Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([CH3:17])[CH:16]=1)[C:11]([OH:13])=O)[CH3:6].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.[NH2:61][C@@H:62]([CH2:76][C:77]1[CH:82]=[C:81]([F:83])[CH:80]=[C:79]([F:84])[CH:78]=1)[C@H:63]([OH:75])[CH2:64][NH:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[C:69]([CH2:73][CH3:74])[CH:68]=1.C(Cl)[Cl:86]>>[ClH:86].[ClH:86].[F:83][C:81]1[CH:82]=[C:77]([CH:78]=[C:79]([F:84])[CH:80]=1)[CH2:76][C@H:62]([NH:61][C:11](=[O:13])[C:10]1[CH:14]=[C:15]([CH3:17])[CH:16]=[C:8]([CH2:7][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH3:6])[CH:9]=1)[C@H:63]([OH:75])[CH2:64][NH:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[C:69]([CH2:73][CH3:74])[CH:68]=1
Reactant: ClCCl
Reactant: COCCN(C)Cc1cc(C)cc(C(=O)O)c1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C)cc(CN(C)CCOC)c2)c1
Product: Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 3-{[(2-methoxyethyl)(methyl)amino]methyl}-5-methylbenzoic acid (140 mg, 0.56 mmol) in methylene chloride (3 mL) is added HBTU (318 mg, 0.84 mmol), HOBt (114 mg, 0.84 mmol), and N, N-diisopropylethylamine (0.284 mL, 1.68 mmol), followed by (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol prepared by the method in Example SP-272 (228 mg, 0.56 mmol). The reaction mixture is stirred for 24 h at room temperature, diluted with methylene chloride, washed with water, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 10% methanol/chloroform) affords the title compound as the free base. The compound is dissolved in methanol (2 mL), and to this solution is added hydrochloric acid (5 mL, 4 N dioxane, 20 mmol). The reaction mixture is stirred for 1 h at room temperature. The reaction mixture is then diluted with ethyl ether (10 mL). The precipitate that is formed is collected by filtration to provide the title compound. ESI MS m/z 554 [M+H]+.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:52]=[CH:51][C:12]([CH2:13][CH:14]([C:41]([O:43]CC2C=CC=CC=2)=[O:42])[C:15]([C@H:27]2[CH2:32][CH2:31][C@@H:30]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:29][CH2:28]2)([OH:26])[C:16]([O:18]CC2C=CC=CC=2)=[O:17])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>[Pd].[C]>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH:14]([C:41]([OH:43])=[O:42])[C:15]([C@H:27]2[CH2:28][CH2:29][C@@H:30]([O:33][Si:34]([C:37]([CH3:38])([CH3:39])[CH3:40])([CH3:36])[CH3:35])[CH2:31][CH2:32]2)([OH:26])[C:16]([OH:18])=[O:17])=[CH:51][CH:52]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(C(=O)OCc2ccccc2)C(O)(C(=O)OCc2ccccc2)[C@H]2CC[C@@H](O[Si](C)(C)C(C)(C)C)CC2)cc1
Agent: [Pd]
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(C(=O)O)C(O)(C(=O)O)[C@H]2CC[C@@H](O[Si](C)(C)C(C)(C)C)CC2)cc1
Reaction time: 24 h

Procedure:
To a solution of dibenzyl 3-(4-((tert-butyldimethylsilyl)oxy)benzyl)-2-(cis-4-((tert-butyldimethylsilyl)oxy)-cyclohexyl)-2-hydroxysuccinate (120 mg, 0.16 mmol) was added 10% Pd-carbon (25 mg) under a nitrogen gas stream. The atmosphere in the reaction vessel was replaced five times with nitrogen gas, the reaction vessel was filled with hydrogen gas, and the system was stirred under a hydrogen gas stream for 24 hr. The mixture was filtered through Celite pad, and the catalyst was washed with ethanol (10 ml×2). The filtrate was concentrated under reduced pressure to give the title compound as an oil (90 mg, yield 99%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[Cl:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[C:34]([N:39]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[CH:33]=[CH:32]2>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:42]2[CH2:43][CH2:44][CH2:45][N:39]([C:34]3[CH:33]=[CH:32][C:31]4[C:36](=[CH:37][CH:38]=[C:29]([Cl:28])[CH:30]=4)[N:35]=3)[CH2:40][CH2:41]2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Reactant: Clc1ccc2nc(N3CCCNCC3)ccc2c1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCCN(c3ccc4cc(Cl)ccc4n3)CC2)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 6-chloro-2-[1.4]diazepan-1-yl-quinoline
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Solvent: c1ccncc1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A suspension of 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.0 g, 7.8 mmol) in pyridine (1 L) was warmed to 60° C. to dissolve the starting material. The solution was cooled to about 30° C. and then benzoyl chloride (1.1 g, 7.8 mmol) diluted with pyridine (100 mL) was slowly added. After 1 hour analysis by high performance liquid chromatography (HPLC) indicated that some starting material remained. Additional benzoyl chloride (0.3 g) was added and the reaction was warmed to 50° C. overnight. The reaction mixture was concentrated under vacuum. The resulting residue was combined with chloroform (200 mL) and 1% sodium carbonate (200 mL). The organic layer was separated and then concentrated under vacuum. The resulting residue was combined with propyl acetate (30 mL) and heated on a steam bath to dissolve the residue. The solution was allowed to cool. The resulting precipitate was isolated by filtration to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzamide as a solid, m.p. 210-212° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:33]=[CH:32][C:27]2[N:28]=[C:29]([CH3:31])[NH:30][C:26]=2[CH:25]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:33]=[CH:32][C:27]2[N:28]=[C:29]([CH3:31])[NH:30][C:26]=2[CH:25]=1
Reactant: Cc1nc2ccc(O)cc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Product: COc1cc2c(Oc3ccc4nc(C)[nH]c4c3)ncnc2cc1OCC1CCN(C)CC1
Yield: 25 %

Procedure:
Using an analogous procedure to that described in Example 189, 4-chloro-6-methoxy-7-(1-methylpiperidin-4-yl)methoxyquinazoline, (prepared as described for the starting material in Example 10); was reacted with 5-hydroxy-2-methylbenzimidazole (200 mg, 0.62 mmol) and after work-up and purification on a 10 g silica ISOLUTE column using successively dichloromethane, dichloromethane/methanol (95/5) and dichloromethane/methanol saturated with ammonia (95/5), gave 6-methoxy-4-(2-methyl-1H-benzimidazol-6-yloxy)-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (68 mg, 25%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[Cl:18][C:19]1[C:25]([CH3:26])=[CH:24][C:22]([NH2:23])=[C:21]([O:27][CH3:28])[CH:20]=1>>[Cl:18][C:19]1[C:25]([CH3:26])=[CH:24][C:22]([NH:23][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)=[C:21]([O:27][CH3:28])[CH:20]=1
Reactant: COc1cc(Cl)c(C)cc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: COc1cc(Cl)c(C)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 4-chloro-2-methoxy-5-methylaniline (50 mg, 0.289 mmol) similar to Example 117 and isolated as a tan solid (26 mg, 34%). 1H NMR (CDCl3): 9.65-9.63 (m, 1H), 8.75-8.70 (m, 2H), 8.18 (s, 1H), 7.46-7.41 (m, 1H), 7.36 (s, 1H), 6.97 (s, 1H), 6.87 (s, 1H), 3.91 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [C:1]([N@:4]1[CH2:6][CH:5]1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[CH2:11]([OH:14])[C:12]#[CH:13].B(F)(F)F.CCOCC>>[C:1]([NH:4][C@@H:5]([CH2:6][O:14][CH2:11][C:12]#[CH:13])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: C#CCO
Reactant: COC(=O)C1CN1C(C)=O
Agent: FB(F)F
Solvent: CCOCC
Product: C#CCOC[C@H](NC(C)=O)C(=O)OC
Yield: 63.2 %

Procedure:
Using (S)-methyl 1-acetylaziridine-2-carboxylate (1.50 g, 10.49 mmol), propargyl alcohol (0.92 mL, 15.74 mmol) and BF3.Et2O (1.39 mL, 11.01 mmol), and the preceding procedure gave 1.32 g (63%) of desired product as a white solid: mp 59-59.5° C.; [α]25D +65.3° (c 1, CHCl3); Rf=0.35 (3/1 EtOAc/hexanes); IR (nujol mull) 3296, 2924, 2116, 1740, 1641, 1543, 1457 cm−1; 1H NMR (CDCl3) δ 2.06 (s, CH3C(O)), 2.46 (t, J=2.4 Hz, CH2CCH), 3.78 (s, OCH3), 3.79 (dd, J=3.2, 9.4 Hz, CHH′OCH2), 3.98 (dd, J=3.0, 9.4 Hz, CHH′OCH2), 4.12 (½HH′q, J=2.4, 16.2 Hz, OCHH′C), 4.18 (½HH′q, J=2.4, 16.2 Hz, OCHH′C), 4.77-4.82 (m, CH), 6.32-6.34 (br d, J=7.2, NHCH); 13C NMR (CDCl3) δ 23.3 (CH3C(O)), 52.6 (CH), 52.8 (OCH3), 58.7 (CH2CCH), 69.6 (CH2OCH2), 75.3 (CH2CCH), 79.0 (CH2CCH), 170.1, 170.7 (2 C(O)); HRMS (ESI) 200.0917 [M+H+] (calcd. for C9H14NO4 200.0923); Anal. (C9H13NO4) Calcd.: C, 54.26%; H, 6.58%; N, 7.03%. Found: C, 54.05%; H, 6.55%; N, 6.95%.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[S:6][CH2:5][CH2:4]1.[CH3:16][C:17]([CH3:19])=O>>[C:17](=[N:1][CH2:2][CH:3]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[S:6][CH2:5][CH2:4]1)([CH3:19])[CH3:16]
Reactant: NCC1CCSc2[nH]c3ccccc3c21
Reactant: CC(C)=O
Product: CC(C)=NCC1CCSc2[nH]c3ccccc3c21
Temperature: 50 °C

Procedure:
A solution of 4-aminomethyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole (1.0 g) in acetone (10 ml) is kept at room temperature for 30 minutes and then heated at 50° C. for 5 minutes. The solution is cooled with ice. The colorless precipitate is collected by filtration to give 4-isopropylideneaminomethyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole (1.07 g) melting at 173° C. (decomp.).
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH3:8][N:9]1[CH2:22][CH2:21][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][C:19]=3[C:11]=2[CH2:10]1.Br[CH2:24][CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][CH:32]=1>O>[F:36][C:33]([F:34])([F:35])[C:30]1[N:31]=[CH:32][C:27]([CH2:26][CH2:25][CH2:24][N:13]2[C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][C:19]=3[C:11]3[CH2:10][N:9]([CH3:8])[CH2:22][CH2:21][C:12]2=3)=[CH:28][CH:29]=1
Reactant: FC(F)(F)c1ccc(CCCBr)cn1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CCCc2ccc(C(F)(F)F)nc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.6 %

Procedure:
To a suspension of DMF (5 mL) and sodium hydride (0.024 g, 0.0006 mol) at 0° C., 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.0005 mol) was added and stirred for 2 h at room temperature, Reaction mix was cooled to −20° C. and 5-(3-Bromo-propyl)-2-trifluoromethyl-pyridine (0.2 g, 0.00075 mol) was added, stirred for 1 h at 15° C. After completion (TLC), reaction mass was cooled to 0° C. and water (10 mL) was added, and extracted with ethyl acetate (3×100 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (3-4% methanol:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide desired compound as brown oil (0.04 g, 20% yield). 2,8-Dimethyl-5-[3-(6-trifluoromethyl-pyridin-3-yl)-propyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.04 g, 0.000103 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.012 g, 0.0000952 mol) in THF (1.0 mL) was added and stirred for 30 min at RT. The precipitate was filtered and dried to give oxalate salt as off white solid (0.030 g, 61% yield).
Reaction SMILES: [CH:1](Cl)([O:6][CH:7]([F:9])[F:8])[C:2]([F:5])([F:4])[F:3].[F-:11].[K+]>>[CH:7]([O:6][CH:1]([C:2]([F:5])([F:4])[F:3])[F:11])([F:9])[F:8]
Reactant: FC(F)OC(Cl)C(F)(F)F
Reactant: [F-]
Agent: [K+]
Product: FC(F)OC(F)C(F)(F)F
Temperature: 195 °C
Reaction time: 10 h
Yield: 29 %

Procedure:
12.9 g of isoflurane (FORANE® isoflurane commercially available from Anaquest Division of BOC, Inc. in Madison, Wis.) were combined with 5.5 g of potassium fluoride and 20 ml of diethylglycol and the mixture was heated with stirring for 10 hours in a glass pressure vessel at 195° C. The heated mixture was washed with ice water and the organic layer was subjected to gas chromatography, which showed the presence of the compound CHF2OCHFCF3 (29% yield).
Reaction SMILES: O[C:2]1[C:3](=[O:17])[O:4][CH:5]([CH2:13][CH2:14][CH2:15][OH:16])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[C:25](Cl)(=[O:29])[O:26][CH2:27][CH3:28].Cl>O1CCCC1>[OH:16][CH2:15][CH2:14][CH2:13][CH:5]1[O:4][C:3](=[O:17])[C:2]([C:25]([O:26][CH2:27][CH3:28])=[O:29])=[C:6]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1OC(CCCO)C(c2ccccc2)=C1O
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccccc2)C(CCCO)OC1=O

Procedure:
3-Hydroxy-5-(3-hydroxypropyl)-4-phenyl-2(5H)-furanone (25 mg) was dissolved in tetrahydrofuran (6 ml), and triethylamine (0.018 ml) was added with ice-cooling and stirring, followed by dropwise addition of ethyl chlorocarbonate (0.012 ml). The mixture was stirred at the same temperature for 5 minutes, and the reaction mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate. The solvent was then distilled off. The remaining oil was purified by preparative thin layer chromatography (silica gel; developer: 4% methanol-chloroform) to give ethyl 5-(3-hydroxypropyl)-2-oxo-4-phenyl-2,5-dihydro-3-furancarboxylate (30 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][Cl:34])=[CH:25][CH:24]=2)=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)[Cl:36].ClN1C(=O)CCC1=O>C(OCC)(=O)C.CCCCCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][Cl:34])=[CH:27][CH:28]=2)=[C:16]([Cl:36])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCCOc1ccc(C(=Cc2ccccc2)c2ccc(OCc3ccccc3)cc2)cc1
Reactant: ClC(Cl)Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: ClCCCCOc1ccc(C(=C(Cl)c2ccccc2)c2ccc(OCc3ccccc3)cc2)cc1
Reaction time: 18 h

Procedure:
Combine 1-(4-benzyloxyphenyl)-1-(4-(4-chlorobutyloxy)phenyl)-2-phenyl ethylene (3.5 g, 7.5 mmol) and chloroform 935 mL). Add N-chlorosuccinimide (1.99 g, 14.9 mmol). Heat at reflux. After 18 hours, cool the reaction mixture and extract with water, aqueous saturated sodium bicarbonate solution and water. Dry the organic layer over MgSO4, filter, and dry in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 10% ethyl acetate/hexane to give 1-(4-benzyloxyphenyl)-1-(4-(4-chlorobutyloxy)phenyl)-2-chloro-2-phenyl ethylene.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([O:27]C)=[O:26])=[CH:21][CH:20]=4)=[CH:15][C:14]=3[O:29][C:30]([F:33])([F:32])[F:31])[C:8]2=[O:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1COCC1.O.O.[OH-].[Li+]>C(OCC)(=O)C>[CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[CH:23][CH:24]=4)=[CH:15][C:14]=3[O:29][C:30]([F:31])([F:32])[F:33])[C:8]2=[O:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(-c2ccc(CC3CCN(C4CCCCC4)C3=O)c(OC(F)(F)F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(-c2ccc(CC3CCN(C4CCCCC4)C3=O)c(OC(F)(F)F)c2)cc1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
Combine methyl 4′-((1-cyclohexyl-2-oxopyrrolidin-3-yl)methyl)-3′-(trifluoromethoxy)biphenyl-4-carboxylate (9.15 g, 19.2 mmol), THF (175 mL) and water (175 mL) in a 500 mL flask equipped with a magnetic stir bar. While stirring in an ice bath treat the mixture with lithium hydroxide monohydrate (2.42 g, 57.7 mmol). Stir the reaction for 30 minutes, warm to room temperature and stir an additional 16 hours. Dilute with ethyl acetate (250 mL) and wash with water (250 mL). Add hydrochloric acid (2N) to the aqueous layer until it is acidic then extract with ethyl acetate (2×300 mL). Wash the extracts with aqueous saturated sodium chloride solution (1×250 mL), dry over anhydrous magnesium sulfate and concentrate to afford 6.98 g (79%) of the product as a white solid: MS (m/z): 462 (M+1).
Reaction SMILES: FC1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][N:21]=3)[C:15]([O:17]C)=O)[C:8]2=[O:22])=CC=1.C1(CN2CCN(C3C=C(C=CN=3)C(OC)=O)C2=O)CC1.[N:45]1[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][NH2:52])[CH:46]=1>>[CH:5]1([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][N:21]=3)[C:15]([NH:52][CH2:51][C:47]3[CH:46]=[N:45][CH:50]=[CH:49][CH:48]=3)=[O:17])[C:8]2=[O:22])[CH2:23][CH2:24]1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Reactant: NCc1cccnc1
Agent: COC(=O)c1ccnc(N2CCN(CC3CC3)C2=O)c1
Product: O=C(NCc1cccnc1)c1ccnc(N2CCN(CC3CC3)C2=O)c1
Yield: 46 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate with methyl 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)isonicotinate to react with pyridin-3-ylmethanamine, 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-N-(pyridin-3-ylmethyl)isonicotinamide was obtained as a colorless solid in 46% yield: mp 122-123° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.28 (t, J=9.0 Hz, 1H), 8.54-8.50 (m, 2H), 8.43-8.41 (m, 1H), 8.36 (d, J=3.0 Hz, 1H), 7.70-7.67 (m, 1H), 7.35-7.29 (m, 2H), 4.45 (d, J=5.7 Hz, 2H), 3.93 (t, J=9.0 Hz, 2H), 3.56 (t, J=9.0 Hz, 2H), 3.06 (d, J=9.0 Hz, 2H), 0.96-0.85 (m, 1H), 0.48-0.42 (m, 2H), 0.21-0.15 (m, 2H); MS (ES+) m/z 352.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[C:10]([F:22])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[N:28][CH:29]=1.Cl.[F:34][C:35]1([F:40])[CH2:39][CH2:38][NH:37][CH2:36]1>>[F:34][C:35]1([F:40])[CH2:39][CH2:38][N:37]([C:12]2[N:11]=[C:10]([F:22])[C:9]3[O:8][C:5]4[C:4]([C@@:15]5([CH2:19][O:18][C:17]([NH2:20])=[N:16]5)[C:14]=3[CH:13]=2)=[CH:3][C:2]([C:26]2[CH:27]=[N:28][CH:29]=[C:24]([F:23])[CH:25]=2)=[CH:7][CH:6]=4)[CH2:36]1
Reactant: FC1(F)CCNC1
Reactant: OB(O)c1cncc(F)c1
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Agent: Cl
Product: NC1=N[C@@]2(CO1)c1cc(-c3cncc(F)c3)ccc1Oc1c2cc(N2CCC(F)(F)C2)nc1F

Procedure:
The title compound was synthesized by steps analogous to those described in method CC4 above, but using (S)-7-bromo-3-chloro-1-fluoro-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (prepared by steps analogous to those described in BB33), 5-fluoropyridin-3-ylboronic acid and 3,3-difluoropyrrolidine hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][OH:14])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[C:1]([O:5][C:6]([NH:7][C@@H:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][O:14][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:9]1)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](COS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 120.3 %

Procedure:
In a round-bottomed flask, (cis-3-hydroxymethyl-cyclopentyl)-carbamic acid tert-butyl ester (500 mg, 2.21 mmol) was dissolved in dichloromethane (5 ml). The solution was cooled to 0° C. and triethylamine (0.40 ml, 2.87 mmol) was added followed by methanesulfonyl chloride (0.20 ml, 2.57 mmol). The reaction mixture was stirred at 0° C. for 45 min then quenched with water and extracted with dichloromethane (2×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give 780 mg of methanesulfonic acid (cis)-3-tert-butoxycarbonylamino-cyclopentylmethyl ester as a pale yellow oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([I:10])[CH:3]=1.[N-:11]=[N+:12]=[N-:13].[Na+].[CH:15](OC)(OC)OC>CC(O)=O>[Cl:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([N:6]2[CH:15]=[N:13][N:12]=[N:11]2)=[C:4]([I:10])[CH:3]=1
Reactant: Nc1cc(F)c(Cl)cc1I
Reactant: COC(OC)OC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Fc1cc(-n2cnnn2)c(I)cc1Cl
Temperature: 0 °C
Reaction time: 30 h
Yield: 872.9 %

Procedure:
To Intermediate 5A (47 g, 17.3 mmol) in AcOH (470 mL) was added NaN3 (33.76 g, 51.9 mmol) and trimethyl orthoformate (56.8 mL, 51.9 mmol). After 30 h, the reaction was poured into ice water, then solid was filtered-off and washed with petroleum ether to afford 49 g of Intermediate 5B. MS (ESI) m/z: 324.8 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]([NH2:14])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](C)=[CH:21][C:20]=1[S:26](Cl)(=[O:28])=[O:27].N1C=CC=C[CH:31]=1>C(O)(=O)C.C(OCC)(=O)C>[CH3:17][O:18][C:19]1[CH:24]=[C:23]([CH3:31])[CH:22]=[CH:21][C:20]=1[S:26]([NH:14][CH:3]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[C:2]([F:1])([F:15])[F:16])(=[O:27])=[O:28]
Reactant: c1ccncc1
Reactant: NC(Cc1c[nH]c2ccccc12)C(F)(F)F
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(C)ccc1S(=O)(=O)NC(Cc1c[nH]c2ccccc12)C(F)(F)F
Temperature: 65 °C
Reaction time: 16 h
Yield: 14 %

Procedure:
A mixture of 100 mg (0.44 mmol) of 2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethylamine and 97 mg (0.44 mmol) of 2-methyoxy-5-methylbenzenesulfonyl chloride in 4 mL of pyridine was warmed at 65° C. After 16 hours, the mixture was cooled and concentrated to afford a thick oily residue. The residue was diluted with 10% acetic acid and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, decanted, and concentrated in vacuo. The crude material was purified by preparative TLC using ethyl acetate-hexanes (15:85). The material from the plate was isolated by suspending the silica gel in ethyl acetate followed by filtration. The filtrate was concentrated in vacuo to afford 26 mg (14%) of the title compound as a crystalline solid.