Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:22]([CH:23]=[O:24])[CH2:21][CH2:20][C:19]([C:25]([O:27]C)=[O:26])=[CH:18][C:17]=3[CH:29]=2)=[CH:9][CH:8]=1)[CH3:2].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:22]([CH:23]=[O:24])[CH2:21][CH2:20][C:19]([C:25]([OH:27])=[O:26])=[CH:18][C:17]=3[CH:29]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 7-[4-(2-ethoxyethoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.2 g). To the solution was added 1N sodium hydroxide solution (5 ml), and the mixture was stirred at room temperature overnight and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-[4-(2-ethoxyethoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.19 g) as colorless crystals.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[CH3:27][N:28]1[C:32]([S:33](Cl)(=[O:35])=[O:34])=[CH:31][CH:30]=[N:29]1>>[CH3:27][N:28]1[C:32]([S:33]([N:21]2[CH2:20][CH2:19][C:16]3([C:15](=[O:24])[N:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=4)[CH2:18][CH2:17]3)[CH2:23][CH2:22]2)(=[O:35])=[O:34])=[CH:31][CH:30]=[N:29]1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: Cn1nccc1S(=O)(=O)Cl
Solvent: CC(=O)O
Product: Cn1nccc1S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and 2-methyl-2H-pyrazole-3-sulfonyl chloride. Off-white solid. MS (ESI): 459.3 (MH+)
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2([CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)[CH2:3][NH:2]1.C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>ClCCl>[C:26]([N:2]1[CH2:3][C:4]2([CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)CC1(CNCc3ccccc31)O2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1Cc2ccccc2C2(Cc3ccccc3O2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.8 %

Procedure:
To a cooled solution of spiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (8.0 g) and triethylamine (4.1 g) in dichloromethane (35 ml) is added dropwise acetyl chloride (3.2 g) in dichloromethane (20 ml). After stirring at ambient temperature for 20 hours, the reaction mixture is washed with water (2x), saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Removal of the solvent yields a solid (6.2 g), of which 2.5 g is recrystallized from ethyl acetate to yield 1.4 g (56%) of product as a powder, mp 141°-142°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]3[C:17]=2[CH2:18][C:19](O)=[O:20])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:29][NH:30][CH3:31].C(N(CC)CC)C.[C:39]([OH:48])(=[O:47])[CH:40]([CH:42]([C:44]([OH:46])=[O:45])[OH:43])[OH:41]>C(Cl)Cl.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[N:11]([CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15]3)[C:17]=2[CH2:18][C:19]([N:30]([CH3:31])[CH3:29])=[O:20])=[CH:6][CH:7]=1.[CH:40]([OH:41])([C:39]([OH:48])=[O:47])[CH:42]([OH:43])[C:44]([OH:46])=[O:45]
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)O)cc1
Reactant: CNC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)N(C)C)cc1
Temperature: 15 °C
Reaction time: 1 h
Yield: 117.2 %

Procedure:
A suspension of 2-(4-methylphenyl)-6-methylimidazo[1,2-a]-pyridine-3-acetic acid (59.2 g; 0.21 mols) in methylene chloride (820 mL) is added dropwise with oxalyl chloride (29.9 g; 0.23 mols) adjusting the addition according to the gas evolution and keeping the temperature below 35° C. The resulting suspension is added with 2-(4-methylphenyl)-6-methylimidazo[1,2-a]-pyridine-3-acetic acid (59.2 g; 0.21 mols) and oxalyl chloride (29.9 g; 0.23 mols) is added dropwise with the same procedure as in the previous step. The suspension is refluxed for 30 minutes, then cooled to 10÷15° C. and added with N,N-dimethylamine hydrochloride (98% titre, 41 g, 0.49 mols). Keeping the temperature below 15° C., triethylamine (167 g, 1.65 mols) is added dropwise. After one hour at room temperature, water is added (200 mL), the phases are separated and the lower organic phase is washed with a 5% sodium carbonate aqueous solution (200 mL) and subsequently with water (200 mL). The organic phase is concentrated to a residue, which is redissolved in methanol (1100 mL) under reflux, then added with natural tartaric acid (33.0 g, 0.22 mols). The resulting solution is slowly cooled to 0° C. and the precipitated solid is filtered under nitrogen and washed with cold methanol (2×50 mL). The humid solid is taken up in methanol (900 mL), refluxed until dissolution and added with active carbon (5 g). The hot clear solution is filtered, then slowly cooled to 0° C. and the precipitated solid is filtered under nitrogen, washed with cold methanol (2×50 mL) then dried at 50° C. under vacuum to yield Zolpidem tartrate (112.6 g, 100.8% titre, 99.85% HPLC purity, 70.1% yield).
Reaction SMILES: CC(C)(C)[C@H](NC(=O)[C@@H](NC)C)C(N1[C@H](C(N[C@H]2C3C(=CC=CC=3)CCC2)=O)CC2C(=CC(C(N[C@H]3C[C@@H](C(=O)N[C@H]4C5C(=CC=CC=5)CCC4)N(C(=O)[C@@H](NC(=O)[C@@H](NC)C)C(C)(C)C)C3)=O)=CC=2)C1)=O.[CH:73]1[C:85]2[CH:84]([CH2:86][O:87][C:88]([NH:90][C@@H:91]([C:142]([CH3:145])([CH3:144])[CH3:143])[C:92]([N:94]3[C@H:98]([C:99](=[O:111])[NH:100][C@H:101]4[C:110]5[C:105](=[CH:106][CH:107]=[CH:108][CH:109]=5)[CH2:104][CH2:103][CH2:102]4)[CH2:97][C@H:96]([C:112]4[CH:121]=[C:120]5[C:115]([CH2:116][C@@H:117]([C:129](=[O:141])[NH:130][C@H:131]6[C:140]7[C:135](=[CH:136][CH:137]=[CH:138][CH:139]=7)[CH2:134][CH2:133][CH2:132]6)[N:118](C(OC(C)(C)C)=O)[CH2:119]5)=[CH:114][CH:113]=4)[CH2:95]3)=[O:93])=[O:89])[C:83]3[C:78](=[CH:79][CH:80]=[CH:81][CH:82]=3)[C:77]=2[CH:76]=[CH:75][CH:74]=1>>[CH3:143][C:142]([CH3:145])([CH3:144])[C@H:91]([NH:90][C:88](=[O:89])[O:87][CH2:86][CH:84]1[C:85]2[CH:73]=[CH:74][CH:75]=[CH:76][C:77]=2[C:78]2[C:83]1=[CH:82][CH:81]=[CH:80][CH:79]=2)[C:92](=[O:93])[N:94]1[CH2:95][C@@H:96]([C:112]2[CH:121]=[C:120]3[C:115]([CH2:116][C@@H:117]([C:129](=[O:141])[NH:130][C@H:131]4[C:140]5[C:135](=[CH:136][CH:137]=[CH:138][CH:139]=5)[CH2:134][CH2:133][CH2:132]4)[NH:118][CH2:119]3)=[CH:114][CH:113]=2)[CH2:97][C@H:98]1[C:99](=[O:111])[NH:100][C@H:101]1[C:110]2[C:105](=[CH:106][CH:107]=[CH:108][CH:109]=2)[CH2:104][CH2:103][CH2:102]1
Reactant: CC(C)(C)OC(=O)N1Cc2cc([C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)[C@@H](NC(=O)OCC4c5ccccc5-c5ccccc54)C(C)(C)C)C3)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Agent: CN[C@@H](C)C(=O)N[C@H](C(=O)N1Cc2cc(C(=O)N[C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)[C@@H](NC(=O)[C@H](C)NC)C(C)(C)C)C3)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C
Product: CC(C)(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N1C[C@@H](c2ccc3c(c2)CN[C@H](C(=O)N[C@@H]2CCCc4ccccc42)C3)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Yield: 96.1 %

Procedure:
Following a procedure analogous to that for the synthesis of Compound G of Example 1, (S)-tert-butyl 7-((3R,5S)-1-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3,3-dimethylbutanoyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (97 mg, 0.10 mmol) was converted to the title compound (85 mg, 97%). MS (ESI+) m/z 884.4 (M+H)+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[N:26]1[CH2:31][CH2:30][CH:29]([C:32]([OH:36])([CH3:35])[CH2:33][OH:34])[CH2:28][CH2:27]1.C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:34][CH2:33][C:32]([OH:36])([CH:29]2[CH2:30][CH2:31][N:26]([C:17]3[C:16]4[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH3:12])[CH:15]=4)[N:20]=[CH:19][N:18]=3)[CH2:27][CH2:28]2)[CH3:35])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: COc1cc2ncnc(N3CCC(C(C)(O)CO)CC3)c2cc1OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc2ncnc(N3CCC(C(C)(O)COS(=O)(=O)c4ccc(C)cc4)CC3)c2cc1OC
Reaction time: 3 h

Procedure:
Toluene-4-sulphonylchloride (0.285 g) was added at 0° to a stirred solution of 2-[1-(6,7-dimethoxyquinazolin-4-yl)piperid-4-yl]propane-1,2-diol (0.35 g) in pyridine (3 cm3) and the mixture was stirred for 3 hours. The mixture was poured into a mixture of chloroform (20 cm3) and saturated sodium bicarbonate solution (20 cm3) and the dried (MgSO4) chloroform layer was evaporated. The residue was chromatographed on silica ("Merck" 60.9385) eluting with methanol:chloroform, 1:49, to give an oil which was crystallised from ethyl acetate to afford 1-[4-toluenesulphonyloxy]-2-hydroxy-2-[1-(6,7-dimethoxyquinazolin-4-yl)piperid-4-yl]propane, m.p. 120°-124° (0.285 g).
Reaction SMILES: [CH2:1]([C:5]1[N:9]2[CH:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[CH2:11][CH:12]=[CH:13][C:8]2=[N:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[H][H]>[Pd].C(O)C>[CH2:1]([C:5]1[N:9]2[CH:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[CH2:11][CH2:12][CH2:13][C:8]2=[N:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCc1cnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CC=C2
Agent: [Pd]
Solvent: CCO
Product: CCCCc1cnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CCC2

Procedure:
A suspension of bicyclic olefin amidazole (0.1 mmol, the title compound of Example 1451) and 20 mg (0.019 mmol) of 10% palladium on charcoal in 2 mL of absolute ethanol is agitated on a Parr apparatus under 50 psi of hydrogen gas at room temperature until the reaction is complete. The mixture is filtered through a pad of celite, concentrated in vacuo and purified to give the title compound of Example 1453.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH2:18])[C:3]=1[N+:19]([O-:21])=[O:20].[H-].[Na+].[C:24]([C:28]1[CH:29]=[C:30]([C:34](Cl)=[O:35])[N:31]([CH3:33])[N:32]=1)([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:15])([F:16])[F:17])[N:5]=[C:4]([NH:18][C:34]([C:30]2[N:31]([CH3:33])[N:32]=[C:28]([C:24]([CH3:26])([CH3:25])[CH3:27])[CH:29]=2)=[O:35])[C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: Cn1nc(C(C)(C)C)cc1C(=O)Cl
Reactant: Cc1nc(-c2ccccc2C(F)(F)F)nc(N)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2C(F)(F)F)nc(NC(=O)c2cc(C(C)(C)C)nn2C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 6-methyl-5-nitro-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-ylamine (150 mg, 0.503 mmol, prepared as described in Example 2, STEP A) in THF (10 mL) was treated with NaH (60.4 mg, 1.51 mmol, 60% dispersion in oil), and the resulting mixture was allowed to stir for 30 min at room temperature. 5-tert-Butyl-2-methyl-2H-pyrazole-3-carbonyl chloride (131 mg, 0.654 mmol) was added as a solution in THF (3 mL). After 15 min, the mixture was quenched with saturated aqueous NH4Cl (20 mL) and extracted twice with EtOAc (25 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 12-g SEPRA Si 50 SPE column (Isco system: Flow rate=15 mL/min; Eluent=EtOAc/hexanes, 1:99 v/v for 10 min, then 1:99 to 1:4 v/v over 40 min) to yield 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid [6-methyl-5-nitro-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-amide as a colorless glassy solid. 1H-NMR (400 MHz, CDCl3) δ: 9.10 (s, 1H), 7.79-7.86 (m, 2H), 7.60-7.72 (m, 2H), 6.64 (s, 1H), 4.14 (s, 3H), 2.83 (s, 3H), 1.33 (s, 9H). Mass Spectrum (LCMS, APCI pos.): Calculated for C21H21F3N6O3: 463.2 (M+H); Measured: 463.2.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[S:15][C:16]([C:20]([OH:22])=O)=[C:17]([CH3:19])[N:18]=3)[C:10](=[O:23])[CH:9]=2)=[CH:4][CH:3]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH2:33])[CH:27]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[S:15][C:16]([C:20]([NH:33][CH2:32][C:28]4[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=4)=[O:22])=[C:17]([CH3:19])[N:18]=3)[C:10](=[O:23])[CH:9]=2)=[CH:24][CH:25]=1
Reactant: NCc1cccnc1
Reactant: Cc1nc(-n2ccc(OCc3ccc(F)cc3)cc2=O)sc1C(=O)O
Product: Cc1nc(-n2ccc(OCc3ccc(F)cc3)cc2=O)sc1C(=O)NCc1cccnc1
Yield: 52 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-(4-fluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a colorless solid in 52% yield: mp 231-233° C. (dichloromethane/methanol); 1H NMR (300 MHz, DMSO-d6) δ 8.83 (t, J=5.6 Hz, 1H), 8.60 (d, J=8.1 Hz, 1H), 8.50 (s, 1H), 8.43 (d, J=4.2 Hz, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.51-7.47 (m, 2H), 7.37-7.29 (m, 1H), 7.22 (t, J=8.8 Hz, 2H), 6.41-6.35 (m, 1H), 6.23 (s, 1H), 5.13 (s, 2H) 4.40 (d, J=4.2 Hz, 2H), 2.53 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.4, 164.1, 162.0, 161.6, 160.9, 154.0, 150.6, 149.3, 148.5, 135.6, 132.1, 131.0, 130.9, 123.9, 116.0, 115.7, 104.4, 97.5, 70.1, 42.2, 17.5; MS (ES+) m/z 451.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.ClC1C=CC=CN=1.ClC1N=C(C2C=CC=CC=2)C(C(OCC)=O)=CC=1.N[C:57]1[N:62]=[C:61]([NH:63][CH2:64][CH2:65][NH:66][C:67]2[CH:72]=[CH:71]C(C3NC=CN=3)=C(C3C=CC(Cl)=CC=3Cl)[N:68]=2)[CH:60]=[CH:59][C:58]=1[N+:86]([O-:88])=[O:87]>CC#N.C1COCC1.C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:71][CH:72]=[C:67]([NH:66][CH2:65][CH2:64][NH:63][C:61]2[CH:60]=[CH:59][C:58]([N+:86]([O-:88])=[O:87])=[CH:57][N:62]=2)[N:68]=1
Reactant: Nc1nc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1Cl
Agent: CCOC(=O)c1ccc(Cl)nc1-c1ccccc1
Agent: Clc1ccccn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1ccc(NCCNc2ccc([N+](=O)[O-])cn2)nc1-c1ccc(Cl)cc1Cl

Procedure:
Ethyl 2-(2,4-dichlorophenyl)-6-({2-[(5-nitro(2-pyridyl))amino]ethyl}amino)pyridine-3-carboxylate was prepared from ethyl 3-(2,4-dichlorophenyl)-3-oxopropanoate (ref. Wemple, J.; et. al. Synthesis 1993, 290-292.) as the starting material and THF/ethanol ratio of 3:1 as the solvent in the first step. The oxidation uses DDQ. The final product is achieved directly from the chloropyridine by reacting ethyl 6-chloro-2-phenylpyridine-3-carboxylate with 2-(2-aminoethylarnine)-5-nitropyridine in CH3CN and Hüing's Hüing's base at 120° C. for 18 hours. The procedures are analogous to the general method for {2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[6-(2,4-dichlorophenyl)-5-imidazolyl(2-pyridyl)]amine.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH:12]([NH:15][CH:16](O)[CH3:17])([CH3:14])[CH3:13].C1C[O:22]CC1>>[CH:12]([N:15]([CH2:16][CH2:17][OH:22])[C:1](=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)([CH3:14])[CH3:13]
Reactant: C1CCOC1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)NC(C)O
Product: COc1ccc(C(=O)N(CCO)C(C)C)cc1
Temperature: 7 °C
Yield: 88 %

Procedure:
Anisoyl chloride (17.1 g, 0.1 mol) in THF (100 mL) was added dropwise to a solution of N-isopropylaminoethanol (41.3 g, 0.4 mol) in THF (200 mL) under magnetic stirring at 4 to 10° C. The reaction mixture was stirred for 2 h at room temperature, and the solvent was evaporated in vacuo. The residue was dissolved in ice-cold water (200 mL), and the solution was neutralized with conc. hydrochloric acid. The 10 emulsion was extracted with ethyl acetate (3′ 150 mL). Extracts were washed with saturated aqueous NaCl (3′ 50 mL), dried over Na2SO4, and evaporated to a solid. Recrystallization from warm toluene-hexanes gave pure 8 as white crystals (20.5 g, 88%). 1H NMR (CDCl3): 7.32 (2H, d, J=8.6 Hz); 6.89 (2H, d, J=8.6 Hz); 4.40 (1H, br. s); 4.09 (1H, m); 3.80 (3H, s); 3.90-3.70 (1H, m); 3.53 (2H, t, J=4.6 Hz); 1.13 (6H, d, J=6.8 Hz). 13C NMR (CDCl3): 173.56 (C═O); 160.60 (C—OMe); 128.71 [C—C(O)]; 128.16 (Arom. CH); 113.89 (Arom. CH); 63.69 (CH2OH); 55.39 (OCH3); 50.60 (N—CH); 44.45 (N—CH2); 21.19 (C—CH3).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][CH:5]=[CH:6][C:7]=1Cl>CNCCO>[Cl:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][CH:5]=[CH:6][C:7]=1[N:4]([CH2:3][CH2:9][OH:10])[CH3:5]
Reactant: OCc1nccc(Cl)c1Cl
Agent: CNCCO
Product: CN(CCO)c1ccnc(CO)c1Cl

Procedure:
A mixture of 3,4-dichloro-2-hydroxymethylpyridine (J. Med. Chem. 1989, 32, 1970) (2.5 g) in 2-methylaminoethanol (30 ml) is heated at 160° C. in a steel autoclave for 2.5 h, the excess amine is stripped off under high vacuum, and the remaining residue is chromatographed on silica gel (dichloromethane/methanol 95/5). Yield: 2.3 g as yellowish oil.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=[O:9].C([Li])CCC.[CH:17]([CH:19]=[CH2:20])=[O:18]>C1COCC1>[OH:18][CH:17]([CH:19]=[CH2:20])[CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:11])[C:8]([OH:10])=[O:9]
Reactant: C=CC=O
Reactant: Cc1ccccc1CC(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CC(O)C(C(=O)O)c1ccccc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
A solution of o-tolylacetic acid (45.0 g.) in dry THF (300 ml.) was treated under argon at 5°-10° C. with a 1.60M solution (376 ml.) of butyl lithium. The suspension was stirred 2 hours at 5°-10° C. and then acrolein (dried over 3A molecular sieve) (20.0 ml., 16.8 g.) was added over 5 minutes. The mixture was stirred for 2 hours and then carefully treated with ice-water (1 1.) The aqueous mixture was washed with ether (200 ml.). The aqueous layer was separated and acidified to pH4 (HCl) and extracted with ether (3×150 ml.). The extracts were washed with water, dried (magnesium sulphate) and evaporated to give 3-hydroxy-2-o-tolyl-4-pentenoic acid (A) (55.2 g.), which was used without purification.
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[CH2:15]1[NH:20][CH2:19][CH2:18][N:17]2[CH2:21][CH2:22][CH2:23][CH2:24][C@H:16]12.C(N(C(C)C)CC)(C)C.Cl[C:35]1[N:36]=[N:37][C:38]([C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)=[CH:39][CH:40]=1>ClCCl.CS(C)=O>[F:50][C:47]([F:48])([F:49])[C:44]1[CH:43]=[CH:42][C:41]([C:38]2[N:37]=[N:36][C:35]([N:20]3[CH2:19][CH2:18][N:17]4[CH2:21][CH2:22][CH2:23][CH2:24][C@@H:16]4[CH2:15]3)=[CH:40][CH:39]=2)=[CH:46][CH:45]=1
Reactant: C1CCN2CCNC[C@H]2C1
Reactant: FC(F)(F)c1ccc(-c2ccc(Cl)nn2)cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: FC(F)(F)c1ccc(-c2ccc(N3CCN4CCCC[C@@H]4C3)nn2)cc1
Temperature: 160 °C
Yield: 98.1 %

Procedure:
A mixture of the dihydrochloride salt of (R)-octahydropyrido[1,2-a]pyrazine (649 mg, 3.05 mmol), diisopropylethylamine (1.17 ml, 6.72 mmol), 3-chloro-6-(4-trifluoromethylphenyl)-pyridazine (290 mg, 1.12 mmol) and dimethylsulfoxide (1 ml) was heated in a closed vessel at 160° C. for 40 min. The reaction mixture was cooled to room temperature, diluted with dichloromethane (10 ml) and washed with water (2×15 ml) and brine (15 ml). The organic layer was dried over magnesium sulphate. The solvent was removed in vacuo to give 398 mg of the title compound as the free base.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=1)[CH2:17][OH:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.O1CCCC1>O>[CH3:1][S:2]([O:18][CH2:17][C:16]1[CH:19]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[C:14]([O:13][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:15]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Methanesulfonyl chloride (5.03 ml) was slowly added to a mixture of 3,5-dibenzyloxybenzyl alcohol (16.0 g), triethylamine (9.06 ml), and tetrahydrofuran (200 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The colorless crystals obtained were collected by filtration to yield 3,5-dibenzyloxybenzyl methanesulfonate (22.20 g, yield: 91%). This was recrystallized from ethyl acetate-hexane. Melting point: 85–86° C.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH2:14][CH3:15].C([SiH](CC)CC)C.CO[C:26](=O)[C:27]([C:29]1[C:37]2C(=NC=CC=2)N[C:30]=1[CH2:38]C)=O.[C:41](O)([C:43]([F:46])([F:45])[F:44])=O>>[CH2:14]([C:6]1[N:7]([CH2:37][C:29]2[CH:30]=[CH:38][C:41]([C:43]([F:46])([F:45])[F:44])=[CH:26][CH:27]=2)[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[C:5]=1[CH2:4][C:3]([OH:2])=[O:16])[CH3:15]
Reactant: O=C(O)C(F)(F)F
Reactant: CCc1[nH]c2ncccc2c1CC(=O)OC
Reactant: CCc1[nH]c2ncccc2c1C(=O)C(=O)OC
Agent: CC[SiH](CC)CC
Product: CCc1c(CC(=O)O)c2cccnc2n1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-Ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester: To a solution of triethylsilane (818 μl, 5.12 mmol) in TFA (1.6 ml) at −10° C. is added portion wise (2-ethyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-oxo-acetic acid methyl ester (0.34 g, 1.46 mmol). After stirring at room temperature overnight, the solvent is removed in vacuo and the resulting residue is neutralized with saturated sodium bicarbonate solution. The solution is extracted with DCM (3×20 ml) and the organic portions are combined, dried (Na2SO4) and concentrated in vacuo. The residue is loaded on a pre-packed Isolute™ silica column and eluted with DCM/MeOH (100:0 increasing to 98:2) to yield the titled compound as a yellow powder. (MH+ 219)
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:10]#[N:11])[C:8]#[N:9])=[CH:4][CH:3]=1.O.[NH2:15][NH2:16]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:10]([NH2:11])=[N:15][NH:16][C:8]=2[NH2:9])=[CH:12][CH:13]=1
Reactant: NN
Reactant: N#CC(C#N)Cc1ccc(F)cc1
Solvent: O
Product: Nc1n[nH]c(N)c1Cc1ccc(F)cc1

Procedure:
The product from Example 5A (1.5 g, 8.61 mmol) and hydrazine monohydrate (2.111 mL, 43.1 mmol) was processed using the method analogous to that described in Example 1B to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.96 (s, 1H) 7.15-7.51 (m, 2H) 6.79-7.11 (m, 2H) 4.30 (s, 4H) 3.48 (s, 2H). MS (ESI) m/z 259.3 (M+H)+.