Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]2[CH3:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32](Cl)=[O:33]>C(Cl)Cl>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=3)=[O:33])[CH2:14][C@@H:13]2[CH3:18])(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: C[C@H]1CNCCN1S(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CN(C(=O)c2ccccn2)CCN1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 72.6 %

Procedure:
To a solution of (2S)-1-[(4-chlorophenyl)sulfonyl]-2-methylpiperazine hydrochloride (Description 4) (200 mg, 0.728 mmol) in DCM (8 mL) was added triethylamine (0.172 ml, 1.237 mmol) and the reaction was cooled to 0° C. and stirred under argon. 2-pyridinecarbonyl chloride (155 mg, 0.873 mmol) was added portionwise and the reaction was slowly allowed to warm to rt, stirring continued for 18 hours. The sample was evaporated, the crude residue was purified by silica chromatography (5 g silica SPE), (eluting a gradient from 20-90% ethyl acetate in hexane) and the product containing fractions were concentrated. The product was then dissolved in 1,4-dioxane (2 ml) to this was added 1M ethereal HCl (4 ml) the sample was evaporated and then triturated in diethyl ether until solid. The solid was dried under vacuum at 40° C. for 18 hours to yield the title compound as a white solid (110 mg)
Reaction SMILES: O=[C:2]1O[C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([O-])=[C:3]1O.C[N:14](CC1C=CC=CC=1)[CH2:15][C:16]#C.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[NH2:14][CH2:15][CH2:16][C:5]1[CH2:7][CH:9]([C:11](=[CH:2][CH:3]=1)[OH:12])[OH:10]
Reactant: C#CCN(C)Cc1ccccc1
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: NCCC1=CC=C(O)C(O)C1

Procedure:
3H-DA was obtained from NEN (Boston, MA). Ascorbate, pargyline, BZT, and glucose were obtained from Sigma (St. Louis, Mo.). The ultimagold scintillation fluid was purchased from Packard (Sterling, Va.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](SC)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:13]1C=C(C=CC=1)C(OO)=O.C(OCC)(=O)C.[S:29](=[O:32])(O)[O-:30].[Na+]>C(Cl)(Cl)Cl>[CH3:13][S:29]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:32])=[O:30]
Reactant: O=S([O-])O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 3 h
Yield: 95 %

Procedure:
To a stirring solution of methyl 4-nitrophenyl sulfide (10 g, 59.1 mmol) in chloroform at 0° C. was added m-chloroperoxybenzoic acid (55.6 g, 177.3 mmol). After 3 h, ethyl acetate (1.2 L) was added followed by satd aq sodium bisulfite. After stirring overnight, the layers were separated and the organic phase was washed with satd aq sodium bicarbonate (3×200 mL), followed by brine, and then dried over MgSO4, filtered and concentrated in vacuo to give 11.27 g (95%) of the title compound.
Reaction SMILES: P(=O)(O)(O)[OH:2].Cl[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:16][N:17]2[C:23](=[O:24])[C@@H:22]([NH:25][C:26](=[O:38])[C@@H:27]([N:29](C)[C:30](=O)OC(C)(C)C)[CH3:28])[CH2:21][O:20][C:19]3[CH:39]=[CH:40][CH:41]=[CH:42][C:18]2=3)[N:9]([CH2:43][CH3:44])[CH:8]=1>C([O-])(O)=O.[Na+]>[CH2:43]([N:9]1[C:10]2[C:15](=[C:14]([CH2:16][N:17]3[C:23](=[O:24])[C@@H:22]([NH:25][C:26](=[O:38])[C@@H:27]([NH:29][CH3:30])[CH3:28])[CH2:21][O:20][C:19]4[CH:39]=[CH:40][CH:41]=[CH:42][C:18]3=4)[CH:13]=[CH:12][CH:11]=2)[CH2:7][C:8]1=[O:2])[CH3:44]
Reactant: CCn1cc(Cl)c2c(CN3C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc4ccccc43)cccc21
Reactant: O=P(O)(O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: CCN1C(=O)Cc2c(CN3C(=O)[C@@H](NC(=O)[C@H](C)NC)COc4ccccc43)cccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.8 %

Procedure:
Phosphoric acid (13.2 mg, 2 mL, 108 μmol, Eq: 1.00) was added to tert-butyl (S)-1-((S)-5-((3-chloro-1-ethyl-1H-indol-4-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (60 mg, 108 μmol, Eq: 1.00) and the mixture stirred at RT for 2 h. The mixture was diluted with sat. NaHCO3 and extracted with DCM. The combined extracts were concentrated and the residue was purified by preparative TLC to give the title compound (7 mg, 14%) as a solid. MS m/z 437 (MH+)
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]1([CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:17][NH:16][C:15](=[O:18])[CH2:14]1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:16]1[CH2:17][C:13]([C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:3]=2)([CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:14][C:15]1=[O:18])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C1CC(CCOC2CCCCO2)(c2ccc3ccccc3c2)CN1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: O=C1CC(CCOC2CCCCO2)(c2ccc3ccccc3c2)CN1Cc1ccccc1
Yield: 113.2 %

Procedure:
Sodium hydride (0.07 g, 2.94 mmol, 1.25 eq.) was added slowly to a solution of 4-naphthalen-2-yl-4-[2(tetrahydropyran-2-yloxy)-ethyl]-pyrrolidin-2-one (003F144) (0.81 g, 2.39 mmol). The solution was treated with benzyl bromide (0.6 mL, 4.9 mmol, 2 eq.) at 20° C. for 7 hours. The solution was partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel with 50% ethyl acetate in hexane to give 1.1620 g (92%) of the title compound.
Reaction SMILES: [Cl-].[OH:2][NH3+:3].[F:4][C:5]([F:15])([F:14])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O>C(O)C>[F:4][C:5]([F:15])([F:14])[C:6](=[N:3][OH:2])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(c1ccccc1)C(F)(F)F
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: CCO
Product: ON=C(c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.5 %

Procedure:
A mixture of hydroxylammonium chloride (13.9 g, 200 mmol) and 2,2,2-trifluoroacetophenone (17.4 g, 92 mmol) in absolute ethanol (150 ml) was heated at reflux for 1 h and then stirred at ambient temperature for 16 h. The solvent was evaporated in vacuo, the residue suspended in water (100 ml), filtered and washed with water (20 ml), n-heptane (20 ml) and dried to give 14.0 g 2,2,2-trifluoroacetophenone oxime.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[Cl:19][CH2:20][CH2:21][CH2:22][N:23]1[C:28]([CH3:29])=[CH:27][C:26](=[O:30])[NH:25][C:24]1=[O:31]>>[ClH:19].[F:18][C:2]([F:1])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:20][CH2:21][CH2:22][N:23]2[C:28]([CH3:29])=[CH:27][C:26](=[O:30])[NH:25][C:24]2=[O:31])[CH2:13][CH2:12]1
Reactant: FC(F)(F)COc1ccccc1N1CCNCC1
Reactant: Cc1cc(=O)[nH]c(=O)n1CCCCl
Product: Cc1cc(=O)[nH]c(=O)n1CCCN1CCN(c2ccccc2OCC(F)(F)F)CC1
Product: Cl

Procedure:
substituting 1-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine and 1-(3-chloropropyl)-6-methyl-2,4(1H,3H)-pyrimidinedione gave 1-(3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propyl)-6-methyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 217°-219° C.; Anal.: Calcd. for C20H25F3N4O3.(HCl)2 : C, 48.10; H, 5.44; N, 11.22%; Found: C, 47.96; H, 5.46; N, 11.15%;
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:27])C>[Zn]>[NH2:22][C:17]1[CH:18]=[CH:19][C:20]([OH:27])=[CH:21][C:16]=1[CH2:15][NH:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1ccccc1CNC1CCN(Cc2ccccc2)CC1
Agent: [Zn]
Product: Nc1ccc(O)cc1CNC1CCN(Cc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
(1-Benzyl-piperidin-4-yl)-(2-nitro-benzyl)-amine (0.25 g, 0.7 mmol) and zinc dust (0.2 g, excess) were combined in 75% aqueous acetic acid (8 mL) and stirred at 60° C. for 2 h. After cooling to room temperature, the solvents were removed in vacuo and the resultant crude mixture dissolved in water (10 mL), followed by addition of ammonium hydroxide until pH 3 was attained. The solution was extracted with methylene chloride (3×). The organic layers were pooled together, washed with water (2×), brine (2×), dried over sodium sulfate, filtered, and concentrated to afford 0.18 g (79%) of the desired product.
Reaction SMILES: [CH3:1][NH:2][N:3]=[CH:4][C:5]1[N:6]([CH3:13])[C:7]([N+:10]([O-:12])=[O:11])=[CH:8][N:9]=1.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH3:1][NH:2][N:3]=[C:4]([Br:14])[C:5]1[N:6]([CH3:13])[C:7]([N+:10]([O-:12])=[O:11])=[CH:8][N:9]=1
Reactant: CNN=Cc1ncc([N+](=O)[O-])n1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CNN=C(Br)c1ncc([N+](=O)[O-])n1C

Procedure:
The hydrazones formed in this manner are in turn allowed to react with N-bromosuccinimide at about room temperature in a suitable solvent, such as chloroform, to yield 1-methyl-5-nitroimidazole-2-carbonyl bromide alkyl or hydroxy-alkyl hydrazones. The reaction with N-bromosuccinimide is applicable to any of the substituted hydrazones to yield the bromo-substituted hydrazones. As a specific example, when 1-methyl-5-nitroimidazole-2-carboxaldehyde methyl hydrazone is allowed to react with N-bromosuccinimide at room temperature in chloroform solvent, there is obtained 1-methyl-5-nitroimidazole-2-carbonyl bromide methyl hydrazone.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:24][C:25]1([F:37])[O:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:33](B(O)O)[C:27]=2[O:26]1>>[F:37][C:25]1([F:24])[O:26][C:27]2[CH:33]=[CH:32][CH:31]=[C:30]([C:2]3[CH:11]=[CH:10][C:9]4[N:8]=[CH:7][C:6]5[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]6[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=6)[C:5]=5[C:4]=4[CH:3]=3)[C:28]=2[O:29]1
Reactant: OB(O)c1cccc2c1OC(F)(F)O2
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cccc5c4OC(F)(F)O5)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and 2,2-difluorobenzo[1,3]dioxole-4-boronic acid (Apollo, Cheshire, United Kingdom, 26 mg, 0.130 mmol) to give the title compound as a white solid. (HPLC: tR 2.95 min (Method A); M+H=450 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.01 (s, 1H), 8.18-8.13 (m, 1H), 8.08 (s, 1H), 7.97-7.91 (m, 1H), 7.88-7.84 (m, 1H), 7.441-7.38 (m, 2H), 7.36-7.29 (m, 1H), 3.85 (s, 3H), 3.58 (s, 3H), 1.94 (s, 3H))
Reaction SMILES: [OH:1][C@@H:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[N:8]=[C:7]([C:25](O)=[O:26])[CH:6]=1)[CH2:3][OH:4].[NH2:28][C@@H:29]([CH2:33][C:34]([NH2:36])=[O:35])[C:30]([NH2:32])=[O:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][C@@H:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[CH:15][CH:16]=2)[N:8]=[C:7]([C:25]([NH:28][CH:29]([CH2:33][C:34]([NH2:36])=[O:35])[C:30]([NH2:32])=[O:31])=[O:26])[CH:6]=1)[CH2:3][OH:4]
Reactant: O=C(O)c1cc([C@H](O)CO)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reactant: NC(=O)C[C@H](N)C(N)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CC(NC(=O)c1cc([C@H](O)CO)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1)C(N)=O
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of (S)-4-(1,2-dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)picolinic acid (assume 0.44 mmol) in DMF (5 mL) was added (S)-2-aminosuccinamide (0.076 g, 0.45 mmol), DIEA (0.20 mL, 1.1 mmol) and HBTU (0.203 g, 0.54 mmol). The reaction was stirred overnight then partitioned between 50 mL EtOAc and 50 mL brine. The aqueous layer was extracted once more with 25 mL EtOAc and combined. The organics were dried over Na2SO4, filtered and evaporated in vacuo. The residue was crystallized from 4 mL warm acetone, the solid filtered off, rinsed with additional acetone and dried under vacuum at 50° C. to yield the product S)-2-(4-((S)-1,2-Dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)picolinamido)succinamide as a light tan powder (0.125 g, 0.26 mmol, 59% yield, LC/MS: m/z=483.1 [M+H]+, 1H NMR (400 MHz, DMSO-d6): δ 9.29 (d, J=8.4 Hz, 1H), 8.25 (d, J=8.8 Hz, 2H), 8.06 (s, 1H), 7.99 (s, 1H), 7.48 (s, 1H), 7.40 (s, 1H), 7.32-7.25 (m, 2H), 7.21-7.15 (m, 2H), 7.14-7.07 (m, 3H), 6.99 (s, 1H), 5.64 (d, J=4.8 Hz, 1H), 4.85 (t, J=6.0 Hz, 1H), 4.75-4.64 (m, 2H), 3.62-3.49 (m, 2H), 2.79-2.70 (m, 1H), 2.61-2.53 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:21]([OH:23])=O)[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])[CH3:3].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:39][C@H:40]([C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH:41]([CH3:43])[CH3:42].S(C1C=CC(C)=CC=1)([O-])(=O)=O>CN(C=O)C>[NH:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C@H:9]([C:21]([NH:39][C@H:40]([C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH:41]([CH3:43])[CH3:42])=[O:23])[CH2:10][C:11](=[O:12])[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: -15 °C
Yield: 103.3 %

Procedure:
A solution, cooled to -20° C., of 32.3 g of Boc-Asp-(OBzl)-OH in 150 ml of DMF is treated with 11 ml of N-methylmorpholine and 13.07 ml of isobutyl chloroformate. The suspension obtained is stirred at -15° C. and treated with a suspension, cooled to -20° C., of 37.95 g of H-Val-OBzl.tosylate and 11 ml of N-methylmorpholine in 150 ml of DMF. The reaction mixture is stirred at below -10° C. for 10 minutes and at room temperature for 2 hours, filtered and the filtrate is concentrated. The residue is dissolved in ethyl acetate and washed with 5% KHSO4 /10% K2SO4 solution, water, saturated NaHCO3 solution, water and saturated NaCl solution and dried. The organic phase is concentrated. 52.9 g of Boc-Asp(OBzl)-Val-OBzl are obtained. 10.24 g thereof are dissolved in 30 ml of TFA and then concentrated. The residue, is crystallized from ethyl acetate/hexane. There are obtained 8.3 g of H-Asp- (OBzl)-Val-OBzl.TFA (1:1),.m.p. 147°-148° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.CN(CCN(CCN(C)C)C)C.C([Li])CCC.B(OC)(OC)[O:28]C.OO>O.C(O)(=O)C.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:28]
Reactant: COB(OC)OC
Reactant: COc1ccc(F)cc1
Agent: CN(C)CCN(C)CCN(C)C
Agent: OO
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)c(O)c1
Reaction time: 3 h

Procedure:
To a 200 ml THF solution containing 50.1 g of 1-fluoro-4-methoxybenzene and 70 g of N,N,N′,N′,N″-pentamethyldiethylenetriamine there was added dropwise 150 ml of n-butyllithium (2.66 M, hexane solution) over a period of 30 minutes, at −74° C. under a nitrogen atmosphere. After stirring for 3 hours at between −74° C. and −70° C., 100 ml of trimethyl borate was added. The temperature of the reaction mixture was then slowly allowed to rise to room temperature. Next, 70 ml of acetic acid and 75 ml of 30% aqueous hydrogen peroxide were added, and the reaction mixture was stirred overnight at room temperature. Water was then added to the reaction mixture, and then it was extracted with a mixture of hexane and ethyl acetate and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product of 1-fluoro-2-hydroxy-4-methoxybenzene (65.59 g) as a white solid.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:12]=2)[CH:10]=1)CCC.Br[C:40]1[CH:41]=[C:42]([S:46]([NH:49][C:50]([CH3:54])([CH3:53])[CH2:51][OH:52])(=[O:48])=[O:47])[CH:43]=[CH:44][CH:45]=1.CCCCCCC>C1(C)C=CC=CC=1>[OH:52][CH2:51][C:50]([NH:49][S:46]([C:42]1[CH:43]=[CH:44][CH:45]=[C:40]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:14]=[C:13]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][CH:22]=4)[N:12]=3)[CH:10]=2)[CH:41]=1)(=[O:48])=[O:47])([CH3:54])[CH3:53]
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)n2)cn1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CC(C)(CO)NS(=O)(=O)c1cccc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)c1
Temperature: 25 °C
Yield: 65.5 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (Example G.11) (0.503 g, 0.7 mmol), 3-bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (Example H.4) (0.237 g, 0.77 mmol), tetrakis(triphenyl-phosphine)palladium (0.040 g, 0.030 mmol) in toluene (5 mL) was heated under reflux conditions for 18 h. Cooled to rt, some precipitate occurred, diluted with toluene (5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (268 mg, 66%). MS (ISP) 585.2 [(M+H)+]; mp 150° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:12](=[C:14]([C:18](O)=[O:19])[CH:15]=[CH:16][CH:17]=3)[N:13]=2)=[C:5]([CH3:21])[CH:4]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:46][CH:47]1[CH2:54][CH:53]2[N:55]([CH3:56])[CH:49]([CH2:50][CH2:51][CH2:52]2)[CH2:48]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:56][N:55]1[CH:49]2[CH2:50][CH2:51][CH2:52][CH:53]1[CH2:54][CH:47]([NH:46][C:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:11]3[O:10][C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH3:21])=[N:13][C:12]=13)=[O:19])[CH2:48]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: COc1ccc(-c2nc3c(C(=O)O)cccc3o2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(-c2nc3c(C(=O)NC4CC5CCCC(C4)N5C)cccc3o2)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.3 %

Procedure:
A mixture of 2-(4-methoxy-2-methylphenyl)benzoxazole-4-carboxylic acid (100 mg, 0.35 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (134 mg, 0.70 mmol), 1-hydroxybenzotriazole (95 mg, 0.70 mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (99 mg, 0.44 mmol) in DMF (3 mL) was stirred at room temperature for 10 min, then triethylamine (0.20 mL, 1.40 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic layers were washed with water (2×50 mL), brine (2×50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) and recrystallization from acetonitrile to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-methoxy-2-methylphenyl)benzoxazole-4-carboxamide (24 mg, 16%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.11 (d, J=7.2 Hz, 1H), 8.22-8.16 (m, 2H), 7.67 (dd, J=8.8, 0.8 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 6.94-6.90 (m, 2H), 4.66-4.60 (m, 1H), 3.90 (s, 3H), 3.15-3.10 (m, 2H), 2.89 (s, 3H), 2.66-2.58 (m, 2H), 2.55 (s, 3H), 2.10-1.90 (m, 3H), 1.58-1.42 (m, 3H), 1.20-1.05 (m, 2H); MS (ESI+) m/z 420 (M+H); HPLC>99% (AUC), tR=13.54 min.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[C:10]([CH3:14])([CH3:13])[CH2:11]Cl.Cl.N1C=CC=CC=1.Cl.CCOCC>N1C2C(=CC=CC=2)C=CC=1>[Br:9][C:6]1[CH:7]=[CH:8][C:3]2[O:2][CH2:14][C:10]([CH3:11])([CH3:13])[C:4]=2[CH:5]=1
Reactant: COc1ccc(Br)cc1C(C)(C)CCl
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: c1ccc2ncccc2c1
Product: CC1(C)COc2ccc(Br)cc21
Reaction time: 3 h

Procedure:
2-(2-Methoxy-5-bromophenyl)-2-methyl-1-chloropropane (from example 5(a)) (120 g, 0.43 mole) was heated under reflux (163°-9° C.) with pyridine hydrochloride (220 g) in quinoline (220 g) with stirring for 3 hours. Addition to iced dilute hydrochloric acid and isolation through ether gave after distillation 73 g (75%) title product b.p. 62°-4° C. at 0.01 mm Hg.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:64]1[CH:69]=[CH:68][N:67]([CH2:70][CH:71]2[CH2:73][CH2:72]2)[C:66](=[O:74])[CH:65]=1>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:71]1([CH2:70][N:67]2[CH:68]=[CH:69][C:64]([N:13]3[CH2:14][CH2:15][CH:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:16])=[CH:5][CH:6]=4)[CH2:11][CH2:12]3)=[CH:65][C:66]2=[O:74])[CH2:72][CH2:73]1
Reactant: COC(=O)c1ccc(C2CCNCC2)cc1
Reactant: O=c1cc(Br)ccn1CC1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(C2CCN(c3ccn(CC4CC4)c(=O)c3)CC2)cc1
Temperature: 100 °C

Procedure:
4-Piperidin-4-ylbenzoic acid methyl ester (0.40 g, 1.81 mmol), palladium(II) acetate (0.015 g, 0.069 mmol) sodium tert-butoxide (0.34 g, 3.44 mmol) and BINAP (0.06 g, 0.096 mmol) were added to a stirred solution of intermediate D3 (0.31 g, 1.37 mmol) in toluene (10 ml). The reaction mixture was heated at 100° C. for 16 hours in a sealed tube. After cooling to room temperature the mixture was diluted with EtOAc and then filtered through diatomaceous earth, after which the solvent was evaporated in vacuo. The crude residue was treated with a mixture of DCM/methanol and then filtered off. The filtrate was evaporated to dryness in vacuo to yield crude D37 (0.48 g, 100%) that was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]2[CH:26]=[C:27]([NH:31][C:32]3[C:35](=O)[C:34](=[O:37])[C:33]=3[O:38]CC)[CH:28]=[C:29]([CH3:30])[C:5]=2[N:4]=1)[CH3:2].[CH3:41][NH:42][CH3:43]>>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]2[CH:26]=[C:27]([NH:31][C:32]3[C:33](=[O:38])[C:34](=[O:37])[C:35]=3[N:42]([CH3:43])[CH3:41])[CH:28]=[C:29]([CH3:30])[C:5]=2[N:4]=1)[CH3:2]
Reactant: CNC
Reactant: CCOc1c(Nc2cc(C)c3nc(CC)n(Cc4ccc(-c5ccccc5-c5nnn[nH]5)cc4)c3c2)c(=O)c1=O
Product: CCc1nc2c(C)cc(Nc3c(N(C)C)c(=O)c3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 14b from 4'-[[2-ethyl-4-methyl-6-[(2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)-amino]-1H -benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)biphenyl and dimethylamine.