Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:18])([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])=[CH:4][CH:3]=1.C([NH:29][C@H:30]([C:32](O)=[O:33])[CH3:31])(OCC1C=CC=CC=1)=O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[NH2:29][C@@H:30]([CH3:31])[C:32]([NH:18][C:9]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)([CH3:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:33]
Reactant: CC(N)(Cc1ccc(F)cc1)c1ccc(F)cc1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: C[C@H](N)C(=O)NC(C)(Cc1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 3 h
Yield: 10.5 %

Procedure:
To a stirred solution of 1,2-bis(4-fluorophenyl)-2-propylamine (11.07 g, 0.045 mol) in 200 ml of chloroform under nitrogen, were added N-CBZ-L-alanine (10.0 g, 0.045 mol) and then a solution of dicyclohexylcarbodiimide (9.90 g, 0.05 mol) in 100 ml of chloroform, and the mixture was stirred for 16 hours. The precipitated solid was removed by filtration and the solvent evaporated. The residue was treated with ethyl acetate (100 ml), filtered, an additional 300 ml of ethyl acetate added, and then washed with 1% cold HCl (100 ml), brine (2×100 ml), dried over MgSO4, and the solvent evaporated. The residue was dissolved in 450 ml of methanol and 35 ml of 10% HCl and hydrogenated at 40 psi in a Parr apparatus over 3.0 g of 5% Pd/C catalyst for 3 hours. The catalyst was removed by filtration, the solvent evaporated and the residue dissolved in water (200 ml) and chloroform (300 ml), basified to pH 11 with 50% NaOH, shaken and separated. The aqueous phase was extracted with chloroform (2×200 ml), and the combined organic phases were washed with water (2×200 ml), and dried over MgSO4. Removal of solvent gave a white solid. This solid was recrystallized from cyclohexane/hexane and then from hexane/ethanol, and vacuum dried to give 1.5 g of (2S)-2-amino-N-[1,2-bis(4-fluorophenyl)-1-methylethyl]propanamide, mp. 134°-135° C.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][C:25]=2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:11]=1
Reactant: CCCCCCc1ccncc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: CCCCCCc1ccncc1C#Cc1cc(Cl)ccc1OCC(=O)O

Procedure:
Following the general method as outlined in Example 8, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and 3-bromo-4-hexylpyridine (Intermediate 13), the title compound was obtained as a beige solid after purification by preparative HPLC.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:16]=[C:17]([C:21]([NH:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:55])=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:38]5[CH2:43][CH2:42][N:41](C(OCC6C=CC=CC=6)=O)[C@@H:40]([CH3:54])[CH2:39]5)[CH:32]=4)[CH:30]=3)=[O:22])[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3]>CO.[Pd]>[F:55][C:28]1[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:38]3[CH2:43][CH2:42][NH:41][C@@H:40]([CH3:54])[CH2:39]3)[CH:32]=2)=[CH:30][C:25]([CH2:24][NH:23][C:21]([C:17]2[CH:16]=[C:15]([CH2:14][CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:4])[CH3:3])=[O:7])[CH2:13][CH2:12]3)[CH:20]=[CH:19][CH:18]=2)=[O:22])=[CH:26][CH:27]=1
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)ccc3F)c2)CCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)ccc3F)c2)CCN1
Yield: 4.9 %

Procedure:
A solution of phenylmethyl (2S)-4-[(5′-{[({3-[(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)methyl]phenyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate (1.5 g, 2.0 mmol) and 10% Pd/C (450 mg) in methanol (50 mL) was allowed to react with H2 at rt under atmospheric pressure for 12 hours. The solvent was removed under vacuum. The resulting residue was purified by loading onto 20 g aminopropyl SPE cartridge and eluting sequentially with DCM (3×50 mL), EtOAc (3×50 mL), and MeOH (3×50 mL). The methanol fractions were combined and evaporated to give the title compound as a pale yellow solid (60 mg, 35%). LC/MS: m/z, 615 (M+H), 1.93 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[S:42](Cl)(=[O:44])=[O:43]>ClC(Cl)C>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)[S:42]([C:38]2[S:37][CH:41]=[CH:40][CH:39]=2)(=[O:44])=[O:43])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2cccs2)c1
Reaction time: 24 h
Yield: 53.1 %

Procedure:
To a solution of {3-[(4-thiazol-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester (87.3 mg, 0.213 mmol), prepared in Step A of Example 13i, triethylamine (47.3 mg, 0.234 mmol) and dichloroethane (10 mL) was added thiophene-2-sulfonyl chloride (42.7 mg, 0.234 mmol). The reaction was stirred for 24 h and additional triethylamine (0.234 mmol) and thiophene-2-sulfonyl chloride (42.7 mg, 0.234 mmol) were added. The reaction was stirred for an additional 24 h. The organic solution was washed sequentially with 5.5% HCl, water, saturated sodium bicarbonate solution, and brine. The organic solution was dried (MgSO4), filtered, and concentrated. Flash chromatography (CHCl3:MeOH 99:1) provided the title compound of Step A (63 mg). MS 556 (M+1)
Reaction SMILES: [CH2:1]([C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2)[CH3:2].[Br:13]Br.S([O-])([O-])=O.[Na+].[Na+]>>[Br:13][C:5]12[CH2:11][CH:9]3[CH2:8][CH:7]([CH2:12][C:3]([CH2:1][CH3:2])([CH2:10]3)[CH2:4]1)[CH2:6]2
Reactant: CCC12CC3CC(CC(C3)C1)C2
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: CCC12CC3CC(CC(Br)(C3)C1)C2
Yield: 83 %

Procedure:
Mix 0.034 mol of ethyl adamantane with a ten times excess of bromine (0.33 mol). Heat slowly and stir under reflux for 4 hrs. Then allow to cool and pour onto ice water. Decompose the excess bromine with sodium sulfite until discoloration of the aqueous solution. Subsequently extract with ether, wash the combined organic phases with sodium bicarbonate solution, dry with magnesium sulfate, filter and evaporate to dryness under vacuum. Recrystallize the residue from methanol. (Yield: 83%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (262 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a pink foam (335 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[O:18][CH:19]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH:20]([NH2:22])[CH3:21].[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)=[CH:4][C:3]=1[O:18][CH:19]([C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)[CH:20]([NH:22][S:33]([CH:30]1[CH2:32][CH2:31]1)(=[O:35])=[O:34])[CH3:21]
Reactant: CC(N)C(Oc1cc2cnn(-c3ccc(F)cc3)c2cc1Cl)c1ccc(F)cc1
Reactant: O=S(=O)(Cl)C1CC1
Product: CC(NS(=O)(=O)C1CC1)C(Oc1cc2cnn(-c3ccc(F)cc3)c2cc1Cl)c1ccc(F)cc1

Procedure:
Prepared according to the procedure described for Example 1 starting with (1RS,2SR)-1-[6-chloro-1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-fluorophenyl)propan-2-amine (35a-rac-2, 55 mg, 0.13 mmol) and cyclopropylsulphonyl chloride (42 μl, 0.4 mmol). Yield: 2 mg (3%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][CH:20]=[CH:21][CH:22]=O.C([O-])(=O)C.[NH4+]>C(N(CC)CC)C>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][C:15]2[N:19]=[CH:20][CH:21]=[CH:22][C:14]=2[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(NC(=O)OCc2ccccc2)CC1
Reactant: NC=CC=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Product: O=C(NC1CCc2ncccc2C1)OCc1ccccc1
Temperature: 115 °C
Reaction time: 72 h
Yield: 10.6 %

Procedure:
A mixture of 4-benzyloxycarbonylaminocyclohexanone (13.75 g, 55.6 mmol), 3-aminopropenal (5.57 g, 78.4 mmol), and ammonium acetate (0.14 g, 1.78 mmol) in triethylamine (85 mL) was stirred at 115° C. under nitrogen for 3 d. The reaction mixture was then partitioned between chloroform and water. The organic layer was separated, washed sequentially with water, saturated aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate, and evaporated under vacuum to yield a residue. The residue was subjected to silica gel chromatography (eluted with 5% methanol in methylene chloride) to obtain the title compound (1.67 g, 10.5%) as a brown oil. 3C NMR (400 MHz, CDCl3) δ 155.6, 147.5, 137.2, 136.4, 129.2, 128.5, 128.1, 121.2, 66.7, 46.2, 35.2, 30.1, 28.7. 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J=4.4 Hz, 1H), 7.27 (m, 6H), 6.98 (dd, J=4.8, 7.5 Hz, 1H), 5.03 (s, 2H), 4.85 (br s, 1H), 4.00 (br s, 1H), 3.06 (d, J=16.3 Hz, 1H), 2.97 (t, J=6.6 Hz, 2H), 2.62 (dd, J=7.9, 16.0 Hz, 1H), 2.08 (d, J=8.4 Hz, 1H), 1.82 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]#[N:12].[K].[C:14]1([SH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(S)C=CC=CC=1.[OH-].[K+]>CO.CN(C)C=O>[C:14]1([S:20][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[C:11]#[N:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Sc1ccccc1
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: N#Cc1cc([N+](=O)[O-])ccc1Sc1ccccc1
Temperature: 105 °C
Reaction time: 2.5 h

Procedure:
4-Chloro-3-cyanonitrobenzene (12.5 g, 6.84 mmol) was added portionwise to a stirred N,N-dimethylformamide (50 mL) solution of thiophenol potassium salt [prepared by adding thiophenol (7.1 mL, 6.9 mmol) to a solution of potassium hydroxide (3.84 g, 6.84 mmol) in methanol followed by removal of the methanol in vacuo]. After stirring at 105° C. for 2.5 hours the mixture was poured into ice-water, filtered, the collected solid washed with water, dissolved in 300 mL of refluxing ethanol (charcoal), filtered, treated with 35 mL of water and refrigerated. The resulting pale yellow solid weighed 13.3 g (76%), mp 82°-84° C. 1H-NMR (250 MHz, CDCl3): 6.93 (d, 1H, J=9.0 Hz, aromatic), 7.51-7.62 (m, 5H, aromatic), 8.12(dd, 1H, J=9.2, 2.5 Hz, aromatic), 8.46 (d, 1H, J=2.5 Hz, aromatic). MS (CI, CH4): 257(M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][C:13](O)=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[OH:14][CH2:13][CH2:12][CH:10]1[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)O)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CCO)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A solution of 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)acetic acid (529 mg, 2.46 mmol) in THF (5.29 mL) was cooled to 0° C. and treated with a borane-methyl sulfide complex 2M in THF (2.46 mL, 4.92 mmol), then slowly warmed to rt. After stirring for 18 h, the reaction mixture was quenched by drop-wise addition of 2 N NaOH (7 mL) then extracted with dichloromethane (4×30 mL). The organic layers were combined, dried (MgSO4), and concentrated to give tert-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate (495 mg, 2.46 mmol, 100%) as a colorless oil. 1H NMR (CDCl3) δ: 3.96 (t, J=8.3 Hz, 2H), 3.47-3.64 (m, 4H), 2.50-2.67 (m, 1H), 1.73-1.86 (m, 2H), 1.37 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[C:7]3[C:11](=[CH:12][CH:13]=[C:5]2[S:4][CH:3]=1)[NH:10][C:9]1[CH2:14][CH2:15][NH:16][CH2:17][C:8]3=1.CN(C)P(=O)(N(C)C)N(C)C.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)[CH2:37][CH2:38][CH2:39]I)=[CH:32][CH:31]=1>CN(C)C=O>[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH:36]([C:41]2[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=2)[CH2:37][CH2:38][CH2:39][N:16]2[CH2:15][CH2:14][C:9]3[NH:10][C:11]4[C:7]([C:8]=3[CH2:17]2)=[C:6]2[C:2]([CH3:1])=[CH:3][S:4][C:5]2=[CH:13][CH:12]=4)=[CH:34][CH:35]=1
Reactant: Cc1csc2ccc3[nH]c4c(c3c12)CNCC4
Reactant: Fc1ccc(C(CCCI)c2ccc(F)cc2)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CN(C)C=O
Product: Cc1csc2ccc3[nH]c4c(c3c12)CN(CCCC(c1ccc(F)cc1)c1ccc(F)cc1)CC4
Temperature: 80 °C

Procedure:
2.4 g of 1-methyl-7,8,9,10-tetrahydrothieno[3,2-e]pyrido[4,3-b]indole are dissolved in 50 ml of dimethylformamide and 10 ml of hexamethylphosphoric acid triamide 4.5 g of 4,4-bis-(4-fluorophenyl)butyl iodide are added and the mixture is warmed to 80° C. under N2 for 5 hours. The solvent is then evaporated off; the residue is taken up in chloroform, the chloroform mixture is washed with water, dried and evaporated, the residue is chromatographed on Al2O3 with chloroform and the product is recrystallised from isopropanol. Melting point: 158° C.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].Cl[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][CH3:17]>>[OH:4][CH2:3][CH2:2][N:1]([CH2:17][CH2:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:9]=1)[CH2:5][CH2:6][OH:7]
Reactant: CCOc1ccccc1Cl
Reactant: OCCNCCO
Product: OCCN(CCO)CCOc1ccccc1

Procedure:
2-[(2-Hydroxy-ethyl)-(2-phenoxy-ethyl)-amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (15.0 g, 150). and 2-chloro-phenetol (15.6 g, 100 mmol). Yield 18 g, (80%); Colorless oil; MS: 226 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([CH3:29])[CH2:15][C:16]3[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([O:24]CC)=[O:23])=[CH:18][CH:17]=3)[NH:8][C:7]=2[N:6]([CH2:30][CH2:31][CH3:32])[C:5]1=[O:33])[CH2:2][CH3:3].[OH-].[K+]>C(O)C.O>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([CH3:29])[CH2:15][C:16]3[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:18][CH:17]=3)[NH:8][C:7]=2[N:6]([CH2:30][CH2:31][CH3:32])[C:5]1=[O:33])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)c2nc(C(C)Cc3ccc(OCC(=O)OCC)cc3)[nH]c2n(CCC)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCn1c(=O)c2nc(C(C)Cc3ccc(OCC(=O)O)cc3)[nH]c2n(CCC)c1=O
Reaction time: 3 h
Yield: 80.7 %

Procedure:
Dissolve (-)-2-[4-[2-(2,3,6,9-tetrahydro-1,3-dipropyl-2,6-dioxo-1H-purin-8-yl)propyl]phenoxy]acetic acid, ethyl ester (0.62 g, 1.36 mmol) in ethanol (15 mL) and treat with a solution of potassium hydroxide (0.091 g, 1.63 mmol) in water (15 mL). Stir for 3 hours, add water (200 mL) and wash with ethyl ether (300 mL). Acidify the aqueous phase with 10% hydrochloric acid and extract into chloroform (4×150 mL). Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound (0.47 g, 81%); [α]d 20 =-79.1° (C=0.537, DMSO).
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][C:16]([OH:18])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.[CH3:31][Si:32]([CH3:37])([CH3:36])[CH2:33][CH2:34]O>C(Cl)Cl>[CH3:31][Si:32]([CH3:37])([CH3:36])[CH2:33][CH2:34][O:17][C:16](=[O:18])[CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)COCCOCCOCc1ccccc1
Reactant: C[Si](C)(C)CCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C[Si](C)(C)CCOC(=O)COCCOCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 97.5 %

Procedure:
10-Phenyl-3,6,9-trioxadecanoic acid (1.71 g, 6.71 mmol) was dissolved in CH2Cl2 (13.4 mL) and the solution was cooled to 0° C. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (1.41 g, 7.38 mmol) and N,N-dimethylaminopyridine (DMAP) (41.0 mg, 0.34 mmol) were added, and the suspension was stirred for 10 minutes at 0° C. 2-(Trimethylsilyl)ethanol (872.4 mg, 7.38 mmol) was added dropwise via syringe, and the solution was stirred for 20 minutes while warming to room temperature. The reaction was quenched with H2O and extracted with Et2O (3×50 mL). The combined Et2O extracts were washed sequentially with 10% HCl (1×50 mL), 5% NaHCO3 (1×50 mL), and saturated NaCl (1×50 mnL), and dried over Na2SO4. Concentration followed by flash chromatography (silica, 4:1 hexanes/EtOAc) afforded 10-phenyl-3,6,9-trioxadecanoic acid 2-(trimethylsilyl)ethyl ester (2.32 g, 97% yield). Rf=0.26 (4:1 hexanes/EtOAc); IR (neat): 3500-3400, 3000-2700, 1751, 1733, 1615, 1455, 1250, 1148, 1124 cm−1; 1H NMR (300 MHz, CDCl3): δ 7.32-7.23 (m, 5H), 4.54 (s, 2H), 4.24-4.18 (m, 2H), 4.10 (s, 2H), 3.72-3.59 (m, 8H), 1.01-0.95 (m, 2H), 0.01 (s, 9H); 13C NMR (75 MHz, CDCl3): δ 170.5, 138.2, 128.3, 127.6, 127.5, 73.2, 70.8, 70.6, 69.4, 68.8, 63.0, 17.3, −1.6; LRMS (LSIMS, 3-NBA): m/z 377.2 [M+Na+, calc'd for C18H30O5NaSi 377.5].
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][Mg+].[Br-]>C1COCC1>[Cl:1][C:2]1[C:11]([CH:12]([OH:13])[CH3:15])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=Cc1cc2ccc(F)cc2nc1Cl
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)c1cc2ccc(F)cc2nc1Cl
Reaction time: 8 h

Procedure:
To a suspension of 2-chloro-7-fluoroquinoline-3-carbaldehyde (44.7 g, 213 mmol) in THF (600 mL) was treated with MeMgBr (78 mL, 1.1 eq) dropwise at −20° C. After overnight, the reaction was quenched with NH4Cl solution and extracted with Ether (300 mL and 100 mL). The organics were washed with water, brine, dried over Na2SO4, concentrated and recrystallized from EtOAc (100 mL) and hexane (1 L). A pale yellow solid was obtained (41 g, 85%). 1H NMR (400 MHz, CDCl3) δ ppm 8.41 (s, 1H), 7.87 (dd, J=8.0, 4.0 Hz, 1H), 7.67 (dd, J=8.0, 2.0 Hz, 1H), 7.38 (td, J=8.0, 2.0 Hz, 1H), 5.38 (q, J=4.0 Hz, 1H), 1.63 (d, J=4.0 Hz, 3H). Mass Spectrum (ESI) m/e=226 (M+1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:12]=[N:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][C:8]=1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)=O.[C:28]([C:30]1([OH:38])[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1)#[CH:29].C(N(CC)CC)C.N>CN(C)C=O>[C:13]1([C:10]2[N:11]=[N:12][C:7]([C:29]#[C:28][C:30]3([OH:38])[CH:35]4[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]4)[CH2:31]3)=[C:8]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Oc1nnc(-c2ccccc2)cc1Cc1ccccc1)C(F)(F)F
Reactant: C#CC1(O)CN2CCC1CC2
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OC1(C#Cc2nnc(-c3ccccc3)cc2Cc2ccccc2)CN2CCC1CC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
A mixture of 484 mg of 3-phenyl-5-benzyl-6-pyridazyl trifluoromethane sulfonate, 223 mg of 3-ethynyl-3-quinuclidinol, 284 mg of tetrakis (triphenylphosphine)palladium(0), 47 mg of cuprous iodide, 513 μl of triethylamine and 5.0 ml of N,N-dimethylformamide was heated under stirring at 80° C. for 2 hours in a nitrogen atmosphere. The reaction solution was poured into aqueous dilute ammonia and the mixture was extracted with ethyl acetate. The organic phase was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (20:1) and then crystallized from hexane/ethyl acetate, to give 413 mg of the target compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N+:13]([O-])([OH:15])=[O:14].[OH-].[NH4+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:11]([N+:13]([O-:15])=[O:14])=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C)c2ncccc12
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1c([N+](=O)[O-])cc(C)c2ncccc12
Temperature: -15 °C
Reaction time: 0.17 h

Procedure:
5,8-dimethylquinoline (1.25 g), in a 250 mL round bottom flask is cooled to 0° C. in an ice-NaCl bath under argon. Concentrated sulfuric acid (50 mL) is added slowly via addition funnel so that the internal temperature does not exceed 5° C. The solution is allowed to stir a few minutes then cooled to -15° C. in an ethylene glycol-dry ice bath. Nitric acid (1.7 mL, 69-71%) in sulfuric acid (50 mL) is added dropwise (via syringe) at such a rate that the reaction temperature does not exceed -3° C. After 10 minutes, the reaction is poured into a beaker of ice and basified slowly to pH 10 by the addition of ammonium hydroxide solution (28-30%). The product is extracted with ethyl acetate (3×500 mL). The organic layer is dried over MgSO4, filtered, and rotary evaporated to yield crude product (2.6 g) which is flash chromatographed on silica gel eluting with 15% ethyl acetate/hexane. Compound-containing fractions are combined and rotary evaporated to yield 5,8-dimethyl-6-nitroquinoline.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH3:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[N:12]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[O:21][CH3:22])=[C:13]=[S:14]>CN(C=O)C>[CH3:22][O:21][C:20]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[NH:12][C:13]([NH:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH3:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1)=[S:14]
Reactant: COc1ccncc1N=C=S
Reactant: Cn1cnc2c(N)cccc21
Solvent: CN(C)C=O
Product: COc1ccncc1NC(=S)Nc1cccc2c1ncn2C
Temperature: 25 °C
Reaction time: 64 h

Procedure:
A mixture of 4-amino-1-methylbenzimidazole (0.100 g, 0.679 mmol) and 3-isothiocyanato-4-methoxy-pyridine (0.113 mg, 0.680 mmol, example 4, step a) in DMF was stirred at room temperature for 64 hours. After removal of DMF in vacuo, the residue was treated with water. The precipitated solid was filtered, washed with water, and dried to give a portion of the title compound. The filtrate was concentrated and the oily brown residue was dried under vacuum to provide a second potion of the title compound.