Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[C:12](=[C:13]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C(=O)C)[C:14]4=[CH:15][CH:16]=3)[O:11][CH2:10][C:9]=2[CH:26]=1)(=O)C.C1C(=O)N([Br:34])C(=O)C1>CN(C=O)C>[Br:34][C:15]1[C:14]2=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=[C:13]2[C:12]2[O:11][CH2:10][C:9]3[CH:26]=[C:5]([OH:4])[CH:6]=[CH:7][C:8]=3[C:17]=2[CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1ccc2c(c1)COc1c-2ccc2c(OC(C)=O)cccc12
Solvent: CN(C)C=O
Product: Oc1ccc2c(c1)COc1c-2cc(Br)c2c(O)cccc12

Procedure:
The title compound was prepared by reacting 1-(Acetyloxy)-6H-dibenzo[c,h]chromen-8-yl acetate (510 mg, 1.46 mmol), NBS (315 mg, 1.77 mmol), and anhydrous DMF (30 ml) at room temperature for 1.5 hours according to method B. The reaction was concentrated under reduced pressure, dissolved in MeOH (30 ml), and NH3 was bubbled in for 1.5 h while acetate removal was monitored by LC-MS. The reaction was concentrated to a dark sludge and purified by silica chromatography (1:1 EtOAc:hexanes) to afford 340 mg (68%) of product as a tan solid. Mp: decomposes above 130° C.; 1H NMR (500 MHz, DMSO-d6) δ 5.23 (2H, s), 6.72 (1H, d, J=1.9 Hz), 6.81 (1H, dd, J=8.2 Hz, 2.5 Hz), 6.92 (1H, dd, J=7.7 Hz, 1.1 Hz), 7.33 (1H, t, J=8.0 Hz), 7.64 (1H, dd, J=8.5 Hz, 1.1 Hz), 7.68 (1H, d, J=8.5 Hz), 8.01 (1H, s), 9.78 (1H, s), 10.15 (1H, s); MS m/z341/343 (Br pattern) (M−H+).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([NH:20][CH3:21])([C:18]#[N:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:22]S(O)(=O)=O>C(Cl)Cl>[CH:1]([N:14]1[CH2:17][C:16]([NH:20][CH3:21])([C:18]([NH2:19])=[O:22])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: CNC1(C#N)CN(C(c2ccccc2)c2ccccc2)C1
Solvent: ClCCl
Product: CNC1(C(N)=O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A vigorously stirred solution of 1-benzhydryl-3-methylaminoazetidine-3-carbonitrile (I-3A-2a; 2.10 g, 7.57 mmol) in methylene chloride (25 ml) cooled in an ice bath was treated with H2SO4 (4.0 ml, 76 mmol), dropwise. After the reaction mixture was allowed to warm to room temperature and stir overnight, it was cooled in an ice bath and then carefully quenched with concentrated aqueous NH4OH to pH 11. The mixture was extracted with methylene chloride; the combined organic layers were dried (Na2SO4) and then concentrated, in vacuo, to afford I-3A-2b (1.2 g, 54%) as an off-white solid: +ESI MS (M+1) 296.3; 1H NMR (400 MHz, CD3OD) δ 7.41 (d, J=7.5 Hz, 4H), 7.25 (t, J=7.5 Hz, 4H), 7.16 (t, J=7.1 Hz, 2H), 4.48 (s, 1H), 3.41 (d, J=8.7 Hz, 2H), 3.09 (d, J=8.7 Hz, 2H), 2.24 (s, 3H).
Reaction SMILES: [CH2:1]([N:4]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:5]1)[CH2:2][CH3:3].[F:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl.N1C=CC=CC=1>[F:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([CH:6]3[CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:7]3)=[CH:13][CH:12]=2)(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(CCF)cc1
Reactant: CCCN1CC(c2ccc(N)cc2)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(CCF)cc3)cc2)C1
Yield: 5.6 %

Procedure:
Following the same procedure as described in example 55, 4-(1-propyl-azetidin-3-yl)phenylamine (100 mg, 0.52 mmol) in CH2Cl2/pyridine 9:1 (12 ml) was treated with 4-(2-fluoro-ethyl)-benzenesulfonyl chloride (117 mg, 0.52 mmol). Purification of the crude product by chromatography on reversed phase silica gel (H2O+0.1% acetic acid:CH3CN+0.1% acetic acid, 75:25) provided the title compound (11 mg, 6%) as a colourless gum.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:13]([F:16])([F:15])[F:14])=[N:5][N:6]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:7]=1[Cl:8].O.[SH-:18].[Na+].O>CN(C)C=O>[C:9]([N:6]1[C:7]([Cl:8])=[C:3]([CH2:2][SH:18])[C:4]([C:13]([F:16])([F:15])[F:14])=[N:5]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: [SH-]
Reactant: CC(C)(C)n1nc(C(F)(F)F)c(CBr)c1Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)n1nc(C(F)(F)F)c(CS)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
43.5 g (136.1 mmoles) of 4-bromomethyl-1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole was added to a solution of 21.8 g of sodium hydrosulfide hydrate (purity: 70%, 272.2 mmoles) dissolved in 300 ml of N,N-dimethylformamide. The mixture was stirred at room temperature overnight to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with diethyl ether. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 32.3 g (yield: 87.0%) of (1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanethiol.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19](CC[Si](C)(C)C)[C:18](=[O:29])[CH2:17]1)C1C=CC=CC=1.I[CH2:31][CH2:32][CH2:33][CH2:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36]>>[C:38]1([S:35]([CH2:34][CH2:33][CH2:32][CH2:31][C:13]2[CH:12]=[CH:11][C:10]([N:16]3[S:20](=[O:21])(=[O:22])[NH:19][C:18](=[O:29])[CH2:17]3)=[C:9]([OH:8])[CH:14]=2)(=[O:37])=[O:36])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=S(=O)(CCCCI)c1ccccc1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Product: O=C1CN(c2ccc(CCCCS(=O)(=O)c3ccccc3)cc2O)S(=O)(=O)N1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and (4-iodobutane-1-sulfonyl)-benzene analogous to Example 57, steps B, C and D: (M−1)−=423. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.49-1.60 (m, 4 H) 2.40 (t, J=6.69 Hz, 2 H) 4.01 (s, 2 H) 6.46 (s, 1 H) 6.58 (s, 1 H) 7.21 (d, J=7.83 Hz, 1 H) 7.65 (t, J=7.58 Hz, 2 H) 7.71-7.77 (m, 1 H) 7.85-7.90 (m, 2 H)
Reaction SMILES: [CH:1]1([C@@H:7]([NH:9][C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:13]=2[CH2:28][N:29]2[CH2:34][CH2:33][N:32]([C:35](=[N:38][S:39]([CH3:42])(=[O:41])=[O:40])SC)[CH2:31][CH2:30]2)=[O:11])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1>>[CH:1]1([C@@H:7]([NH:9][C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:13]=2[CH2:28][N:29]2[CH2:30][CH2:31][N:32]([C:35](=[N:38][S:39]([CH3:42])(=[O:41])=[O:40])[N:43]3[CH2:47][CH2:46][CH2:45][CH2:44]3)[CH2:33][CH2:34]2)=[O:11])[CH3:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C1CCNC1
Reactant: CSC(=NS(C)(=O)=O)N1CCN(Cc2c(-c3ccccc3)nc3ccccc3c2C(=O)N[C@@H](C)C2CCCCC2)CC1
Product: C[C@H](NC(=O)c1c(CN2CCN(C(=NS(C)(=O)=O)N3CCCC3)CC2)c(-c2ccccc2)nc2ccccc12)C1CCCCC1
Yield: 65 %

Procedure:
0.46 g (0.76 mmol) of crude 3-[4-(1-methanesulfonylimino-1-methylsulfanyl-methyl)-piperazin-1-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide (compound of Description 16) and 5 ml of pyrrolidine were heated to reflux for 5 h. The excess of pyrrolidine was removed in vacuo and the residue was purified by flash chromatography on silicagel (CH2Cl2/MeOH: 97/3). After concentration of the desired fractions, the residue was crystallised in di-isopropyl ether to afford 0.310 g (yield 65%) of the title compound as white crystals.
Reaction SMILES: CO[C:3](=[O:21])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:22][NH:23][C:24]([NH2:26])=[O:25].C[O-].[Mg+2].C[O-].CO>>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:12]=[CH:13][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[CH:15][CH:16]=2)[C:3]([NH:26][C:24]([NH:23][CH3:22])=[O:25])=[O:21])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CNC(N)=O
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)cc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Yield: 31.1 %

Procedure:
3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid methyl ester (350 mg, 1.13 mmol) and methyl urea (184 mg, 2.48 mmol) were treated with a solution of magnesium methoxide in methanol (7.4 wt %, 6.0 mL, 4.18 mmol). The reaction mixture was then concentrated in vacuo to approximately one-half the volume of methanol. The resulting reaction mixture was then heated under reflux for 15 h. The reaction mixture was allowed to cool to 25° C., filtered through celite, and the celite was thoroughly washed with ethyl acetate. The ethyl acetate filtrate was washed with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/3 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionyl]-3-methyl urea (124 mg, 31%) as a white solid: mp 205-206° C.; EI-HRMS m/e calcd for C17H24N2O4S (M+) 352.1457, found 352.1445.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[CH3:29][C:30]1[S:31][C:32]([CH:36]=O)=[C:33]([CH3:35])[N:34]=1.C(O)(=O)C.[OH-].[Na+]>ClCCCl>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH2:36][C:32]2[S:31][C:30]([CH3:29])=[N:34][C:33]=2[CH3:35])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1nc(C)c(C=O)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1nc(C)c(CNC2CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
Sodium triacetoxyborohydride (4.5 g, 21.23 mmol) is added to a stirred solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.63 g, 13.13 mmol), 2,4-dimethyl-thiazole-5-carboxaldehyde (1.95 g, 13.81 mmol, Maybridge), acetic acid (0.80 ml, 13.98 mmol) and 1,2-dichloroethane (125 ml). The reaction is stirred overnight at room temperature under nitrogen. The reaction is poured into 2N NaOH (300 ml) and extracted with ethyl acetate (200 ml×3). The ethyl acetate is dried over sodium sulfate, filtered, and the filtrate concentrated. The crude product is purified by flash chromatography on silica gel eluting with 0.5% concentrated ammonium hydroxide/5% ethanol/chloroform to yield (2.93 g, 69%) of 4-{[(2,4-dimethyl-thiazol-5-yl)methyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=326.2 (M+1); 1H NMR (CDCl3): δ=4.10 (2H, br m), 3.91 (2H, s), 2.88-2.79 (2H, brm), 2.73-2.66 (1H, m), 2.66 (3H, s), 2.34 (3H, s), 1.86 (2H, brd), 1.48 (9H, s), 1.36-1.24 (3H, m).
Reaction SMILES: [C:1]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH-:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.[Na+]>C1COCC1>[CH2:2]([C:1]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[C:20]1[CH:19]=[CH:18][CH:17]=[CH:21]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCC(=O)c1ccccc1
Reactant: c1cc[cH-]c1
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCC(=C1C=CC=C1)c1ccccc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 72.5 %

Procedure:
Under a nitrogen atmosphere, 2.0 g (9.2 mmol) of n-nonanophenone and 30 mL of dry THF were put into a 100-mL Schlenk flask to produce a solution. To this solution, 5.6 mL (11.2 mmol) of a solution of 2.0-M sodium cyclopentadienide in THF was added under cooling with ice, and the product was stirred at room temperature for 19 hours. Then, the obtained deep red solution was quenched with dilute aqueous hydrochloric acid under cooling with ice. Then, 30 mL of diethyl ether was added thereto, and the soluble part in diethyl ether was extracted, and the organic layer was neutralized and washed with an aqueous solution of saturated sodium hydrogen carbonate, water, and a saturated salt solution and then dehydrated with anhydrous magnesium sulfate. The solvent was distilled off, and then the residue was purified by silica gel column chromatography to obtain an objective that was a red liquid (amount: 1.77 g and yield: 72.5%).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[CH3:32][C:33]1[O:37][N:36]=[C:35]([CH2:38][NH2:39])[CH:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:39][CH2:38][C:35]1[CH:34]=[C:33]([CH3:32])[O:37][N:36]=1)=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: Cc1cc(CN)no1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(CNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)no1
Reaction time: 1 h
Yield: 48.3 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 25 mg, 0.058 mmol), (5-methylisoxazol-3-yl)methanamine (9.75 mg, 0.087 mmol), HATU (28.7 mg, 0.075 mmol), and 4-methylmorpholine (23.45 mg, 0.232 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 12 min, 20 mL/min, 220 nM, product retention=14.0 min) to provide 2-hydroxy-N-((5-methylisoxazol-3-yl)methyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (15 mg, 0.028 mmol, 48.2% yield) as a single enantiomers. LCMS=526.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.11-8.23 (2 H, m), 7.50-7.82 (7 H, m), 5.98 (1 H, s), 5.18 (1 H, s), 4.43 (2 H, s), 2.36 (3 H, s); HPLC peak RT=10.0 min (Method A).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][CH2:14][C:13]=34)[N:5]=2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26].CN(C1C=CC=CN=1)C.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]2[CH:11]=[N:10][C:9]([C:6]3[N:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[O:8][N:7]=3)=[C:13]2[CH2:14]1)=[O:26]
Reactant: c1ccc2c(c1)NCc1c(-c3noc(C4CC4)n3)ncn1-2
Reactant: O=C(Cl)c1ccccc1Cl
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccc1Cl)N1Cc2c(-c3noc(C4CC4)n3)ncn2-c2ccccc21
Reaction time: 1.5 h

Procedure:
A slurry consisting of 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4,5-dihydroimidazo[1,5-a]quinoxaline (XXXIII, EXAMPLE 88, 0.492 g), 2-chlorobenzoyl chloride (0.268 ml), dimethylaminopyridine (0.0538 g), diisopropylethylamine (0.368 g), and THF (9 ml) is stirred at 20°-25° for 1.5 hr. The mixture is then partitioned between ethyl acetate, aqueous sodium bicarbonate, and saline. The product is poorly soluble in both the organic and aqueous phases, filtration of the extraction solvents gives additional material. The crude product is then triturated with ethyl ether and dried to give the title compound, mp 254°-256°; MS (m/z) at 417, 419; IR (mineral oil) 1659, 1576, 1508, 765 and 1394; NMR (CDCl3) 8.16 δ.
Reaction SMILES: [H-].[Na+].[F:3][CH2:4][CH2:5][CH2:6][OH:7].Cl[C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][N:10]=1.[OH-].[Na+]>CN(C)C=O.C(O)C>[F:3][CH2:4][CH2:5][CH2:6][O:7][C:9]1[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=1
Reactant: OCCCF
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(O)c1ccc(OCCCF)nc1
Reaction time: 0.42 h

Procedure:
Sodium hydride (0.220 g, 5.50 mmol) was added to a solution of 3-fluoropropan-1-ol (0.390 g, 5 mmol) in N,N-dimethylformamide (5 mL). The mixture was stirred under an atmosphere of nitrogen for 25 min and added a solution of ethyl 6-chloronicotinate (0.928 g, 5.00 mmol) in N,N-dimethylformamide (2.5 mL). The reaction mixture was stirred for 35 min and then quenched with water. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. Purification by column chromatography using a gradient of ethyl acetate in heptane yielded an oil. The crude was dissolved in 1M sodium hydroxide, (16.50 mL, 16.50 mmol) and ethanol (20 mL) and heated to 50° C. for 1.5 h. The organic solvent was removed in vacuo, and the residual aqueous solution was cooled on ice. 2 M hydrochloric acid was added until an acidic pH was reached. The obtained precipitate was filtered off, washed with ice-water, and dried in vacuo affording the title compound, 0.53 g (81%) as a white solid; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 (dd, 1 H), 8.14 (dd, 1 H), 6.90 (dd, 1 H), 4.65 (t, 1 H), 4.54 (t, 1 H), 4.43 (t, 2 H), 2.05-2.19 (m, 2 H); MS (APPI/APCI) m/z 228[M+H+].
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.[CH:42]1([C:45](O)=[O:46])[CH2:44][CH2:43]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[C:17]1([C@H:15]([NH:14][C:12](=[O:13])[NH:11][C:9]2[N:8]=[CH:7][C:6]3[C:2]([NH:1][C:45]([CH:42]4[CH2:44][CH2:43]4)=[O:46])=[N:3][N:4]([C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:5]=3[CH:10]=2)[CH3:16])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)C1CC1
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)Nc1cc2c(cn1)c(NC(=O)C1CC1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To an 8 mL vial charged with (R)-1-(3-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (20 mg, 0.037 mmol), cyclopropanecarboxylic acid (4.79 mg, 0.056 mmol), and HATU (21.18 mg, 0.056 mmol) was added DIEA (0.013 ml, 0.074 mmol) and DMA (1 ml). The vial was capped and the contents heated to 60° C. and stirred for 16 h. The reaction mixture was concentrated to afford crude (R)—N-(6-(3-(1-phenylethyl)ureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)cyclopropanecarboxamide which was taken forward without purification. MS ESI calc'd. For C38H35N6O2 [M+H]+ 607. found 607.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][O:18][CH:19]([CH3:21])[CH3:20])[C:13]([CH2:22][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][O:18][CH:19]([CH3:20])[CH3:21])[C:13]([CH2:22][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[C:8]([NH2:38])=[N:9][C:10]=2[CH:11]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCOC(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCOC(C)C
Temperature: 5 °C
Reaction time: 1 h

Procedure:
7-Bromo-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinoline (20 g) was dissolved in chloroform (400 mL). 3-Chloroperoxybenzoic acid (60% pure, 17.1 g) was added in 2 g portions over a 5 minute period and the reaction was stirred for 1 hour. Ammonium hydroxide (300 mL) was added and the mixture was cooled to 5° C. with an ice/water bath. p-Toluenesulfonyl chloride (9.4 g) was added at the rate of 1 g/min to minimize gas evolution. After stirring for 16 hours, the layers were separated and the aqueous fraction was extracted with chloroform. The combined organic fractions were sequentially washed with 5% aqueous sodium bicarbonate, water and brine; dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel. The polar component of the eluent was chloroform:methanol:ammonium hydroxide 80:18:2 (CMA). The purification was carried out eluting with chloroform:CMA in a gradient from 98:2 to 88:12. The material recovered from the column was recrystallized from acetonitrile to yield 7.0 g of 7-bromo-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine as a tan granular powder.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:30]([F:33])([F:32])[F:31])=[C:10]([C:12]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]4)=[N:19][CH:20]=3)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:34][S:35]([NH:38][C:27]([CH:24]1[CH2:25][CH2:26][N:21]([C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:30]([F:33])([F:31])[F:32])=[O:13])=[CH:20][N:19]=2)[CH2:22][CH2:23]1)=[O:28])(=[O:37])=[O:36]
Reactant: O=C(Nc1ccc(N2CCC(C(=O)O)CC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)C1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
To a suspension of 5′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid (39.4 mg, 0.085 mmol) in methylene chloride (5 mL) was added methanesulfonamide (8.2 mg, 0.086 mmol). Then 4-dimethylaminopyridine (10.45 mg, 0.085 mmol) and EDCI (16.4 mg, 0.085 mmol) was added. The mixture was stirred at room temperature overnight. Solvents were evaporated and the residue was purified by flash column chromatography using a linear gradient of ethyl acetate containing 1% acetic acid in hexanes (20% to 100% in 15 minutes) to give the desired compound as a pale yellow solid (16.5 mg). 1H-NMR is consistent with the desired structure. LRMS for C23H22F3N5O5S (m/e) calcd 537.13, obsd 538.1 (M+1).