Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O.[F:44][C:45]([F:55])([F:54])[C:46]1[CH:47]=[C:48]([CH:51]=[CH:52][CH:53]=1)[CH2:49]Cl.COC1C=CC(CCl)=CC=1>>[F:44][C:45]([F:54])([F:55])[C:46]1[CH:47]=[C:48]([CH:51]=[CH:52][CH:53]=1)[CH2:49][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: COc1ccc(CCl)cc1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Product: O=C1N(Cc2cccc(C(F)(F)F)c2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 7 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 3-(trifluoromethyl)benzyl chloride to replace 4-methoxybenzyl chloride, 1′43-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (92%) as a colorless solid: mp 131-134° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ7.62-7.43 (m, 4H), 7.25-7.18 (m, 2H), 7.05 (dd, J=7.5, 7.5 Hz, 1H), 6.75 (d, J=7.5 Hz, 1H), 6.52 (s, 1H), 6.23 (s, 1H), 5.14 (d, J=15.9 Hz, 1H), 4.95 (d, J=9.0 Hz, 1H), 4.88 (d, J=15.9 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.23-4.18 (m, 2H), 4.15-4.11 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.8, 155.4, 144.8, 141.8, 138.5, 137.0, 132.3, 131.4 (q, J=32.4 Hz), 130.7, 129.7, 129.0, 124.9 (q, J=3.7 Hz), 124.25, 124.22 (q, J=3.7 Hz), 124.0 (q, J=272.4 Hz), 123.8, 120.9, 111.6, 109.1, 99.6, 80.2, 64.7, 64.0, 58.2, 43.8; MS (ES+) m/z 453.9 (M+1).
Reaction SMILES: O=[C:2]1[NH:9][CH2:8][CH:7]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:3]1[CH2:4][CH2:5][CH2:6]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1COCC1>[S:27]=[C:2]1[NH:9][CH2:8][CH:7]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:3]1[CH2:4][CH2:5][CH2:6]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N1C2CCCC1C(=O)NC2
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2CCCC1C(=S)NC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 144.4 %

Procedure:
To a solution of tert-butyl 2-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate (733 mg, 3.05 mmol) in THF (10 mL) was added Lawesson's reagent (700 mg, 1.68 mmol). The mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in EtOAc and washed 3× with saturated aqueous NaHCO3 solution. The combined aqueous layers were extracted several times with EtOAc and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on SiO2 eluting with EtOAc/Hex to afford the title compound as a colorless foam (622 mg, 79%). MS (ESI): mass calcd. C12H20N2O2S, 256.12; m/z found, 257.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.54-8.20 (m, 1H), 5.23-4.97 (m, 1H), 4.66-4.33 (m, 1H), 3.81-3.63 (m, 1H), 3.28-3.17 (m, 1H), 2.22-2.11 (m, 1H), 1.90-1.58 (m, 5H), 1.47 (s, 9H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:12]=[CH:13][C:14]([NH:16][CH2:17][C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[C:20]#[N:21])=[CH:15][C:10]=2[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-:26].[Na+].Cl>O1CCOCC1>[O:1]=[C:2]1[C:11]2[CH:12]=[CH:13][C:14]([NH:16][CH2:17][C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[C:20]([NH2:21])=[O:26])=[CH:15][C:10]=2[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: N#Cc1ccccc1CNc1ccc2c(=O)[nH]c3ncccc3c2c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: NC(=O)c1ccccc1CNc1ccc2c(=O)[nH]c3ncccc3c2c1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 7 %

Procedure:
462 (51 mg, 0.16 mmol) and NaOH (1M, aqueous, 2 mL) were suspended in dioxane (2 mL), and stirred for 30 minutes at 150° C. The reaction mixture was acidified with HCl (2M in diethyl ether, 1.6 mL), concentrated, and purified via prep-LC-MS to provide 481 (4 mg, 7% yield) as a white powder. LC-MS (M+H=345, obsd.=345). 1H NMR (400 MHz, DMSO-D6) δ 8.56 (d, J=7.9, 1H), 8.43 (d, J=3.1, 1H), 8.05 (d, J=8.6, 1H), 7.94 (d, J=6.7, 1H), 7.45 (s, 1H), 7.25 (m, 3H), 6.92 (d, J=8.6, 1H), 6.66 (s, 1H), 5.98 (s, 2H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH2:19][CH2:20][N+:21]([O-])=O)=[CH:16][CH:17]=3)[C:12]3[CH:24]=[C:25]([Cl:28])[CH:26]=[N:27][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Ni]>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH2:19][CH2:20][NH2:21])=[CH:16][CH:17]=3)[C:12]3[CH:24]=[C:25]([Cl:28])[CH:26]=[N:27][C:11]2=3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])CCc1ccc2c(c1)c1cc(Cl)cnc1n2S(=O)(=O)c1ccccc1
Agent: [Ni]
Solvent: CO
Product: NCCc1ccc2c(c1)c1cc(Cl)cnc1n2S(=O)(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 15 (72 mg, 0.17 mmol) in MeOH (1 mL) was added a catalytic amount of Ni Raney. This mixture was stirred overnight at 50° C. under nitrogen atmosphere. The solids were filtered off and the filtrate evaporated to give 16. 1H-NMR (300 MHz, DMSO-d6): δ 8.78 (d, 1H, J=2.4 Hz), 8.60 (d, 1H, J=2.4 Hz), 8.30 (d, 1H, J=8.7 Hz), 8.14 (bs, 1H), 8.04 (d, 1H, J=8.7 Hz); 8.02 (d, 1H, J=7.2 Hz), 7.70 (t, 1H, J=7.2 Hz), 7.59-7.54 (m, 3H), 6.74 (bs, 2H); 3.05 (m, 2H), 2.96 (m, 2H); MS (ESI) m/z 386 [M-NH3+], 386 [M+H+], 408 [M+Na+].
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C@H:24]1[O:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][C:33]([S:36][C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[C:32]([F:56])[CH:31]=2)[CH2:25]1)=[N+]=[N-].O>C1COCC1>[NH2:20][CH2:23][C@@H:24]1[O:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][C:33]([S:36][C:37]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[C:32]([F:56])[CH:31]=2)[CH2:25]1
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2ccc(SC(c3ccccc3)(c3ccccc3)c3ccccc3)c(F)c2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC[C@H]1CN(c2ccc(SC(c3ccccc3)(c3ccccc3)c3ccccc3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triphenylphosphine (2.82 g, 10.8 mmol) was added portionwise to a solution of 5-(S)-azidomethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]oxazolidine-2-one (5.00 g, 9.79 mmol) in THF (40 mL), and the mixture stirred for 2 h at r.t. Water (1.41 mL, 78.3 mmol) was added, and the mixture heated at 40° C. overnight. Solvent was removed under vacuum, and the oily residue purified by column chromatography (eluent: DCM, then 10% MeOH in DCM). Yield 3.56 g (75%). MS (m/z): [M+H]+=485.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][NH:12][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=2[N+:23]([O-])=O)[CH2:7][CH2:6]1)=[O:4].[O-]S(S([O-])=O)=O.[Na+].[Na+].[O:34]1CCOC[CH2:35]1>[OH-].[NH4+]>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][N:12]2[C:13]3[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=3[NH:23][C:35]2=[O:34])[CH2:7][CH2:6]1)=[O:4]
Reactant: C1COCCO1
Reactant: COC(=O)[C@H]1CC[C@H](CNc2cc(C(F)(F)F)ccc2[N+](=O)[O-])CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Product: COC(=O)[C@H]1CC[C@H](Cn2c(=O)[nH]c3ccc(C(F)(F)F)cc32)CC1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
trans 4-[(2-Nitro-5-trifluoromethyl-phenylamino)-methyl]-cyclohexane carboxylic acid methyl ester (1.8 g, 5.0 mmol) was dissolved in 35 ml of a mixture 4:1 of dioxane and 25% ammonium hydroxide. Na2S2O4 (2.6 g, 15.0 mmol) was added and the mixture was stirred at 50° C. for 4 hours. The solvent was evaporated and the crude dissolved in 20 ml MeOH. 4 ml of concentrated (37%) HCl and 10 ml of water were added and the mixture was stirred at 50° C. for three hours and then at room temperature overnight. The MeOH was evaporated under reduced pressure and 20 ml of DCM and 5 ml of a saturated solution of Na2CO3 were added. The organic phase was separated and the solvent removed. The crude material was dissolved in THF (40 ml) and 1,1-carbonyldiimidazole (1.62 g, 10 mmol) was added. The mixture was stirred at room temperature overnight. The solvent was evaporated and the crude dissolved in DCM (20 ml). The organic solution was washed with 10 ml of 1M HCl and the solvent removed under reduced pressure. The titled compound was purified by silica column using ethyl acetate cyclohexane 1:1 as eluent. 0.87 g (yield 49%) of the titled compound were isolated.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:18][C:19](=O)[CH:20]([CH3:22])[CH3:21])[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)=[CH:5][CH:4]=1.[NH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.CN(C)C=O>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[C:19]([CH:20]([CH3:22])[CH3:21])[N:24]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:10]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: NN1CCCCC1
Reactant: CC(C)C(=O)CC(C(=O)c1ccccc1)c1ccc(F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1cc(-c2ccc(F)cc2)c(-c2ccccc2)n1N1CCCCC1

Procedure:
7.5 ml of conc. hydrochloric acid are added to 22.5 g (75 mmol) of the compound from Example 2 and 25 g (250 mmol) of N-aminopiperidine in 200 ml of toluene AR and 30 ml of dimethylformamide and the mixture is heated to reflux in a water separator for 48 hours. The mixture is cooled, diluted using 200 ml of ethyl acetate, and extracted three times using 1N hydrochloric acid and twice using saturated sodium hydrogen carbonate solution. The organic phase is dried over magnesium sulphate and concentrated in vacuo, and the residue is chromatographed on a column (silica gel 70-230 mesh, using ethyl acetate/petroleum ether 95:5).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:18])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.Br[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1>C1COCC1.CCOC(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Ni+2].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:26]1[CH:27]=[CH:28][CH:29]=[N:30][C:25]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:18])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Brc1ncccn1
Reactant: OC1(c2ccc(I)cc2)CCC2(CC1)OCCO2
Agent: [Ni+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: CC(C)[Mg]Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC1(c2ccc(-c3ncccn3)cc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
To a solution of 8-(4-iodo-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol (450.0 mg, 1.249 mmol) in THF (1.0 mL) at room temperature was added dropwise isopropylmagnesium chloride (2.0 M in THF, 1.37 mL) and the reaction mixture was stirred at room temperature for 30 mins. To another flask charged with nickel acetylacetonate (20 mg, 0.06 mmol) and 1,3-bis(diphenylphosphino)-propane (26 mg, 0.062 mmol) suspended in THF (3 mL) under N2 was added 2-bromopyrimidine (199 mg, 1.25 mmol). The resulting mixture was stirred at room temperature until it is clear. This mixture was transferred into the degassed Grignard solution prepared above. The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, quenched with water, washed with brine, dried over Na2SO4, and concentrated. The residue was columned on silica gel, eluting with hexane/EtOAc (2/1), to gave the desired compound (270 mg, 69%) as a white solid. LCMS: 313.1, (M+H, 100%). 1H NMR (CDCl3): δ 8.86 (d, 2H), 8.46 (dd, 2H), 7.71 (dd, 2H), 7.24 (t, 1H), 4.05 (d, 4H), 2.30 (dt, 2H), 2.18 (dt, 2H), 1.90 (m, 2H), 1.78 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:4][C:5]3[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]4[CH2:20]CCC[CH2:16]4)[C:11](O)=[O:12])[C:7](=[O:21])[C:6]=3[O:22][C:23]=2[CH:24]=[CH:25][CH:26]=1.C(Cl)(=O)C(Cl)=O.[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=1>C(Cl)Cl.O>[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([NH:40][C:11](=[O:12])[C@@H:10]([N:8]2[CH2:9][C:5]3[CH2:4][C:3]4[C:2]([Cl:1])=[CH:26][CH:25]=[CH:24][C:23]=4[O:22][C:6]=3[C:7]2=[O:21])[CH2:14][CH:15]([CH3:16])[CH3:20])=[N:38][CH:39]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC2=C(Oc3cccc(Cl)c3C2)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)C[C@@H](C(=O)Nc1ccc(Cl)cn1)N1CC2=C(Oc3cccc(Cl)c3C2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.4 %

Procedure:
A solution of (S)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (200 mg, 2.1 mmol) (from Example 3, Step 1c), in methylene chloride (10 mL) was treated with oxalyl chloride (0.12 mL, 1.07 mmol) at 0° C. The mixture was warmed to 25° C. and stirred for additional 2 hours. Then, the reaction mixture was cooled to 0° C., and N,N′-diisopropylethyl amine (0.61 mL, 3.57 mmol) and commercially available 5-chloro-pyridin-2-ylamine (137 mg, 1.07 mmol), were added. The reaction mixture was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradiant elution, afforded (S)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid (5-chloro-pyridin-2-yl)-amide (145 mg, 36.3%), as a white solid. 1H NMR (DMSO-d6) δ: 11.11 (s, 1H), 8.40 (d, J=2.4 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.90 (dd, J=8.8, 2.4 Hz, 1H), 7.21-7.38 (m, 2H), 7.09 (dd, J=7.1, 2.2 Hz, 1H), 5.06 (dd, J=10.5, 4.6 Hz, 1H), 4.42 (d, J=18.6 Hz, 1H), 4.07 (d, J=19.1 Hz, 1H), 3.75 (s, 2H), 1.77-1.89 (m, 1H), 1.61-1.73 (m, 1H), 1.46 (br. s., 1H), 0.93 (t, J=6.4 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH2:17]([N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[CH3:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2n1Cc1ccccc1

Procedure:
To a flask were added 2.5 g 2-methylbenzimidazole, 3.9 g potassium carbonate, 60 ml N,N-dimethylformamide and the mixture was stirred under nitrogen. 3.6 g Benzyl chloride were added and the mixture was heated to 60 C for 16 hours. The reaction was quenched with 80 ml water and cooled to 22 C. The product was extracted twice with 50 ml ethyl acetate and washed with water. Following removal of solvent, the product was dissolved in 100 ml hexane and washed with two portions of water. After drying the hexane layer over sodium sulfate, the mixture was filtered and stripped down to an orange oil.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH2:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([C:27]([F:30])([F:29])[F:28])=[C:21]([S:23](Cl)(=[O:25])=[O:24])[CH:22]=3)[N:16]=2)[N:13]=1)[CH3:6]>C(#N)C>[CH:1]1([NH:4][S:23]([C:21]2[CH:22]=[C:17]([C:15]3[N:16]=[C:11]4[CH:10]=[CH:9][C:8]([O:7][CH2:5][CH3:6])=[N:13][N:12]4[CH:14]=3)[CH:18]=[CH:19][C:20]=2[C:27]([F:30])([F:28])[F:29])(=[O:24])=[O:25])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CCOc1ccc2nc(-c3ccc(C(F)(F)F)c(S(=O)(=O)Cl)c3)cn2n1
Solvent: CC#N
Product: CCOc1ccc2nc(-c3ccc(C(F)(F)F)c(S(=O)(=O)NC4CC4)c3)cn2n1
Temperature: 60 °C
Reaction time: 12 h
Yield: 66.7 %

Procedure:
A solution of cyclopropanamine (0.025 mL, 0.369 mmol) in acetonitrile (1 mL) is added 5-(6-ethoxyimidazo[1,2-b]pyridazin-2-yl)-2-(trifluoromethyl)benzene-1-sulfonyl chloride (0.123 mmol). The mixture is stirred at 60° C. for 12 hours. The mixture is concentrated to dryness and then purified via chromatography using a gradient of hexanes to EtOAc to afford 0.035 g (67%) of the title compound as a white solid: LCMS (m/z)=427.4 [M+H]+, tR=2.76 min. (compound same as Example 212)
Reaction SMILES: [NH2:1][C:2]([C:4]1[O:5][CH:6]=[CH:7][C:8]=1[NH:9][C:10](=O)OC(C)(C)C)=[O:3].C(Cl)Cl>CN(C=O)C>[N:9]1[C:8]2[CH:7]=[CH:6][O:5][C:4]=2[C:2](=[O:3])[NH:1][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccoc1C(N)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=c1[nH]cnc2ccoc12
Temperature: 80 °C
Yield: 64.4 %

Procedure:
tert-Butyl 2-(aminocarbonyl)-3-furylcarbamate (Intermediate 82) (3.38 g) was stirred in DMF (25 mL) and DCM (25 mL) for 30 minutes. The solvent was removed and the crude product was heated at 80° C. in triethylorthoformate (20 mL) for 30 minutes. The mixture was cooled, poured into ether (100 mL) collected by filtration and washed with ether to afford a first crop of the title compound as a pale yellow solid (1.31 g, 65%). The filtrate was evaporated and triturated with EtOAc to afford a further crop (296 mg, 15%);
Reaction SMILES: Br.[NH2:2][C:3]1[C:8]([Cl:9])=[N:7][CH:6]=[CH:5][N:4]=1.Br[CH2:11][CH:12](OCC)OCC.C([O-])([O-])=O.[Na+].[Na+]>CO.O>[Cl:9][C:8]1[C:3]2[N:4]([CH:11]=[CH:12][N:2]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CCOC(CBr)OCC
Reactant: Nc1nccnc1Cl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Clc1nccn2ccnc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
HBr (48% in H2O) is added to a solution of 2-amino-3-chloropyrazine (1.2 g, 9.26 mmol) and BrCH2CH(OEt)2 (1.6 mL, 10 mmol) in MeOH and H2O (5 mL and 10 mL) at RT. The mixture is stirred for 24 h at RT and then heated to 40° C. for 48 h. The pH is adjusted to 7 with sat. Na2CO3. The mixture is extracted with CH2Cl2. The organic phase is dried over anhydrous Na2SO4. The product is purified by silica gel column chromatography (4% MeOH in CH2Cl2) to give the title compound as an off white solid.
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1[Cl:13])([O-])=O.[OH-].[Na+].[CH2:16]([O:20][C:21]1[C:26]([NH2:27])=[CH:25][C:24]([NH:28][C:29](=[O:31])[CH3:30])=[CH:23][CH:22]=1)[CH2:17][CH2:18][CH3:19].C(NC1C=C(NC(=O)C)C=CC=1OCCCC)(=O)C.NC1C=C(N)C=CC=1OCCCC>C(O)CCC>[ClH:13].[CH2:16]([O:20][C:21]1[C:26]([NH2:27])=[CH:25][C:24]([NH:28][C:29](=[O:31])[CH3:30])=[CH:23][CH:22]=1)[CH2:17][CH2:18][CH3:19]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: CCCCOc1ccc(N)cc1N
Agent: CCCCOc1ccc(NC(C)=O)cc1N
Agent: CCCCOc1ccc(NC(C)=O)cc1NC(C)=O
Solvent: CCCCO
Product: Cl
Reaction time: 1 h

Procedure:
The dark butanolic solution, obtained according to European Pat. No. 0,011,048 by reaction of 213 parts of 2,4-dinitrochlorobenzene with 632 parts of n-butanol and 42 parts of sodium hydroxide, after hydrogenation and acetylation, of 6-n-butoxy-3-acetylamino-aniline which, according to HPLC analysis, contains, in addition to 195 parts of target product, 11.9 parts of 2,4-bis-acetylamino-1-n-butoxy-benzene and 8.1 parts of 2,4-diamino-1-n-butoxybenzene, in addition to unknown decomposition products formed by oxidation, is precipitated by gassing with 35-40 parts of hydrogen chloride at 20°-30° C. for one hour and, after cooling to 0°-5° C., the precipitate is filtered off with suction, washed twice with 50 parts of methanol each time and dried in vacuo. 221.2 parts of 6-n-butoxy-3-acetylamino-aniline hydrochloride are obtained which, besides about 3% of magnesium chloride, contains no impurities at all which can be detected by HPLC analysis (purity by diazotization: 95.8%). This corresponds to a yield of 214.1 parts of 100% pure 6-n-butoxy-3-acetylamino-aniline hydrochloride (82.8% of theory, based on 2,4-dinitrochlorobenzene).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4([C:31]#[N:32])[CH2:30][CH2:29]4)[CH:23]=3)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[N:5]=2.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C.CO.N>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:31]([C:28]1([C:24]2[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=2)[C:21]([NH:20][C:14]2[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([O:11][C:6]3[N:5]=[C:4]4[S:3][C:2]([NH:1][C:38](=[O:37])[CH2:39][OH:40])=[N:10][C:9]4=[CH:8][CH:7]=3)[CH:13]=2)=[O:33])[CH2:30][CH2:29]1)#[N:32]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(N)sc2n1
Agent: CN(C)c1ccncc1
Agent: N
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(NC(=O)CO)sc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methoxyphenyl}-3-(1-cyanocyclopropyl)benzamide (313 mg, 683 μmol) produced in Example C1(vii) in pyridine (10 mL) were added 2-chloro-2-oxoethyl acetate (254 mg, 1.86 mmol) and N,N-dimethylpyridine-4-amine (85 mg, 696 μmol), and the mixture was stirred at room temperature for 2 hr. Methanol (10 mL) was added to the reaction solution, the mixture was stirred for 1 hr, conc. aqueous ammonia (4 mL) was added, and the mixture was further stirred for 1 hr. The reaction solution was concentrated under reduced pressure, and residue was dissolved in tetrahydrofuran (10 mL) and ethyl acetate (50 mL). The solution was washed with 0.1N hydrochloric acid (50 mL), saturated aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→80/20), and recrystallized from a mixture of ethyl acetate and diisopropyl ether to give the title compound (125 mg, 35%) as colorless crystals.
Reaction SMILES: [Li+].[OH-].[OH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24].C(O)(=O)C(O)=O>C1COCC1.O>[OH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCO
Agent: O=C(O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCCCCCCCCCCCCCCCCO
Reaction time: 10 h
Yield: 91.3 %

Procedure:
LiOH (45 μL of a 1 M aqueous soln) was added to a stirring, room temperature solution of the above ester (5.2 mg, 0.015 mmol) in THF/H2O (5:1, 1.5 mL). After 10 hours, the pH was adjusted to 4 using 1 M oxalic acid and the reaction mixture was extracted with EtOAc (3×4 mL). The combined organic extracts were evaporated in vacuo to give 20-hydroxyeicosanoic acid (55) (4.5 mg, 92%) as a solid, mp 86° C. 1H NMR (250 MHz, CD3OD): δ1.20-1.45 (m, 30H), 1.45-1.63 (m, 4H), 2.28 (t, J˜7.4 Hz, 2H), 3.55 (t, J˜6.5 Hz, 2H); TLC: EtOAc/hexanes (3:7), Rf˜0.08. 19-Hydroxynonadecanoic Acid (56) was prepared in an analogous manner from ester 8a.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[CH3:17][NH:18][CH3:19]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:18]([CH3:19])[CH3:17])(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: CNC
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Product: CN(C)S(=O)(=O)c1ccc(Br)cc1OC(F)(F)F
Reaction time: 16 h
Yield: 81 %

Procedure:
According to general procedure A, 4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03 mmol) and dimethylamine (10 mL, 33% in ethanol) were stirred in sealed tube for 16 hours. 4-Bromo-N,N-dimethyl-2-trifluoromethoxy-benzenesulfonamide (0.29 g, 81%) was provided after purification. Mp. 55-58° C. MS (ESI) m/z 348.14.