.77 mmol) of 1,3-dibromo-5,5-dimethylhydantoin in five portions at 0° C. The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was quenched by the addition of 8 mL of sat aq. NaHCO3. The mixture was extracted with three 25-mL portions of chloroform. The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under diminished pressure. The residue was purified via flash chromatography on a silica gel column (43×2.5 cm). Step gradient elution with 1:10 ethyl acetate-hexanes as eluent gave 5-bromo-1,4-dimethyl-6-octyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine as a yellow oil: yield 371 mg (71%); silica gel TLC Rf 0.65 (8:1:1 hexanes-ethyl acetate-methanol); 1H NMR (CDCl3) δ 0.81 (t, 2H, J=7.2 Hz), 1.16-1.30 (m, 10H), 1.65 (quint, 2H, J=8.0 Hz), 2.12 (s, 3H), 2.59 (t, 2H, J=8.0 Hz), 2.79-2.85 (m, 5H), 3.41 (t, 2H, J=8.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1.CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[Br:8][C:5]1[N:4]=[N:3][C:2](/[N:1]=[CH:11]/[N:12]([CH3:14])[CH3:13])=[CH:7][CH:6]=1
Reactant: Nc1ccc(Br)nn1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=N/c1ccc(Br)nn1
Temperature: 25 °C
Yield: 74.5 %

Procedure:
3-Amino-6-bromopyridazine (5.0 g, 28.7 mmol) was heated and stirred with dimethylformamide dimethylacetal (5.36 g, 6.0 mL, 45.0 mmol) under nitrogen at 110° C. for 3 h. The brown homogeneous reaction mixture was cooled to room temperature. The resulting heterogeneous slurry was stirred in EtOAc/hexanes (1:1, 75 mL) and filtered. The filtered solid was suction dried to obtain apparently (E)-N′-(6-bromopyridazin-3-yl)-N,N-dimethylformimidamide (4.9 g) as a pale pink crystalline solid. 1H NMR (300 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.64 (d, J=9.1 Hz, 1H), 7.03 (d, J=9.1 Hz, 1H), 3.11 (s, 3H), 3.00 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1(O)[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][CH2:10]1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.CCCCCC>C(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][CH2:10]1
Reactant: OC1(c2cccc(F)c2F)CCC=CCC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCCCCC
Product: Fc1cccc(C2CCC=CCC2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
In a 250 mL round-bottomed flask (t=g) was added (Z)-1-(2,3-difluorophenyl)cyclohept-4-enol (2.05 g, 9.14 mmol) in CH2Cl2 (40 mL) to give a colorless solution. Triethylsilane (7.30 mL, 45.7 mmol) was added, followed by TFA (20 mL). The mixture was stirred at room temperature for 3 hours: TLC showed a complete conversion (Rf=0.42 by pure hexane). It was concentrated down to a bi-layer oil (the lower layer wasn't hexane-soluble). Purification by FCC using only hexane afforded the desired product as a colorless oil (1.684 g, 88%). 1H NMR (400 MHz, CDCl3) δ 7.00-6.90 (m, 3H), 5.90-5.82 (m, 2H), 3.20-3.05 (m, 1H), 2.40-2.15 (m, 4H), 1.90-1.78 (m, 2H), 1.60-1.40 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH:29]1[CH2:34][NH:33][CH2:32][CH2:31][NH:30]1.C(=O)([O-])[O-].[Na+].[Na+].O>CS(C)=O.C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:33]4[CH2:32][CH2:31][NH:30][CH:29]([C:25]5[O:24][CH:28]=[CH:27][CH:26]=5)[CH2:34]4)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Reactant: c1coc(C2CNCCN2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCO
Product: CCOC(=O)c1cn(C)c2nc3cc(N4CCNC(c5ccco5)C4)c(F)cc3cc2c1=O
Temperature: 95 °C
Yield: 95.7 %

Procedure:
A suspension of 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (0.96 g), (RS)-2-(2-furyl)piperazine (0.6 g) and sodium carbonate (0.38 g) in dimethyl sulphoxide (20 cc) is heated to approximately 95° C. for 5 hours and a half. After cooling to approximately 20° C., the mixture is poured into water (50 cc) at a temperature in the region of 5° C. and extracted with dichloromethane (3×100 cc). The combined organic extracts are washed with water (3×50 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 kPa) at approximately 40° C. The residue obtained is taken up with ethanol (20 cc), drained and washed with ethanol (2×20 cc) and ethyl ether (3×30 cc). (RS)-3-Ethoxycarbonyl-7-fluoro-8-[3-(2-furyl)-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.3 g) is obtained in the form of a yellow solid, m.p. 198°-200° C., which is used without further purification for the subsequent steps.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[CH3:24][NH2:25].C(O)(=O)C.O>CCO>[CH3:24][NH:25][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4]
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: CN
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 80 °C
Yield: 72.1 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (40 mg, 0.13 mmol) and methylamine (0.65 mL, 1.3 mmol, 2 M in THF) in 2 mL of EtOH was heated in a sealed tube at 80° C. for 4 h. After cooling to r.t., acetic acid (0.3 mL) and water (3 mL) were added. The resulting suspension was filtered and the solid isolated was washed with water and dried under high vacuum to afford 29 mg of the title compound. MS: (+) m/z 309.97 (M+1).