Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4]N.[CH2:7]([N:9]([CH2:30][CH3:31])[CH2:10][CH:11]([N:13]1[C:26]2[CH:25]=[C:24]([C:27](=[S:29])[NH2:28])[CH:23]=[CH:22][C:21]=2[S:20][C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])[CH3:8].S>C(O)C>[CH2:30]([N:9]([CH2:7][CH3:8])[CH2:10][CH:11]([N:13]1[C:26]2[CH:25]=[C:24]([C:27](=[S:29])[NH:28][CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1])[CH:23]=[CH:22][C:21]=2[S:20][C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])[CH3:31]
Reactant: CC(C)CCN
Reactant: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Agent: S
Solvent: CCO
Product: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(=S)NCCC(C)C)cc21
Reaction time: 16 h

Procedure:
3-Methylbutylamine (10.7 cc) is added to a solution of 10-(1-diethylamino-2-propyl)-2-phenothiazinecarbothioamide acid fumarate, L series (3 g), in absolute ethanol (45 cc) and this solution is saturated with hydrogen sulphide. The mixture is then brought to a temperature in the region of 105° C. for 16 hours and concentrated to dryness under reduced pressure (30 mm Hg; 4 pKa). The residual orange-colored oil is purified by chromatography on a column (height: 35 cm; diameter: 3 cm) of silica gel (0.2-0.063 mm), eluting with mixture (400 cc) of ethyl acetate and cyclohexane (70:30 by volume) and collecting 30-cc fractions. Fractions 7 to 11 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 pKa) at 50° C. to give 10-(1-diethylamino-2-propyl)-N-(3-methyl-1-butyl)-2-phenothiazinecarbothioamide, L series (3.1 g), in the form of an orange-colored oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH2:19][F:20])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:21][OH:22].C[O-].[Na+].O>O1CCCC1>[CH3:21][O:22][C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH2:19][F:20])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CO
Reactant: FCCOc1ccc2cc(-c3ccnc(Cl)n3)sc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1nccc(-c2cc3ccc(OCCF)cc3s2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
2-(2-Chloropyrimidine-4-yl)-6-(2-fluoroethoxy)benzothiophene (105b, 80 mg, 0.26 mmol) obtained in Preparation Example 20 was dissolved in anhydrous tetrahydrofuran (4 mL). A 0.5 M sodium methoxide methanol solution (NaOMe in MeOH, 1.0 mL, 0.5 mmol) was added to the reaction mixture and stirred at room temperature for 18 hours. To the reaction mixture was added water, and organic compounds were extracted with ethyl acetate and evaporated after a treatment with sodium sulfate. Column chromatography was performed to give the target compound 2-(2-methoxypyrimidine-4-yl)-6-(2-fluoroethoxy)benzothiophene (1-34, 60 mg, 70%) as a yellow solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](N1C=CN=C1)=[O:11])[CH2:2]2.[OH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:19]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][C:10](=[O:11])[O:9][C@@H:3]1[CH:4]2[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]2)[CH2:2]1
Reactant: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Reactant: Oc1ccccc1-c1ccccc1
Product: O=C(Oc1ccccc1-c1ccccc1)O[C@H]1CN2CCC1CC2

Procedure:
The desired product was prepared by reacting imidazole-1-carboxylic acid (R)-1-aza-bicyclo[2.2.2]oct-3-yl ester with 2-hydroxy biphenyl.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][N:7]=1)([O-])=[O:2].CO.C[O-].[Li+].C(=O)(O)[O-].[Na+].C(Cl)[Cl:30]>[Ti](Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[O:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:4]([Cl:30])=[N:1][OH:2])=[N:7][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])CCc1ccc(Oc2ccccc2)cn1
Reactant: ClCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[O-]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CO
Product: ON=C(Cl)Cc1ccc(Oc2ccccc2)cn1
Reaction time: 0.05 h
Yield: 69 %

Procedure:
To 2-(2-nitro-ethyl)-5-phenoxy-pyridine (76 mg, 0.31 mmol) described in Manufacturing Example 121-1-4 and methanol (6.0 mL) was added lithium methoxide (24 mg, 0.62 mmol) at room temperature, which was stirred for 3 minutes, and then the solvent was evaporated under a reduced pressure. Methylene chloride (10 mL) was added to the residue, titanium (IV) chloride (0.11 mL, 1.0 mmol) was added at room temperature, which was stirred for 10 minutes. Cold aqueous sodium bicarbonate and ethyl acetate were added to the reaction solution, which was filtered through a Celite pad, and then the organic layer was separated. The organic layer was concentrated under a reduced pressure to obtain the title compound (56 mg, 69%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]1([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH:35](=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(O)(=O)C>ClCCl.O>[CH2:35]([NH:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][N:24]2[CH2:23][CH2:22][N:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:26][CH2:25]2)=[CH:33][CH:32]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(CN2CCN(c3ccccc3)CC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc(CNc2ccc(CN3CCN(c4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
Sodium triacetoxyborohydride (282 mg, 1.34 mmol) was added in one portion to a stirred solution of 4-(4-phenyl-piperazin-1-yl methyl)-phenylamine, benzaldehyde (75 μl, 0.73 mmol) and acetic acid (43 μl, 0.73 mmol) in dry dichloromethane (6 ml) and the reaction was stirred for 16 hours at room temperature. Water was added and the organic layer separated then washed with brine and dried over magnesium sulfate. The solution was concentrated in vacuo and the crude residue purified by column chromatography (hexanes/ethyl acetate 1:1) to afford the title compound as a colourless solid (175 mg, 72%). HPLC retention time 7.53 min. Mass spectrum (ES+) m/z 358 (M+H).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1C=C[CH:5]=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:20]=[CH:19][C:14]([O:15][CH2:16][CH2:17][OH:18])=[CH:13][CH:12]=1.O1C=CCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C(Cl)Cl>[O:9]1[CH2:1][CH2:2][CH2:3][CH2:4][CH:5]1[O:18][CH2:17][CH2:16][O:15][C:14]1[CH:19]=[CH:20][C:11]([Br:10])=[CH:12][CH:13]=1
Reactant: OCCOc1ccc(Br)cc1
Reactant: O=C(O)c1ccccc1
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: Brc1ccc(OCCOC2CCCCO2)cc1

Procedure:
The starting benzoic acid (I) is made by the reaction of 2-(4-bromophenoxy)ethanol (V) with dihydropyran, in the presence of methylene chloride and p-toluenesulfonic acid.H2O, to give 4-(2-tetrahydropyranyloxyethoxy)bromobenzene (VI). The bromobenzene (VI) is converted to 4-(2-tetrahydropyranyloxyethoxy)benzoic acid (VII) by reacting with magnesium, in tetrahydrofuran and dibromoethane, and then with carbon dioxide. Reaction of (VII) with methanol yields the starting benzoic acid (I). ##STR2##
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14].[CH:15]([C:17]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]2[C:18]=1[CH:19]=[CH:20][CH:21]=[N:22]2)=O>C1C=CC=CC=1>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]=[CH:15][C:17]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]2[C:18]=1[CH:19]=[CH:20][CH:21]=[N:22]2
Reactant: O=Cc1ccc(O)c2ncccc12
Reactant: NCCCCCCC1CC2C=CC1C2
Solvent: c1ccccc1
Product: Oc1ccc(C=NCCCCCCC2CC3C=CC2C3)c2cccnc12
Yield: 99.8 %

Procedure:
Amine 4 (0.726 g, 0.00376 mol) and 5-formyl-8-hydroxyquinoline 6 (0.650 g, 0.00376 mol) were dissolved in 40 mL of benzene and refluxed for 18 hours. After cooling, the solvent was removed under reduced pressure to yield the product as an orange solid (1.308 g, 100%). 1H NMR (300 MHz, CDCl3) δ9.75 (1H, dd J=8.79, 1.64); 8.81 (1H, dd, J=1.64, 4.39); 8.59 (1H, s); 7.69 (1H, d, J=8.24); 7.56 (1H, dd, J=4.39, 8.79); 7.19 (1H, d, J=7.69); 6.10 (1H endo, dd, J=2.74, 5.49); 6.06–5.99 (2H exo, m); 5.91 (1H endo, dd, J=2.74, 5.94); 3.67 (2H, t, J=7.14); 2.74 (2H, s); 1.99–1.69 (4H, m); 1.42–1.01 (12H, m); 0.50–0.44 (1H, m). 13C NMR (75 MHz, CDCl3) δ160.8; 154.2; 148.1; 138.4; 137.0; 135.3; 133.0; 132.6; 127.0; 123.3; 123.2; 109.2; 62.9; 49.7; 45.6; 42.7; 38.9; 34.9; 32.6; 31.4; 29.9; 28.8; 27.6. HRMS (EI): calcd for C23H28N2O1 [M]+348.2201, found 348.2186.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][CH2:11]OS(C)(=O)=O)=[N:7][C:6]=2[CH:17]=1.[CH3:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1.CCN(CC)CC>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][CH2:11][N:20]3[CH2:21][CH2:22][CH2:23][C@H:19]3[CH3:18])=[N:7][C:6]=2[CH:17]=1
Reactant: CS(=O)(=O)OCCc1nc2cc(Br)ccc2s1
Reactant: C[C@@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@@H]1CCCN1CCc1nc2cc(Br)ccc2s1
Temperature: 60 °C

Procedure:
The methanesulfonic acid 2-(5-bromo-benzothiazol-2-yl)-ethyl ester from Example 1B, and 2 equivalents (7.3 mmol) of 2-(R)-methylpyrrolidine (at a concentration of 10 mg/mL solution in acetonitrile), was combined with excess Et3N (0.99 g, 9.8 mmol), and the resulting mixture was heated to 60° C. for 2 hr. The solvent was removed under vacuum, and the residue dissolved in CH2Cl2. and washed with saturated NaHCO3 (twice). The organic layer as dried over MgSO4 and concentrated in vacuo to give crude product, 1.15 g (97.1%). 1H NMR (400 MHz, CDCl3) δ ppm 1.06 (d, J=6.04 Hz, 3 H) 1.78-1.6 (m, 3 H) 1.88 (m, 1H) 2.20 (m, 1 H) 2.38 (m, 1H) 2.55 (m, 1H) 3.23 (m, 4 H) 7.37 (dd, J=8.44, 1.85 Hz, 1 H) 7.61 (d, J=8.51 Hz, 1 H) 8.02 (d, J=1.92 Hz, 1 H). MS m/z 125, 127 (M+H)+, (M+3H)+.
Reaction SMILES: C([N:8]1[CH2:27][CH2:26][C:11]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C>[CH3:24][N:23]([CH3:25])[C:21]([N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]2([CH2:26][CH2:27][NH:8][CH2:9][CH2:10]2)[CH2:12][CH2:13]1)=[O:22]
Reactant: CN(C)C(=O)N1CCC2(CCN(Cc3ccccc3)CC2)c2ccccc21
Solvent: CCO
Product: CN(C)C(=O)N1CCC2(CCNCC2)c2ccccc21
Temperature: 45 °C

Procedure:
The crude 1-benzyl-N,N-dimethyl-2′,3′-dihydro-1′H-spiro[piperidine-4,4′-quinoline]-1′-carboxamide 2ab (3.1 g, 8.01 mmol) was dissolved in 30 mL absolute ethanol, flushed with nitrogen, and treated with 500 mg of 10% Pd/C. The flask was flushed with nitrogen then fitted with an H2 balloon. The rapidly stirring solution was heated to 45° C. overnight. The reaction was filtered through Celite and concentrated to yield N,N-dimethyl-2′,3′-dihydro-1′H-spiro[piperidine-4,4′-quinoline]-1′-carboxamide 2ac as an amber oil. LC/MS (10-99% CH3CN/0.05% TFA gradient over 5 min): m/z 274.2, retention time 1.39 minutes.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C.[CH3:42][C:43]1[CH:44]=[C:45]([CH2:50][CH:51]([NH:55][C:56]([N:58]2[CH2:63][CH2:62][CH:61]([N:64]3[CH2:73][C:72]4[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=4)[NH:66][C:65]3=[O:74])[CH2:60][CH2:59]2)=[O:57])[C:52]([OH:54])=O)[CH:46]=[CH:47][C:48]=1[CH3:49].[CH3:75][N:76]1[CH2:81][CH2:80][N:79]([CH:82]2[CH2:87][CH2:86][NH:85][CH2:84][CH2:83]2)[CH2:78][CH2:77]1>CN(C=O)C.C1COCC1>[CH3:42][C:43]1[CH:44]=[C:45]([CH:46]=[CH:47][C:48]=1[CH3:49])[CH2:50][CH:51]([NH:55][C:56]([N:58]1[CH2:59][CH2:60][CH:61]([N:64]2[CH2:73][C:68]3[C:67](=[CH:72][CH:71]=[CH:70][CH:69]=3)[NH:66][C:65]2=[O:74])[CH2:62][CH2:63]1)=[O:57])[C:52]([N:85]1[CH2:84][CH2:83][CH:82]([N:79]2[CH2:78][CH2:77][N:76]([CH3:75])[CH2:81][CH2:80]2)[CH2:87][CH2:86]1)=[O:54]
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: Cc1ccc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.90 g (2.80 mmol) TBTU, 0.35 g (2.55 mol) HOBt, 0.49 mL (2.80 mmol) ethyldiisopropylamine was added to a mixture of 1.15 g (2.55 mol) 3-(3,4-dimethyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 100 mL THF and the mixture was stirred for 30 min at RT. Then 20 mL DMF was added, the mixture was stirred for 15 min and combined with 0.49 g (2.65 mmol) 1-methyl-4-piperidin-4-yl-piperazine. The reaction mixture was stirred overnight at RT, evaporated down under reduced pressure and the residue was combined with 70 mL saturated NaHCO3 solution. The aqueous phase was extracted three times with DCM, the combined organic phases were dried over Na2SO4, filtered and evaporated down under reduced pressure. The residue was purified by column chromatography over silica gel, the product fractions were evaporated down under reduced pressure, triturated with diethyl ether and suction filtered.
Reaction SMILES: I[C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C(N(CCCC)CCCC)CCC.[CH:31]([CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)=[CH2:32].C(Cl)(Cl)Cl>CN(C=O)C.O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CO>[CH:33]1([CH:31]=[CH:32][C:2]2[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=2)[C@@H:7]2[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: C=CC1CCCCC1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1C=CC1CCCCC1
Temperature: 100 °C
Yield: 84 %

Procedure:
5-iodo-2′-deoxyuridine (1) (505 mg, 1.42 mmol) was dissolved in DMF (2.5 ml) and dioxane (2.5 ml), and palladium acetate (33 mg, 0.14 mmol) was added thereto to obtain a suspension. Tributylamine (340 μl, 1.41 mmol) and vinylcyclohexane (2.0 ml, 14.1 mmol) were further added to the mixture, which was heated by microwaves for the reaction at 100° C. for 20 minutes. Disappearance of the raw materials was confirmed by TLC (CHCl3:MeOH=9:1). Thereafter, the purification was carried out by using a silica gel column with the development solvent of CHCl3 and MeOH(CHCl3:MeOH=9:1). (2b) was found to be 400 mg, 1.19 mmol and the yield was 84%. The target compound was determined by 1H NMR for identification. Further, mass analysis was carried out by MALDI-TOF MS and it was identified as the target compound (calcd. for C17H25N2O5 [M+H]+ 337.176, found 337.156).
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:16]1([C:3]2[C:2]([N:31]3[CH2:32][CH2:33][N:28]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=4)[CH2:29][CH2:30]3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccccn4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 106.5 %

Procedure:
A solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (50 mg, 0.15 mmol, 1.00 equiv), 1-(pyridin-2-yl)piperazine (50 mg, 0.31 mmol, 2.00 equiv), and DIEA (100 mg, 0.78 mmol, 3.00 equiv) in DMF (10 mL) was placed in a 20-mL sealed tube under an inert atmosphere and stirred overnight at 100° C. in an oil bath and then concentrated under vacuum. Purification via silica gel column (ethyl acetate/petroleum ether (1:10)) yielded 68 mg (crude) of methyl 2-phenyl-3-(4-(pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylate as a yellow solid
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1([C:12](=[NH:15])[NH:13][OH:14])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])#[C:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[Cl:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1([C:12](=[NH:15])[NH:13][O:14][C:16](=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: N=C(NO)C1(COCCCl)CCOCC1
Product: CCOC(=O)C=C(ONC(=N)C1(COCCCl)CCOCC1)C(=O)OCC
Yield: 84 %

Procedure:
Reaction of 4-((2-chloroethoxy)methyl)-N-hydroxytetrahydro-2H-pyran-4-carboximidamide (10.50 g, 44.36 mmol) with diethyl acetylenedicarboxylate gave 15.25 g (84% yield) of title material as light yellow oil after chromatography. 1HNMR 400 MHz (CDCl3) δ (ppm): (mixture of E/Z isomers ratio˜3:2) 1.25-1.4 (6H, quartet of triplets), 1.6 (2H, m), 2.05 (2H, m), 3.52 (1H, s), 3.54 (1H, s), 3.65-3.85 (8H, m), 4.16-4.23 (2H, m), 4.28-4.41 (2H, m), 5.33 (1H, broad s), 5.59 (1H, broad s), 5.64 (1H, s), 5.78 (1H, s). MS (ESI+) m/e 407 [M+H+].
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:20])[CH2:15][S:16][C:17](=O)[CH3:18])([CH3:3])[CH3:2].CO.[OH-].[Na+].BrCC[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][N:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40][CH2:39]1>C(OCC)(=O)C>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:20])[CH2:15][S:16][CH2:17][CH2:18][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][N:41]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:40][CH2:39]1)([CH3:3])[CH3:2]
Reactant: CC(=O)SCC(=O)Nc1c(C(C)C)cccc1C(C)C
Reactant: BrCCCCCCCCCCCCN1CCN(c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CSCCCCCCCCCCCCN1CCN(c2ccccc2)CC1
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
To a mixture of 1.47 g of N-(2,6-diisopropylphenyl)-2-(acetylthio)acetamide and 12 ml of methanol was added dropwise 1.7 ml of a 30% aqueous sodium hydroxide solution at 0° C. in an argon atmosphere. After stirring for 30 minutes, a mixture of 2.05 g of 1-bromo-12-(4-phenylpiperazinyl)dodecane synthesized in (1) above and 14 ml of methanol was added thereto, followed by stirring at 60° C. for 1 hour and then at room temperature for 16 hours. To the reaction mixture was added 100 ml of ethyl acetate, and the mixture was washed successively with water and a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography using a 1:2 mixture of ethyl acetate and hexane as a developing solvent. The resulting crystals were recrystallized from isopropyl alcohol-water to yield 1.66 g of the title compound as white powder (m.p.=76.5° -77.5° C.).
Reaction SMILES: C([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34]C=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)C.[N:40]1([C:47](=O)[CH2:48]Cl)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[N:40]1([CH2:47][CH2:48][O:10][C:8]2[CH:7]=[CH:6][C:36]([CH2:37][CH2:32][CH2:31][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=3[C@@H:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=4[CH2:15]3)=[CH:35][CH:34]=2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: O=C(CCl)N1CCCCCC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1cc(NCCCc2ccc(OCCN3CCCCCC3)cc2)c([C@@H]2CCc3cc(O)ccc3C2)cc1OC
Yield: 89.2 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and 1-azepan-1-yl-2-chloroethanone (9.5 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.5 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]([C:9]1[CH:33]=[CH:32][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=3)=[O:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[CH3:36][Mg]Br.C(OCC)C>O1CCCC1>[F:35][C:2]([F:1])([F:34])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[CH2:15][CH2:16][CH:17]([C:20]([C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:26][CH:27]=3)([OH:21])[CH3:36])[CH2:18][CH2:19]2)=[CH:32][CH:33]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: C[Mg]Br
Reactant: CC(=O)Nc1ccc(C(=O)C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(C)(O)C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
N-(4-(1-(4-(1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-yl)benzyl)piperidine-4-carbonyl)phenyl)acetamide (1.702 mmol, 855 mg) was dissolved in anhydrous tetrahydrofuran (20 mL) under nitrogen and cooled to −78° C. 3M methylmagnesium bromide in diethyl ether (3.40 mmol, 1.134 mL) was added and the mixture stirred at −78° C. for 30 minutes before allowing to warm to room temperature and stirring for a further 4 hours. After this time, further 3M methylmagnesium bromide in diethyl ether (3.40 mmol, 1.134 mL) was added and the mixture stirred for 2 hours. The mixture was cooled to 0° C. and quenched with a saturated solution of ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (100 mL) and washed with water (30 mL) then brine (30 mL). The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting with dichloromethane to 15% methanol/dichloromethane) to afford the title compound (300 mg). MS (ESI) m/z 519.2 [M+H]+
Reaction SMILES: O[CH2:2][C:3]1[S:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[Br-:9].[C:10]1([PH+:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(#N)C>[Br-:9].[CH3:8][C:5]1[S:4][C:3]([CH2:2][P+:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][CH:6]=1
Reactant: Cc1ccc(CO)s1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CC#N
Product: Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)s1
Temperature: 75 °C

Procedure:
2-Hydroxymethyl-5-methyl-thiophene (4.6 g.) was dissolved in 100 ml. of acetonitrile and 12.2 g. of triphenylphosphonium bromide were added. The reaction mixture was heated to 75° C. for 2.5 hours. After cooling the resulting precipitate was filtered off, washed with benzene and dried at 80° C. under high vacuum. The resulting (5-methyl-2-thenyl)triphenylphosphonium bromide has a m.p. 262°-266° C.
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-])=O)[CH:3]=1.[Cl-].[NH4+]>C1COCC1.CCO.O.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:6])=[CH:7][C:8]=1[F:9]
Reactant: Nc1cc(F)c(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cc(F)c(Br)cc1N
Temperature: 95 °C
Yield: 81.4 %

Procedure:
To a solution of 4-bromo-5-fluoro-2-nitroaniline (1.0 g, 4.3 mmol) in THF (9.0 mL), EtOH (9.0 mL) and H2O (3 mL) was added iron powder (1.2 g, 21.3 mmol) and ammonium chloride (0.34 g, 6.4 mmol), and the mixture was heated at 95° C. for 4 hours. The cooled mixture was diluted with EtOH, filtered through diatomaceous earth until no further color came through the filter, and concentrated. The residue was dissolved in EtOAc, washed with H2O, brine, dried (Na2SO4), filtered and concentrated. Hexane was added and the resulting solid collected by filtration to give the title compound (710 mg, 3.5 mmol, 81%).