Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:36][CH2:37][CH3:38])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:32][C:33]([OH:35])=[O:34])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:26][C:27]2[NH:28][CH:29]=[CH:30][N:31]=2)[CH2:19][C:20]2[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=2)=[CH:13][CH:12]=1)[CH2:2][CH3:3].C(Cl)(Cl)Cl.[OH2:43]>>[N:4]1([CH2:36][CH2:37][O:34][C:33](=[O:35])[CH2:32][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:36][CH2:37][CH3:38])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:26][C:27]3[NH:28][CH:29]=[CH:30][N:31]=3)[CH2:19][C:20]3[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:6][O:43][CH2:2][CH2:1]1
Reactant: CCCN(CCC)CCCCN(CC(=O)O)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Reactant: O
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)CCCCN(CC(=O)OCCN1CCOCC1)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Reaction time: 8 h

Procedure:
The compound (185.8 mg) obtained in Example 65-1 was dissolved in a small amount of water. The solution was added with chloroform and a 1 mol/l sodium hydroxide aqueous solution, and the organic layer and an oily substance were collected, followed by drying with anhydrous magnesium sulfate. After filtration, the solvent was distilled off. An anhydrous DMF solution (2 ml) containing the resultant sodium salt (143.6 mg) and N-(2-hydroxyethyl)morpholine (38 mg) was added with HOBt (37 mg) and WSCI hydrochloride (63 mg) and the whole was stirred overnight. After the solvent was distilled off, the resultant was dissolved in chloroform and washed with a saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with chloroform and dried with anhydrous magnesium sulfate. The reaction mixture obtained by distillating the solvent off was purified through silica gel column chromatography (chloroform). The resultant was dissolved in dioxane and a salt was allowed to precipitate with a 4 mol/l hydrogen chloride/dioxane solution. After the solvent was distilled off, the solid substance was pulverized and dried under reduced pressure, thereby obtaining a hydrochloride (143,4 mg) of the subject compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:34])[CH:32]=O)[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:35])[C@H:20]4[O:36][C:37](=[O:39])[CH3:38])=[O:17])[CH2:15][C@@:7]3([OH:40])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)=[CH:44][CH:43]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>ClCCl.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([C@@H:31]([CH3:32])[CH2:34][N:52]6[CH2:53][CH2:54][CH:49]([O:48][C:45]7[CH:46]=[CH:47][C:42]([Cl:41])=[CH:43][CH:44]=7)[CH2:50][CH2:51]6)[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:35])[C@H:20]4[O:36][C:37](=[O:39])[CH3:38])=[O:17])[CH2:15][C@@:7]3([OH:40])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H](C(C)C=O)CC[C@@H](C)[C@]2(O)[C@H]1OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Reactant: Clc1ccc(OC2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H]([C@@H](C)CN3CCC(Oc4ccc(Cl)cc4)CC3)CC[C@@H](C)[C@]2(O)[C@H]1OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Temperature: 25 °C
Reaction time: 17 h
Yield: 33.6 %

Procedure:
To a solution of (1S,2R,4aS,5R,8R,8aR)-2-(acetyloxy)-8a-hydroxy-3,8-dimethyl-5-[1-methyl-2-oxoethyl]-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (Preparation 141, 60 mg, 0.11 mmol) and 4-[(4-chlorophenyl)oxy]piperidine (Preparation 200, 25 mg, 0.1 mmol) was added dichloromethane (2 ml) and sodium triacetoxyborohydride (35 mg, 0.16 mmol), followed by triethylamine (0.02 ml, 0.17 mmol). The reaction mixture was stirred at room temperature for 17 h, before diluting with dichloromethane (5 ml) and saturated aqueous sodium hydrogen carbonate (3 ml). The reaction mixture was shaken vigorously and the layers were separated using a hydrophobic filter cartridge. The filtrate was concentrated under a stream of nitrogen and purified to give the title compound (26 mg).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(Br)c1
Reactant: OC[C@H]1CCNC1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 9.2 using 5-bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Stage 9.3) and (S)-1-pyrrolidin-3-yl-methanol to afford an off-white crystalline solid. HPLC (Condition 4) tR5.82 min, UPLC-MS (Condition 3) tR=1.14 min, m/z=476.2/478.3 [M+H]+.
Reaction SMILES: C([O:4][C:5]1([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[S:43][C:20]4[N:21]([CH2:34][C:35]5[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=5[F:42])[CH:22]=[C:23]([C:26](=[O:33])[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:24](=[O:25])[C:19]=4[C:18]=3[CH2:44][N:45]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH3:46])=[CH:13][CH:12]=2)=[O:9])[CH2:7][CH2:6]1)(=O)C.[OH-].[Na+]>C(O)C.C(Cl)(Cl)Cl>[CH2:47]([N:45]([CH2:44][C:18]1[C:19]2[C:24](=[O:25])[C:23]([C:26](=[O:33])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:22][N:21]([CH2:34][C:35]3[C:36]([F:42])=[CH:37][CH:38]=[CH:39][C:40]=3[F:41])[C:20]=2[S:43][C:17]=1[C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:8]([C:5]2([OH:4])[CH2:7][CH2:6]2)=[O:9])=[CH:16][CH:15]=1)[CH3:46])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CC(=O)OC1(C(=O)Nc2ccc(-c3sc4c(c3CN(C)Cc3ccccc3)c(=O)c(C(=O)c3ccccc3)cn4Cc3c(F)cccc3F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CN(Cc1ccccc1)Cc1c(-c2ccc(NC(=O)C3(O)CC3)cc2)sc2c1c(=O)c(C(=O)c1ccccc1)cn2Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
A mixture of the compound obtained in Example 19 (0.24 g, 0.33 mmol) and 5N sodium hydroxide (0.07 ml) in ethanol (8 ml) was stirred at room temperature for 1 hour. After the solvent was distilled of f under reduced pressure, the residue obtained was dissolved in chloroform (30 ml) and the solution was washed with aqueous sodium bicarbonate (saturated, 20 ml) and brine (20 ml). After the organic layer was dried (Na2SO4), the solvent was distilled off under reduced pressure and the residue obtained was recrystallized from chloroform-ether to yield pale yellow powders (0.17 g, 75%).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[C:23]([C:25]1[S:26][C:27]([Cl:32])=[C:28]([Cl:31])[C:29]=1[Cl:30])#[N:24].[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:24]=[C:23]([C:25]2[S:26][C:27]([Cl:32])=[C:28]([Cl:31])[C:29]=2[Cl:30])[N:2]([CH3:1])[N:3]=1
Reactant: N#Cc1sc(Cl)c(Cl)c1Cl
Reactant: CN(N=C(Cl)c1c(F)cccc1Cl)S(=O)(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1sc(Cl)c(Cl)c1Cl
Temperature: 145 °C
Reaction time: 2 h
Yield: 55.3 %

Procedure:
To a mixture of N-methyl-N-benzenesulfonyl-2-chloro-6-fluorobenzhydrazonoyl chloride (47.5 g, 0.131 mol) and 2-cyano-3,4,5-trichlorothiophene (26.5 g 0.125 mol in o-dichlorobenzene (18 mL),was added aluminum chloride (11.1 g, 0.083 mol). The mixture was lowered into a preheated oil bath maintained at 140-150° C. The mixture was allowed to remain in the hot oil bath 40 min and was then removed from the bath and stirred for 2 hr as it gradually cooled. The reaction mixture was poured into 2N sodium hydroxide (300 mL-enough to dissolve the aluminum salts) and extracted with methylene chloride (3×250 mL). The organic phases were combined, washed with brine, dried (MgSO4), and the solvent removed in vacuo to give the crude product. The residue was placed on silica gel (150 g) and then chromatographed using ethyl acetate/hexanes as eluant to obtain 39.7 g (55.3% yield) of the title compound; 99.4% pure by GC analysis; mp 129-130° C.; 1H NMR (CDCl3) δ 7.3 (m, 2H), 7.1 (m, 1H), 4.0 (s, 3H); Anal. for C13H6Cl4FN3S: Calcd. C, 39.32; H, 1.52; N, 10.58. Found C, 39.08; H, 1.30; N, 10.34.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[CH:11]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)=[O:12].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C([O-])([O-])=O.[K+].[K+]>C(O)CCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=[N:4][CH:3]=2)=[CH:15][CH:14]=1)=[O:12]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: NC(=O)c1cncc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCCCO
Product: NC(=O)c1cncc(-c2ccc(C=O)cc2)c1
Temperature: 80 °C

Procedure:
A mixture of 5-bromonicotinamide (0.201 g; 1.00 mmol), 4-formylphenyl boronic acid (0.180 g; 1.2 mmol), Pd(OAc)2 (0.0022 g; 0.010 mmol), S-Phos (0.0082 g; 0.020 mmol) and K2CO3 (0.345 g; 2.5 mmol) in n-butanol (3 mL) was sparged with nitrogen ca. 10 min, then heated at 80° C. for 1 h. Upon cooling, the mixture was poured into water, layered with Et2O and sonicated at room temperature ca. 5 min. Solid was collected by filtration, and the cake was air-dried on the filter, affording the title compound as a colorless solid which was used without further purification. LC/MS (method A) 1.57 min; m/z 227 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[CH3:31][NH:32][CH2:33][CH2:34][C:35]1[CH:36]=[C:37]([OH:42])[C:38]([OH:41])=[CH:39][CH:40]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([N:32]([CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([OH:41])=[C:37]([OH:42])[CH:36]=3)[CH3:31])[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CNCCc1ccc(O)c(O)c1
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Product: CN(CCc1ccc(O)c(O)c1)c1nccc(-c2cccc(CN(CCCN)S(C)(=O)=O)c2)n1

Procedure:
Intermediate 4 from above was coupled with 4-(2-Methylamino-ethyl)-benzene-1,2-diol following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 486. 1H NMR (Varian 300 MHz, CDCl3—CD3OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.2 (m, 2H) 8.0 (m, 2H) 7.6 (d, 1H) 7.5 (m, 1H) 6.6 (m, 1H) 6.4 (m, 2H) 4.4 (s, 2H) 4.0 (m, 2H) 3.2 (m, 5H) 2.9 (s, 3H) 2.8 (m, 4H) 1.7 (m, 2H).
Reaction SMILES: [OH:1][CH:2]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:7]([O:8][C@@H:9]2[O:17][C@H:16]([CH2:18][OH:19])[C@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[C@H:5]([OH:6])[C@H:3]1[OH:4].C(O)[C@H]1[O:30][C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O>>[CH2:18]([OH:19])[C@H:16]1[O:17][C@@H:9]([O:8][C@@H:7]([C@H:5]([OH:6])[C@@H:3]([OH:4])[C:2]([OH:21])=[O:1])[C@H:20]([OH:30])[CH2:22][OH:23])[C@H:10]([OH:11])[C@@H:12]([OH:13])[C@@H:14]1[OH:15]
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Product: O=C(O)[C@H](O)[C@@H](O)[C@H](O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)[C@H](O)CO

Procedure:
An aldobiose such as lactose or maltose, is electrolytically oxidised in the presence of the alkali metal carbonates/bicarbonates and alkali bromides to obtain the solution of alkali metal lactobionate, maltobionate, etc. The resulting solution is concentrated under reduced pressure to a thin syrup from which the salt is precipitated by adding 95% ethyl alcohol or isopropyl alcohol. The crude salt is dissolved in a minimum amount of hot water and then filtered through decolorizing carbon and the salt recrystallized by adding a suitable amount of the desired alcohol. The process is repeated 3-4 times to get the desired alkali salt in the pure state.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([O-])=[O:21])=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.[Li+].ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[CH:36]1([C:39]2[C:47]3[C:46]([NH2:48])=[CH:45][CH:44]=[CH:43][C:42]=3[N:41]([CH2:49][C:50]3[S:51][C:52]([CH3:55])=[N:53][N:54]=3)[N:40]=2)[CH2:38][CH2:37]1>CN1CCCC1=O.O>[CH:36]1([C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][C:46]=3[NH:48][C:20]([C:17]3[N:14]4[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)=[CH:12][C:13]4=[N:19][CH:18]=3)=[O:21])[N:41]([CH2:49][C:50]3[S:51][C:52]([CH3:55])=[N:53][N:54]=3)[N:40]=2)[CH2:37][CH2:38]1
Reactant: CN1CCN(CCOc2ccn3c(C(=O)[O-])cnc3c2)CC1
Reactant: Cc1nnc(Cn2nc(C3CC3)c3c(N)cccc32)s1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1nnc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(OCCN6CCN(C)CC6)ccn45)cccc32)s1
Temperature: 88 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To lithium 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (Example 56, Step A; 70.5 mg, 0.23 mmol) was added N-Methylpyrrolidinone (1 mL). The suspension was heated in order to affect dissolution. The reaction mixture was cooled in an ice-water bath under nitrogen, and 2,4,6-trichlorobenzoyl chloride (35.5 μL, 0.23 mmol) was added dropwise. The cold bath was removed once the addition was complete and the reaction mixture was stirred for a further 1 hour. The reaction mixture became cloudy. A solution of 3-cyclopropyl-1-((5-methyl-1,3,4-thiadiazol-2-yl)methyl)-1H-indazol-4-amine (48 mg, 0.168 mmol) in anhydrous N-Methylpyrrolidinone (1 mL) was then added to the reaction mixture, and the mixture was heated to 88° C. for 13.5 hours. The reaction mixture was cooled, diluted with water, and extracted multiple times with dichloromethane. The combined dichloromethane extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by preparative thin-layer chromatography (silica, eluting with 7N ammonia/MeOH:MeOH:DCM in a 3:7:90 ratio) to afford the product (51.6 mg) as a dark yellow solid. MS (ES+APCI) m/z=572 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=[C:8]([C:17](O)=[O:18])[C:7]=2[CH:20]=1>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=[C:8]([CH2:17][OH:18])[C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)C(C(=O)O)=Cc1ccccc1O2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc2c(c1)C(CO)=Cc1ccccc1O2
Yield: 96 %

Procedure:
Preparation analogous to Example 12f) from 8-methoxy-dibenz[b,f]oxepine-10-carboxylic acid. Yield: 96% in the form of a brown oil; TLC (silica gel; ethyl acetate/hexane=1:1; UV): Rf =0.31; 1H-NMR (CDCl3, 300 MHz): 1.80 (sbr, 1H); 3.78 (s, 3H); 4.69 (s, 2H); 6.82-7.33 (m, 8H) MS: 254 (M+), 211, 182, 181, 168, 165, 153, 152.
Reaction SMILES: F[B-](F)(F)F.C([O+:8]([CH2:11][CH3:12])[CH2:9][CH3:10])C.C(N(CC)C(C)C)(C)C.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]([C:45]2C(=O)C[CH:48]([C:52]([F:55])([F:54])[F:53])[CH2:47][C:46]=2[OH:56])[NH:31][C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)=[O:33])=[CH:26][CH:25]=1)#[N:23]>ClCCl>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([CH:30]([C:45]2[C:46](=[O:56])[CH2:47][CH:48]([C:52]([F:53])([F:55])[F:54])[CH2:12][C:11]=2[O:8][CH2:9][CH3:10])[NH:31][C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:42])([F:43])[F:44])[CH:36]=2)=[O:33])=[CH:28][CH:29]=1)#[N:23]
Reactant: N#Cc1ccc(C(NC(=O)Nc2cccc(C(F)(F)F)c2)C2=C(O)CC(C(F)(F)F)CC2=O)cc1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CC(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethyloxonium tetrafluoroborate (1.82 g, 9.57 mmol) is added to a mixture of N,N-diisopropylethylamine (1.92 mL, 11.0 mmol) and 1-((4-cyanophenyl)(2-hydroxy-6-oxo-4-(tri-fluoromethyl)cyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 12, 2.38 g, 4.79 mmol) in dichloromethane (30 mL). The mixture is stirred at room temperature for 1 h and washed three times with water. The organic layer is dried over Na2SO4 and concentrated under reduced pressure. Yield: 1.66 g; ESI mass spectrum [M+H]+=525, Retention time HPLC: 1.25 min (V011_S01).
Reaction SMILES: [C:1]1([C:7]([NH:20][CH2:21][C:22]2[N:23]([CH2:27][CH:28]3[CH2:33][CH2:32][N:31](C=O)[CH2:30][CH2:29]3)[CH:24]=[CH:25][N:26]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:7]([NH:20][CH2:21][C:22]2[N:23]([CH2:27][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:24]=[CH:25][N:26]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CN1CCC(Cn2ccnc2CNC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: c1ccc(C(NCc2nccn2CC2CCNCC2)(c2ccccc2)c2ccccc2)cc1
Temperature: 50 °C
Yield: 37 %

Procedure:
A mixture of 4-[(2-triphenylmethylaminomethyl-1H-imidazol-1-yl)methyl]-1-piperidinecarboxaldehyde (0.48 g, 0.00103 M), 2 N sodium hydroxide (24 ml) and methanol (24 ml) was heated at 50° C. for 4 hrs. The reaction was concentrated to about 20 ml at room temperature and extracted with ethylacetate. The extracts, dried over sodium sulfate, was stripped to dryness and purified on preparative thin layer chromatography plates to give 4-[(2-triphenylmethylaminomethyl-1H-imidazol-1-yl)methyl]-piperidine (0.167 g, 37% yield).
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(O)(=O)C>[C:10]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([I:1])[C:3]=1[CH3:9])(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(N)cccc1I
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(I)c1C
Temperature: 0 °C

Procedure:
Charge a 5 L, 3 neck flask equipped with a mantle, stirrer, condenser, with 708 grams (5M) 3-Iodo-2-Methyl Aniline, followed by 700 ml glacial acetic acid. Add in a stream of 520 grams (5.1M) acetic anhydride and allow the solution to come to a gentle reflux for an hour. The solution is allowed to cool and poured in a stream in a large container of 8 L ice water. The product will crystallize immediately and is filtered and squeezed under vacuum and air-dried. Yield was 900 grams (Theoretical yield=918 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13]CC)=[O:12])=[CH:7]2.[H-].[Na+].[CH3:18]I.[OH-].[Na+]>CN(C)C=O.O.CO>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:18])[C:8]([C:11]([OH:13])=[O:12])=[CH:7]2
Reactant: CI
Reactant: CCOC(=O)c1cc2cccc(Br)c2[nH]1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: Cn1c(C(=O)O)cc2cccc(Br)c21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
7.37 g ethyl 7-bromo-1H-indole-2-carboxylate are dissolved in 50 ml N,N-dimethylformamide, cooled to 0° C. and combined with 1.16 g sodium hydride (60% in mineral oil). The mixture is stirred for 20 minutes and then 1.78 ml methyl iodide are added dropwise. Then the mixture is allowed to come up to ambient temperature and stirred for 12 hours. Then 80 ml of methanol and 27.5 ml 2 N sodium hydroxide solution are added and the mixture is stirred for 3 hours at ambient temperature. The methanol is eliminated in vacuo, the residue is mixed with water and the precipitate is suction filtered. The filtrate is washed twice with ethyl acetate and the aqueous phase is combined with sufficient 2 N hydrochloric acid to give a pH of 2. The precipitated solid is suction filtered, washed with water and dried.
Reaction SMILES: C(OC(N1CCN(C(C([NH:21][C:22]([C:24]2[CH:33]=[C:32]([O:34][CH3:35])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[O:23])CC2N=CNC=2)=O)CC1)=O)C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>[NH2:21][C:22]([C:24]1[CH:33]=[C:32]([O:34][CH3:35])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1)=[O:23]
Reactant: CCOC(=O)N1CCN(C(=O)C(Cc2c[nH]cn2)NC(=O)c2cc(OC)c3ccccc3n2)CC1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(N)=O)nc2ccccc12
Temperature: 50 °C
Yield: 88.3 %

Procedure:
To a solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(imidazol-4-yl)ethyl]aminocarbonyl-4-methoxyquinoline (69 mg, 0.14 mmol) in DMF (2 mL) was added t-butyl bromo acetate (0.026 mL, 1.2 eq.), potassium carbonate (30 mg, 1.5 eq), Nal (2.0 mg, 0.1 eq.). The reaction mixture was heated at 50° C. for 1 hour. Evaporation followed by flash column chromatography with 2%–3% MeOH in methylene chloride afforded 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(1-(t-butoxycarbonyl)methyl)imidazol-4-yl)ethyl]-aminocarbonyl-4-methoxyquinoline (25 mg) which was treated with neat trifluoroacetic acid (0.5 mL) for 1.5 hours at ambient temperature. Repeated evaporation of the solvents and treatment with methylene chloride afforded 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(1-(carboxymethyl)imidazol-4-yl)ethyl]-aminocarbonyl-4-methoxyquinoline (27 mg) as a trifluoroacetic acide salt: NMR (DMSO) 1.20 (t, 3), 3.2–3.6 (m, 11), 4.05 (q, 2), 4.1 (s, 3), 5.0 (s, 2), 5.3 (m, 1 ), 7.45 (s, 1), 7.5 (s, 1), 7.65 (t, 1), 7.8 (t, 1), 8.05 (d, 1), 8.95 (s, 1) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14](=[O:16])[CH3:15])=[CH:4][CH:3]=1.[Br:17]Br.BrBr.C(O)(=O)C>C(O)(=O)C.CCCCCC>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14](=[O:16])[CH2:15][Br:17])=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccccc1-c1ccc(C)cc1
Reactant: BrBr
Solvent: CCCCCC
Solvent: CC(=O)O
Product: Cc1ccc(-c2ccccc2C(=O)CBr)cc1
Temperature: 30 °C
Yield: 943.7 %

Procedure:
A solution of 4'-methyl-2-acetyl-1,1'-biphenyl (2.06 g,9.79 mmol) in 10 mL of glacial acetic acid was treated dropwise with a solution of bromine (1.722 g,1.07 mmol) dissolved in 3.0 mL of glacial acetic acid. After initiating the reaction with the first few drops of the bromine/acetic acid reagent by heating the reaction mixture at 30° C., the remainder of the bromine solution was added dropwise at 25°-30° C. The reaction mixture was stirred at room temperature until the consumption of bromine was complete (approximately 2 hrs). The reaction mixture was diluted with 150 mL of hexane then washed with water (3×50 mL). The organic layer was removed, dried over magnesium sulfate, filtered and evaporated under vacuum to give 2.92 g of an oil that was used in the next step without purification. 1H NMR (crude product) (200 MHz,CDCl3): 2.38 (s,3H), 3.66 (s,2H), 7.21 (s,4H), 7.3-7.6 (m,4H).