Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[CH2:21]([N:1]([CH2:8][C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)[C@H:2]1[CH2:3][CH2:4][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](N)CC1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A stirred suspension of 13A.HCl (5.12 g, 24.65 mmol) in acetonitrile (75 mL) was treated with K2CO3 (13.63 g, 99 mmol) and (bromomethyl)benzene (7.32 mL, 61.6 mmol). The resulting suspension was stirred at 80° C. overnight. Upon cooling, the solid was filtered off and filtrate was concentrated. The residue was purified by Isco silica column (80 g) eluted with ethyl acetate-hexane: 0%-20%. Concentration of the appropriate fractions provided 13B (7.92 g, 91% yield) as a colorless oil. MS (ES): m/z=352.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 7.08-7.34 (m, 10H); 4.01 (q, 2H, J=7.1 Hz); 3.55 (s, 4H); 2.40-2.49 (m, 1H); 2.06-2.14 (m, 1H); 1.86-2.00 (m, 2H); 1.24-1.38 (m, 2H); 1.18 (t, 3H, J=7.1 Hz).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:7][S:8]([OH:11])(=O)=[O:9].[Cl:12][C:13]1[O:14][CH:15]=[CH:16][CH:17]=1>>[Cl:12][C:13]1[O:14][C:15]([S:8]([Cl:7])(=[O:11])=[O:9])=[CH:16][CH:17]=1
Reactant: Clc1ccco1
Reactant: O=S(=O)(O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(Cl)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
Phosphorus pentachloride (40.53 g, 0.1947 mol) was added portionwise (caution, foaming) over 5 min at 25° C. to chlorosulfonic acid (56.8 g, 32.4 mL, 0.487 mol) and the resulting solution was stirred at 25° C. for 10 min. Then, 2-chlorofuran (20.0 g, 0.1947 mol) was added in one portion and the resulting dark suspension was heated to 55° C. for 1.0 h during which time foaming occurred and subsided. The reaction mixture was then poured onto ice and the resulting suspension was extracted with CH2Cl2 (250 mL). The organic was filtered through a pad of celite, washed with brine (70 mL) and dried over MgSO4. The solvent was removed in vacuo to provide 5-chlorofuran-2-sulfonyl chloride as a black oil (14.1 g, 36.02%). 1H-NMR (DMSO-d6, 400 MHz) δ 7.05 (d, 1H); 6.35 (d, 1 H).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]([C:8]1[CH:9]=[C:10]([NH:14][C:15]([C:17]2[CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[CH:20]=[CH:21]C=2O)=[O:16])[CH:11]=[CH:12][CH:13]=1)#[N:7]>O1CCCC1.N1C=CC=CC=1>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[C:19]1[CH:20]=[CH:21][C:5]2[O:4][C:2](=[O:3])[N:14]([C:10]3[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=3)[C:6]#[N:7])[C:15](=[O:16])[C:17]=2[CH:18]=1
Reactant: COC(=O)Cl
Reactant: N#Cc1cccc(NC(=O)c2cc(-c3ccc(F)cc3F)ccc2O)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: N#Cc1cccc(-n2c(=O)oc3ccc(-c4ccc(F)cc4F)cc3c2=O)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 49 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 9 (1.4 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% 1HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 21.
Reaction SMILES: [P:1](Cl)([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])([O:3][CH2:4][CH:5]=[CH2:6])=[O:2].[F:17][C:18]([F:31])([F:30])[C:19]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]2[C:20]=1[CH2:21][CH2:22][C:23]2=[O:29].C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:1]([O:28][C:25]1[CH:26]=[CH:27][C:19]([C:18]([F:17])([F:30])[F:31])=[C:20]2[C:24]=1[C:23](=[O:29])[CH2:22][CH2:21]2)([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])([O:3][CH2:4][CH:5]=[CH2:6])=[O:2]
Reactant: C=CCOP(=O)(Cl)Oc1ccccc1OC
Reactant: O=C1CCc2c(C(F)(F)F)ccc(O)c21
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CCOP(=O)(Oc1ccccc1OC)Oc1ccc(C(F)(F)F)c2c1C(=O)CC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
O-Allyl O-(2-methoxyphenyl) chlorophosphate (0.015 mole) dissolved in dry toluene (80) is charged into a glass reaction vessel equipped with a stirrer, thermometer and gas inlet tube. The solution is cooled to about 0° C. and a solution of 4-trifluoromethyl-7-hydroxyindan-1-one (0.015 mole) and triethylamine (0.0175 mole) in toluene (20 ml) is slowly added with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 8 hours. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed solution is then dried and is stripped of solvent leaving a residue. This residue is chromatographed through a 200 ml clay column using ethyl acetate and hexane mixtures as the eluant. Ten separate fractions each containing increasing percentages of ethyl acetate are collected and analyzed by IR for the product. The appropriate fractions are then combined stripped of solvent and subjected to vacuum to yield the desired product O-allyl O-(2-methoxyphenyl) O-(4-trifluoromethylindan-1-on-7-yl) phosphate.
Reaction SMILES: C([O:8][C:9](=[O:22])[C@H:10]([CH3:21])[NH:11][C@H:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:13][CH2:14][CH3:15])C1C=CC=CC=1.C.[H][H]>C(O)C>[CH2:19]([O:18][C:16]([C@@H:12]([NH:11][C@H:10]([C:9]([OH:22])=[O:8])[CH3:21])[CH2:13][CH2:14][CH3:15])=[O:17])[CH3:20]
Reactant: CCC[C@H](N[C@@H](C)C(=O)OCc1ccccc1)C(=O)OCC
Reactant: [H][H]
Solvent: CCO
Product: CCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Yield: 59.5 %

Procedure:
A solution of N-[1-(S)-ethoxycarbonyl-1-butyl]-(S)-alanine benzyl ester (14.5 g, as obtained in Step-I) in ethanol (150 ml) was hydrogenated in the presence of 10% palladised charcoal (0.8 g) under 40-45 psi hydrogen pressure for 1.5 to 2 hrs. The reaction mixture was concentrated under reduced pressure to give an oil. Crystallization from a mixture of acetonitrile and ethanol (1:3) gave 6.1 g the title compound
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[CH2:13]=O.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>ClCCl.CCCCCC>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([S:12][CH2:13][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:10][CH:11]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: C=O
Reactant: C1COCCN1
Reactant: Sc1ccc(-n2cnnn2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: c1cc(-n2cnnn2)ccc1SCN1CCOCC1

Procedure:
Following the general procedure of Example 10, p-(1H-tetrazol-1-yl)benzenethiol is treated with formalin and morpholine to give the 4-[p-(1H-tetrazol-1-yl)phenylthiomethyl]morpholine as white crystals from dichloromethane-hexane, m.p. 118.5°-121° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[N:14]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][CH:27]=[C:20]3[C:21]=2[C:16](=[CH:17][CH:18]=[CH:19]3)[C:15]1=O)([O-])=O.[H][H]>[Pd].C(O)(=O)C>[F:13][C:10]([F:12])([F:11])[C:8]1[CH:7]=[CH:6][C:5]2[N:14]3[C:23](=[O:24])[C:22]4=[CH:25][CH:26]=[CH:27][C:20]5[C:21]4=[C:16]([CH:17]=[CH:18][CH:19]=5)[C:15]3=[N:1][C:4]=2[CH:9]=1
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: O=c1c2cccc3cccc(c32)c2nc3cc(C(F)(F)F)ccc3n12
Reaction time: 1.5 h
Yield: 59 %

Procedure:
2-[2-nitro-4-(trifluoromethyl)phenyl]-1H-benz[de]isoquinoline-1,3(2H)-dione, 134.3 g. (0.347 m.), was hydrogenated at 55° C. in 600 ml. of glacial acetic acid with 15 g. of palladium-on-carbon (5 percent) at 60 psi. The temperature rose to about 100° C., and after 1.5 hours, three equivalents of hydrogen were absorbed with the temperature returning to room temperature. The reaction mixture was heated to boiling and filtered to remove the catalyst. Upon cooling, the precipitated product was collected and washed with 2B ethanol. Recrystallization from N,N-dimethylformamide yielded about 69.2 g. (59 percent yield) of 11-(trifluoromethyl)-7H-benzimidazo[2,1-a]benz[de]isoquinoline-7-one, m.p. about 212°-214° C.
Reaction SMILES: [CH2:1](Cl)[C:2](=[CH2:4])[CH3:3].OS(O)(=O)=O.[C:11]1([CH3:18])[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1>>[CH3:3][C:2]1([CH3:4])[C:15]2[C:16](=[C:11]([CH3:18])[CH:12]=[C:13]([CH3:17])[CH:14]=2)[C:2]([CH3:4])([CH3:3])[CH2:1][CH2:1]1
Reactant: Cc1cccc(C)c1
Reactant: C=C(C)CCl
Agent: O=S(=O)(O)O
Product: Cc1cc(C)c2c(c1)C(C)(C)CCC2(C)C
Temperature: 20 °C
Reaction time: 3 h

Procedure:
The starting material 1,1,4,4,5,7-hexamethyl-1,2,3,4-tetrahydronaphthalene is prepared by substantially following the procedures of Fehr et al., U.S. Pat. No. 5,162,588. Specifically, in a 1 liter three-neck flask, equipped with a mechanical stirrer and kept under nitrogen, 150.0 g of methallyl chloride are slowly (2 hrs) added to a mixture of meta-xylene (490.9 g) and H2SO4 (30.0 g), while the temperature is maintained at 20° C. After 3 hrs, the H2SO4 is decanted and the organic phase is washed with, in succession, water, an aqueous solution saturated with NaHCO3, and an aqueous solution saturated with NaCl. The excess of meta-xylene is recovered through distillation, and the residue is distilled. A mixture of two isomers, 1-(2-chloro-1,1-dimethylethyl)-2,4-dimethylbenzene and 1-(2-chloro-1,1-dimethylethyl)-3,5-dimethylbenzene, is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:13][CH3:14])[N:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:15](Cl)=[O:16])[CH3:2].[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:13][CH3:14])[N:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:15]([NH:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1)=[O:16])[CH3:2]
Reactant: Nc1nccs1
Reactant: CCOc1nc2c(cnn2CC)nc1C(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOc1nc2c(cnn2CC)nc1C(=O)Nc1nccs1

Procedure:
A mixture of 15.3 g. of 6-ethoxy-1-ethyl-1H-pyrazolo-[3,4-b]pyrazine-5-carbonyl chloride (0.06 mol.), 6.6 g. of 2-amino-thiazole (0.66 mol.) and 9.1 ml. of triethylamine (0.66 mol.) in 400 ml. of dry benzene are refluxed for 21/2 hours. After cooling the reaction mixture, the precipitated triethylamine hydrochloride is filtered off and the filtrate is evaporated to dryness. The crude 6-ethoxy-1-ethyl -N-2-thiazolyl-1H-pyrazolo-[3,4-b]pyrazine-5-carboxamide is recrystallized from ethyl acetate, m.p. 151°-152°, yield 9.9 g. (52 %).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:17][C:18]([CH3:20])=[O:19].Cl>C1COCC1>[OH:19][C:18]([C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6])([CH3:20])[CH3:17]
Reactant: CC(C)=O
Reactant: O=C(O)c1cc(Br)cc(S(F)(F)(F)(F)F)c1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon, 7.6 g (23.3 mmol) of the compound of Example 15A were dissolved in 76 ml of THF, and a few granules of 4 Å molecular sieve were added. The mixture was then cooled to 0° C., and 53.7 ml (69.8 mmol) of a 1.3 M solution of 2-propylmagnesium chloride/lithium chloride complex in THF were slowly added dropwise. After the addition had ended, the reaction mixture was stirred at 0° C. for another 30 min. 2.6 ml (34.9 mmol) of anhydrous acetone were then added, and the reaction was stirred at 0° C. for another 1 h. 90 ml of 1 M hydrochloric acid were then added, and the reaction was allowed to slowly warm to RT over a period of 40 min. The mixture was then extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The residue was triturated with petroleum ether with a little diethyl ether added, filtered off and dried. This gave 5.8 g (80% of theory) of the title compound as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([OH:18])=O)=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:43]1([C:49]2[O:53][N:52]=[C:51]([NH2:54])[CH:50]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CN1CCOCC1>CN1C(=O)CCC1>[O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([NH:54][C:51]4[CH:50]=[C:49]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)[O:53][N:52]=4)=[O:18])=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1
Reactant: O=C(O)c1ccc2cc3n(c2c1)CCCNC3=O
Reactant: Nc1cc(-c2ccccc2)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: O=C(Nc1cc(-c2ccccc2)on1)c1ccc2cc3n(c2c1)CCCNC3=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.2 %

Procedure:
A 2-5 mL microwave reactor vial is charged with a solution of 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylic acid (Intermediate J, 25 mg, 0.10 mmol) in NMP (2 mL). HATU (47 mg, 0.12 mmol) is added and the mixture is stirred at room temperature for 30 min. 5-phenyl-3-aminoisoxazole (66 mg, 0.41 mmol) and N-methylmorpholine (41 mg, 0.41 mmol) are added and the vial is sealed with a Teflon lined septa cap and is irradiated in a microwave reactor at 100° C. for 30 min then at 150° C. for 90 min. The mixture is purified via preparative HPLC using a gradient elution from 10-90% acetonitrile/water with 0.1% TFA to obtain the title compound (2 mg, 5%). LCMS: 387.20 (M+H+). (System V1)
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[I:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[CH:14]2.C([O-])([O-])=O.[Cs+].[Cs+].O>CS(C)=O>[I:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)[N:15]=[CH:14]2
Reactant: Ic1ccc2[nH]ncc2c1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Ic1ccc2c(cnn2CCN2CCCC2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 52.3 %

Procedure:
1-(2-Chloroethyl)pyrrolidine hydrochloride (9.88 g, 58.1 mmol) was added to a suspension of 5-iodo-1H-indazole (8.86 g, 36.3 mmol) and Cs2CO3 (50.8 g, 456 mmol) in anhydrous DMSO (100 mL) and the resulting suspension was stirred at 25° C. for 14 h. H2O (100 mL) was added and the aqueous solution was extracted with EtOAc (3×200 mL). The combined organic extracts were washed with brine (2×200 mL), dried over MgSO4 and concentrated under reduced pressure. Flash chromatography on silica gel (9:1 Et2O/Et3N) afforded 6.473 g (52%) of the title compound as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.08 (br d, J=13 Hz, 1H), 7.91 (d, J=0.9 Hz, 1H), 7.60 (dd, J=87, 1.3 Hz, 1H), 7.25 (d, J=8.7 Hz, 1H), 4.50 (t, J=7.4 Hz, 2H), 2.98 (t, J=7.4 Hz, 2H), 2.59-2.50 (m, 4H), 1.82-1.70 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)C(C)C)(C)C.[C:45]([C:47]1[CH:76]=[CH:75][C:50]([O:51][C:52]2[C:57]([C:58]([N:60]3[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]3)=[O:59])=[CH:56][CH:55]=[C:54]([O:66][C:67]3[CH:72]=[CH:71][C:70]([C:73]#[N:74])=[CH:69][CH:68]=3)[N:53]=2)=[CH:49][CH:48]=1)#[N:46]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]([N:63]1[CH2:64][CH2:65][N:60]([C:58]([C:57]2[C:52]([O:51][C:50]3[CH:49]=[CH:48][C:47]([C:45]#[N:46])=[CH:76][CH:75]=3)=[N:53][C:54]([O:66][C:67]3[CH:68]=[CH:69][C:70]([C:73]#[N:74])=[CH:71][CH:72]=3)=[CH:55][CH:56]=2)=[O:59])[CH2:61][CH2:62]1)=[O:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: N#Cc1ccc(Oc2ccc(C(=O)N3CCNCC3)c(Oc3ccc(C#N)cc3)n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCN(C(=O)c2ccc(Oc3ccc(C#N)cc3)nc2Oc2ccc(C#N)cc2)CC1
Reaction time: 0.17 h

Procedure:
A solution of 3-tert-butoxycarbonylamino-propionic acid, 0.177 g (0.94 mmol), in 3 ml of DMF was added dropwise to a stirred suspension of 0.72 g (3.76 mmol) of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and hydroxybenzotriazole (HOBT) 0.508 g (3.76 mmol) in 5 ml of DMF at RT. That was followed by the addition of N,N-diisopropylethylamine (DIPEA) 0.242 g (1.88 mmol) while the temperature was maintained below 5. The mixture was stirred for 10 min and a solution of 4-[2,6-Bis-(4-cyano phenoxy)pyridine-3-carbonyl]piperazine (0.4 g, 0.94 mmol) in DMF (10 ml) was added followed by stirring overnight at RT. The reaction mixture was concentrated under reduced pressure and partitioned between water (150 ml) and ethyl acetate (150 ml) after the pH was adjusted to 2-3 with 6 N HCl. The organic phase was washed with 1 M Na2CO3 and saturated brine solution, dried over sodium sulphate and concentrated. The crude oily residue was purified by column chromatography using hexane-ethyl acetate (10:2) to afford 0.45 g of the required product. Percentage purity (LCMS): 10.3%. (M+1)=596.2 (with BOC).
Reaction SMILES: C([O:8][C:9]1[C:14]2[N:15]=[C:16]([CH3:19])[N:17]([CH3:18])[C:13]=2[CH:12]=[C:11]([N:20]([CH3:24])[C:21](=[O:23])[CH3:22])[CH:10]=1)C1C=CC=CC=1.C(O)(=O)C>C(O)C.[Pd]>[OH:8][C:9]1[C:14]2[N:15]=[C:16]([CH3:19])[N:17]([CH3:18])[C:13]=2[CH:12]=[C:11]([N:20]([CH3:24])[C:21](=[O:23])[CH3:22])[CH:10]=1
Reactant: CC(=O)N(C)c1cc(OCc2ccccc2)c2nc(C)n(C)c2c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)N(C)c1cc(O)c2nc(C)n(C)c2c1
Yield: 102.1 %

Procedure:
A solution of 3.1 g (18.9 mmol) N-(7-benzyloxy-2,3-dimethy-3H-benzimidazol-5-yl)-N-methyl-acetamide and 1.2 ml acetic acid in 600 ml ethanol was hydrogenated over 1.2 g 10%. Pd/C in an autoclave (5 bar H2) at 50° C. for 18 h. The catalyst was filtered off and the filtrate was concentrated in vacuo to afford 4.5 g (100%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12](CC3C=CC=CC=3)[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[H][H]>[Pd].CC(O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:14]([CH2:13][NH:12][CH2:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3ccccc3)CC2C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2CNCC2C1

Procedure:
5-Benzyl-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (19.85 g, 65.6 mmol), MeOH (200 mL), HOAc (3 mL) and 10% Pd/C Degussa type (400 mg) were charged to a Parr shaker vial and shaken for 3 days at 70 psi hydrogen gas. The resulting material was filtered through Celite® and concentrated. The crude mixture was purified by flash column chromatography (FCC), DCM to 10% MeOH/DCM containing 1% NH4OH, to afford the product. MS (ESI) mass calcd. for C11H20N2O2, 212.29; m/z found, 213.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 3.60-3.55 (m, 2H), 3.38-3.25 (m, 4H), 2.95-2.86 (m, 4H), 1.47 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[Cl:30][CH2:31][C:32](Cl)=O>ClCCl>[Cl:30][CH2:31][C:32]1[N:12]([CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NCCNc1c(N)cnc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCn1c(CCl)nc2cnc3ccccc3c21

Procedure:
A modification of the method described in Part E of Example 1 was used to treat tert-butyl 2-[(3-aminoquinolin-4-yl)amino]ethylcarbamate (15.65 g, 51.76 mmol) with triethylamine (10.82 mL, 77.64 mmol) followed by chloroacetyl chloride (4.5 mL, 57 mmol). The reaction was carried out in dichloromethane (60 mL). After the reaction mixture was filtered, the filtrate was washed with dilute aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated under reduced pressure to provide tert-butyl 2-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethylcarbamate as an amber-colored solid, which was combined with material from two other runs for use in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12](C(OC(C)(C)C)=O)[CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH3:29])=[CH:8][C:7]=1[CH3:37].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:38])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH3:29])=[CH:8][C:7]=1[CH3:37]
Reactant: COC(=O)COc1ccc(N(Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)C(=O)OC(C)(C)C)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)COc1ccc(NCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 22.7 %

Procedure:
A solution of crude (4-{tert-butoxycarbonyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-2-methyl-phenoxy)-acetic acid methyl ester (2.1 g containing 1.83 g, 3.32 mmol) in CH2Cl2 (33 ml) was treated at 0° C. with TFA (12.7 ml) and stirred at RT for 45 min. The reaction was evaporated, treated with chilled aqueous saturated NaHCO3 solution/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated. Purification by flash chromatography with a gradient of n-heptane:EtOAc 95:5 to 4:1 yielded 0.34 g of (2-methyl-4-{[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenoxy)-acetic acid methyl ester as an light yellow solid, MS: 451.3 (MH+).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:17])=[C:13]([CH2:14][CH2:15][CH3:16])[C:8]=2[O:7][N:6]=1)[CH3:4].CS(O[CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:29][CH:28]=1)(=O)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:17][CH:24]([CH3:23])[CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:29][CH:28]=3)=[C:13]([CH2:14][CH2:15][CH3:16])[C:8]=2[O:7][N:6]=1)[CH3:4]
Reactant: CCCc1c(O)ccc2c(CC)noc12
Reactant: COC(=O)Cc1ccc(CCCCOS(C)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(OC(C)CCc2ccc(CC(=O)OC)cc2)ccc2c(CC)noc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.2 %

Procedure:
A suspension of sodium hydride (15 mg, 0.36 mmole) in DMF (1.5 mL) was treated with 3-ethyl-6-hydroxy-7-propylbenz-[4,5]-isoxazole (68 mg, 0.33 mmole) and the mixture stirred at room temperature for 10 minutes under a nitrogen atmosphere. A solution of methyl 4-(4-methansulfonyloxybutyl)phenylacetate (100 mg, 0.33 mmole) in DMF (0.5 mL) was added and the mixture stirred at 80° C. for 5 hours. The cooled reaction mix was dissolved in ethyl acetate and washed with water (twice), brine, dried over magnesium sulfate and concentrated in vacuo to an oil. The crude product was purified by thin layer chromatography on silica gel eluting with hexane:ethyl acetate (4:1) to give the title compound (80 mg) as an oil. NMR (CDCl3): δ 0.97 (t, 3H); 1.44 (t, 3H); 1.71 (m, 2H); 1.87 (m, 4H); 2.71 (t, 2H); 2.88 (t, 2H); 2.97 (q, 2H); 3.62 (s, 2H); 3.71 (s, 3H); 6.89 (d, 1H); 7.18 (d, 2H); 7.22 (d, 2H); 7.39 (d, 1H).