Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=3)[O:16][N:15]=2)[CH:5]=[C:6]([CH3:13])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][O:11]1.[NH3:29]>CO>[NH2:29][CH2:12][CH:10]([OH:11])[CH2:9][O:8][C:7]1[C:6]([CH3:13])=[CH:5][C:4]([C:14]2[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH:26]([CH3:27])[CH3:28])=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:3][C:2]=1[CH3:1]
Reactant: N
Reactant: Cc1cc(-c2noc(-c3ccc(OC(C)C)cc3)n2)cc(C)c1OCC1CO1
Solvent: CO
Product: Cc1cc(-c2noc(-c3ccc(OC(C)C)cc3)n2)cc(C)c1OCC(O)CN

Procedure:
A solution of 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-5-(4-isopropoxy-phenyl)-[1,2,4]oxadiazole (250 mg, 0.657 mmol) in 7 N NH3 in methanol (10 mL) is stirred at 60° C. for 16 h. The solvent is evaporated and the remaining residue is dried under HV to give 1-amino-3-{4-[5-(4-isopropoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propan-2-ol (278 mg) as a beige oil; LC-MS: tR=0.86 min, [M+1]+=398.44.
Reaction SMILES: Cl.O.[C:3]([O:6][C:7](=[O:18])[C:8]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=1[Cl:17])(=[O:5])[CH3:4]>C(O)C.[Fe]>[C:3]([O:6][C:7](=[O:18])[C:8]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:9]=1[Cl:17])(=[O:5])[CH3:4]
Reactant: CC(=O)OC(=O)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(=O)OC(=O)c1cc(N)ccc1Cl
Yield: 88.2 %

Procedure:
24 g of iron powder was added to a solution of 1.6 ml of concentrated HCl, 16.8 ml of water, and 70 ml of ethanol. 29.6 g of the 2-chloro-5-nitrobenzoyl acetate prepared above in Step 2 dissolved in 45 ml of ethanol, was then added to the mixture in three equal portions. The resultant reaction mixture was refluxed for 5 hours. An additional 2.4 g of iron and 0.1 ml of concentrated HCl was then added to the reaction mixture. The reaction mixture was then refluxed for an additional one hour, filtered through Celite and evaporated. 100 ml of water was then added to the evaporated material and the resultant mixture was extracted with 100 ml of ether. The ether solution was washed with water, dried over magnesium sulfate, and evaporated, to produce 22.9 g of 5-amino-2-chlorobenzoyl acetate as an oil.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[C:18]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)(=[O:20])[CH3:19].Cl>C(=O)(O)[O-].[Na+]>[C:18]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:2]2[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N+:15]([O-:17])=[O:16])=[CH:24][CH:23]=1)(=[O:20])[CH3:19]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)Nc1ccc(Oc2c([N+](=O)[O-])cc(C(=O)O)cc2S(N)(=O)=O)cc1
Temperature: 25 °C

Procedure:
The starting material is prepared as follows: The mixture of 14 g of 4-chloro-3-nitro-5-sulfamoylbenzoic acid, 200 ml of 1N aqueous sodium bicarbonate and 15.9 g of 4-acetamidophenol is heated to about 95°-100°C for 21 hours while stirring under nitrogen. It is cooled to room temperature and made strongly acidic with concentrated hydrochloric acid. The precipitate formed is filtered off, to yield the 4-(4-acetamidophenoxy)-3-nitro-5-sulfamoylbenzoic acid, which after trituration with aqueous ethanol melts at 293° with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]2[CH:10]=[C:11]([S:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[C:20](=O)[CH2:19][CH2:18]4)[S:12][CH:13]=2)[CH2:7][CH2:6][O:5][CH:4]1[CH3:8].Cl.[NH2:26][OH:27]>>[CH3:1][O:2][C:3]1([C:9]2[CH:10]=[C:11]([S:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)/[C:20](=[N:26]/[OH:27])/[CH2:19][CH2:18]4)[S:12][CH:13]=2)[CH2:7][CH2:6][O:5][CH:4]1[CH3:8]
Reactant: COC1(c2csc(Sc3ccc4c(c3)CCC4=O)c2)CCOC1C
Reactant: NO
Agent: Cl
Product: COC1(c2csc(Sc3ccc4c(c3)CC/C4=N\O)c2)CCOC1C
Yield: 64 %

Procedure:
Using an analogous procedure to that described in Example 66, 5-{4-[(2RS,3SR)-3-methoxy-2-methyltetrahydrofuran-3-yl]thien-2-ylthio}indan-1-one was reacted with hydroxylamine hydrochloride to give (E)-5-{4-[(2RS,3SR)-3-methoxy-2-methyltetrahydrofuran-3-yl]thien-2-ylthio}indan-1-one oxime in 64% yield, m.p. 149°-151° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:40]([CH2:42][NH2:43])[OH:41]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][C:35]([NH:43][CH2:42][CH2:40][OH:41])=[O:36])=[CH:31][CH:32]=2)=[CH:38][CH:39]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)O)cc2)cc1
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)NCCO)cc2)cc1

Procedure:
The product from Example 104A and ethanolamine were processed as described in Example 147 to provide the title compound. 1H NMR (500 MHz, DMSO-D6) δ8.95 (s, 1 H), 7.78 (t, 1 H), 7.26 (m, 6 H), 7.19 (m, 3 H), 7.04 (t, 1 H), 6.97 (m, 2 H), 6.87 (m, 4 H), 4.03 (d, 4 H), 3.35 (m, 2 H), 3.10 (dd, 2 H), 2.91 (s, 3 H), 2.78 (t, 2 H), 2.39 (s, 3 H), 2.36 (m, 2 H); MS (ESI+) m/z 588 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[C:11]1([NH2:18])[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([NH2:18])[CH:12]=2)=[S:10])=[CH:4][CH:3]=1
Reactant: Nc1cccc(N)c1
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: Nc1cccc(NC(=S)Nc2ccc(Cl)cc2)c1
Reaction time: 1 h

Procedure:
A solution of p-chlorophenyl isothiocyanate (39.6 g.) in chloroform (100 ml.) is added dropwise with stirring to a solution of m-phenylene diamine (25.2 g.) in chloroform (200 ml.) at room temperature. The mixture is stirred for 1 hour after the addition is complete, and the precipitated solid is filtered off, washed with chloroform and dried to give 1-(p-chlorophenyl)-3-(m-aminophenyl)thiourea, m.p. 132°-133.5° C. This product (20 g.) is dissolved in ethanol saturated with ammonia gas (300 ml.), yellow mercuric oxide (17.2 g.) is added and the mixture is stirred for 24 hours at room temperature. The black precipitate is filtered off and washed thoroughly with boiling ethanol, and the filtrate is evaporated to dryness. The residue is dissolved in chloroform, the solution is filtered and an excess of ethereal hydrochloric acid is added to the filtrate, followed by a large volume of ether. The oily precipitate is allowed to solidify, is triturated with fresh dry ether, and is filtered off and dried, to give 1-(p-chlorophenyl)-3-(m-aminophenyl)guanidine dihydrochloride, m.p. 236°-238° C.
Reaction SMILES: [CH:1]1([O:7][C:8]2[N:13]3[N:14]=[C:15]([NH2:17])[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27](Cl)=[O:28])[CH:23]=[CH:24][CH:25]=1>>[CH:1]1([O:7][C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:27](=[O:28])[CH2:26][C:22]4[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH3:18])[CH:21]=4)[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: Nc1nc2cccc(OC3CCCCC3)n2n1
Product: COc1cccc(CC(=O)Nc2nc3cccc(OC4CCCCC4)n3n2)c1

Procedure:
The title compound was prepared following procedure and work up described for intermediate B1 but starting from 5-(cyclohexyloxy)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A11), 80 mg; 0.34 mmol; 1.0 eq.) and 3-methoxyphenylacetyl chloride (64 μl; 0.41 mmol; 1.2 eq.) as a white powder (11 mg, 8%). HPLC, Rt: 3.60 min. (purity 88.2%). LC/MS, M+(ESI): 381.1, M−(ESI): 379.1.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[F:8][C:9]1[CH:27]=[CH:26][CH:25]=[CH:24][C:10]=1[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21](N)=[NH2+:22])=[N:13]1.[OH-].[Na+]>C(OCC)(=O)C>[F:8][C:9]1[CH:27]=[CH:26][CH:25]=[CH:24][C:10]=1[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]#[N:22])=[N:13]1
Reactant: NC(=[NH2+])c1nn(Cc2ccccc2F)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: N#Cc1nn(Cc2ccccc2F)c2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2.61 g (24.61 mmol) of sodium carbonate as 10% strength aqueous solution are added to a suspension of 5.00 g (16.41 mmol) of 1-(2-fluorobenzyl)indazole-3-amidinium chloride from Example IIIb) in 100 ml of ethyl acetate, and the mixture is stirred at room temperature for 90 minutes. One molar sodium hydroxide solution is added until the phases have separated. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and filtered, and the solvent is removed in vacuo. 3.33 g (76% of theory) of the product are obtained.
Reaction SMILES: CN([CH2:4][CH2:5]C=C1C2C=CC=CC=2OCC2C=CC=CC1=2)C.CN(CCC=C1C2C=CC=CC=2[O:36]CC2C=CC=CC1=2)C.[ClH:43].CN1[C@@H]2[C@@H]3O[C@H]3[C@H]1C[C@@H](OC([C@@H](C1C=CC=CC=1)CO)=O)C2.C[C:67]1[CH:68]=[C:69]([C:81](C)(C)C)[C:70](O)=[C:71]([CH3:79])[C:72]=1CC1NCCN=1.Cl.CC1C=C(C(C)(C)C)C(O)=C(C)C=1[CH2:93][C:94]1[NH:98][CH2:97][CH2:96][N:95]=1.Cl>>[CH3:4][CH2:5][N:98]([CH2:97][C:96]([NH:95][C:70]1[C:69]([CH3:81])=[CH:68][CH:67]=[CH:72][C:71]=1[CH3:79])=[O:36])[CH2:94][CH3:93].[ClH:43]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CC1=NCCN1
Reactant: CN(C)CCC=C1c2ccccc2COc2ccccc21
Agent: CN1[C@@H]2C[C@@H](OC(=O)[C@H](CO)c3ccccc3)C[C@H]1[C@@H]1O[C@H]12
Agent: Cl
Product: CCN(CC)CC(=O)Nc1c(C)cccc1C

Procedure:
A 2% composition of doxepin in the nanolipid-vesicle composition of Preparation 2 above was prepared by mixing doxepin hydrochloride with the nanolipid vesicle formulation as described in Preparation 2 which had been modified by the addition of Keltrol to render a thick creamy consistency, in a mass/mass ratio of 2:98 with the aid of a high speed stirrer. The composition is designated DOXIPEX CREAM. (b) In similar manner a 1.7307% composition of Lidocaine Hydrochloride was prepared and designated LIDAREX LOTION. (c) A 0.3% composition of Scopolamine HBR was also prepared in the same manner and designated MZL Scopolamine. (d) A 0.5% nasal spray composition of Oxymetazoline HCl was also prepared in the same manner with some modification and designated Oxymetazoline MZL. (e) A 0.5% injection formulation of Bupivicaine HCl was further prepared in the same manner but with some modification and designated Bupivicaine MZL.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[N:10]([CH3:12])[CH:9]=[C:8]2[CH:13]=O.[CH3:15][N:16]1C2C(=CC=CC=2)C(C)=C1C=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[N:10]([CH3:12])[CH:9]=[C:8]2[CH2:13][NH:16][CH3:15]
Reactant: COc1cccc2c(C=O)cn(C)c12
Reactant: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1cn(C)c2c(OC)cccc12
Yield: 94 %

Procedure:
According to the procedure of Preparation 13(c), except substituting 7-methoxy-1-methyl-1H-indole-3-carboxaldehyde for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (1.6 g, 94%) was obtained as an amber oil: MS (ES) m/e 205.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:13][C:12](=[O:14])[C:11]2[C:6](=[CH:7][C:8]([C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:10]=2)[N:5]=1.[CH3:19]I>CN(C=O)C>[CH3:3][C:4]1[N:13]([CH3:19])[C:12](=[O:14])[C:11]2[C:6](=[CH:7][C:8]([C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:10]=2)[N:5]=1
Reactant: CI
Reactant: COC(=O)c1ccc2c(=O)[nH]c(C)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(=O)n(C)c(C)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
To a stirred suspension of sodium hydride (60% in mineral oil, 51 mg, 1.28 mmol) in DMF (5 mL) under an atmosphere of nitrogen was added methyl 2-methyl-4-oxo-3,4-dihydroquinazoline-7-carboxylate (0.14 g, 0.64 mmol) in DMF (2 mL) dropwise. Methyl iodide (80 μL, 1.28 mmol) was then added to the mixture and the resulting solution was stirred at rt overnight. The reaction was quenched with water and extracted with DCM (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford methyl 2,3-dimethyl-4-oxo-3,4-dihydroquinazoline-7-carboxylate (70 mg, 50%). LC-MS: (FA) ES+ 233.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[CH:37]=O)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(=O)(O)[O-].[Na+]>ClCCl>[Br:21][C:20]([Br:24])=[CH:37][C@@H:33]1[CH2:34][CH2:35][CH2:36][N:32]1[C:30]([O:29][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCCC1C=O
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=C(Br)Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of triphenylphosphine (21.1 g, 80.3 mmol) and carbon tetrabromide (13.32 g, 40.16 mmol) in dichloromethane (300 mL) at 0° C. was treated with a solution of 2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (4.0 g, 20.08 mmol) in dichloromethane (10 mL) dropwise via syringe. The solution was stirred for 1 hour at room temperature, poured into a saturated sodium bicarbonate solution and separated. The organic phase was dried (MgSO4), filtered and concentrated. The concentrate was purified by flash chromatography on silica gel using 0–1% methanol/dichloromethane to give 6.13 g (86% yield) of the desired product. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.47 (s, 9H), 1.81 (m, 3H), 2.16 (m, 1H), 3.39 (m, 2H), 4.37 (s, 1H), 6.38 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])=[CH:15][C:14]=1[C:24]#[N:25].[Cl:26]C1C=C(CC(O)=O)C=C(O)C=1>>[Cl:26][C:7]1[CH:6]=[C:5]([CH2:8][C:9]([OH:11])=[O:10])[CH:4]=[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])=[CH:15][C:14]=2[C:24]#[N:25])[CH:2]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)ccc2Cl)c(C#N)c1
Reactant: O=C(O)Cc1cc(O)cc(Cl)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(Cl)cc(CC(=O)O)c2)c(C#N)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of example 12 step (ii) and the product of example 18 step (iv).
Reaction SMILES: ClC(C1C=CC=CC=1)(Cl)Cl.C[O-].[Na+].C[C@@H]1[C@H](O)[C@]2(O)[C@H]([C@:18]34[O:38][C:36]5([C:39]6[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=6)[O:37][C@:21](C(C)=C)([C@H:22]([O:35]5)[C@@H]3[C@@H]3O[C@]3(CO)[C@H]2O)C[C@H]4C)C1>>[CH3:21][O:37][C:36]([O:35][CH3:22])([O:38][CH3:18])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: C=C(C)[C@]12C[C@@H](C)[C@@]34OC(c5ccccc5)(O[C@@H]1[C@@H]3[C@@H]1O[C@]1(CO)[C@@H](O)[C@@]1(O)[C@H]4C[C@H](C)[C@@H]1O)O2
Agent: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)c1ccccc1
Product: COC(OC)(OC)c1ccccc1
Yield: 51 %

Procedure:
Methyl orthobenzoate is prepared by reacting one mole of trichloromethylbenzene with 3.15 moles of sodium methylate in methanolic solution for 20 hours at reflux. After filtration and rectification almost pure methyl orthobenzoate is obtained in a yield of 51%. The orthobenzoate has a boiling point at 15-16 torr of 102°-103° C, and nD25 of 1.4858, and contains 0.8% Cl.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[B:16]1(B2OCC(C)(C)CO2)[O:21]CC(C)(C)C[O:17]1>>[F:14][C:13]1[C:8]([C:4]2[CH:3]=[C:2]([B:16]([OH:21])[OH:17])[CH:7]=[CH:6][CH:5]=2)=[N:9][CH:10]=[C:11]([F:15])[CH:12]=1
Reactant: Fc1cnc(-c2cccc(Br)c2)c(F)c1
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Product: OB(O)c1cccc(-c2ncc(F)cc2F)c1

Procedure:
2-(3-Bromophenyl)-3,5-difluoropyridine (80 mg, 0.30 mmol) was reacted with bis(neopentyl glycolato)diboron (74 mg, 0.33 mmol) using the method of Example 20 to give 3-(3,5-difluoropyridin-2-yl)phenylboronic acid as a tan solid: MS (ES+) m/z 236 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH2:27][CH2:26]1)[NH2:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:21][C:20]3[CH:22]=[CH:23][C:24]([N:25]4[CH2:26][CH2:27][CH:28]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH2:29][CH2:30]4)=[C:18]([CH3:17])[CH:19]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Reactant: Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(Cl)cc3)c2C)ccc1N1CCC(N2CCOCC2)CC1
Yield: 52.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (1.0 g) and 3-methyl-4-(4-morpholinopiperidin-1-yl)aniline (1.07 g), the title compound (1.0 g) was obtained, melting point: 235–245° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][CH:5]=[C:4]([NH2:21])[N:3]=1.[C:22]([C:24]1[CH:25]=[C:26]([CH2:30]O)[CH:27]=[CH:28][CH:29]=1)#[CH:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:22]([C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[CH2:30][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:10]2[CH:9]=[C:8]([C:7]3[C:2]([NH2:1])=[N:3][C:4]([NH2:21])=[CH:5][CH:6]=3)[O:12][N:11]=2)=[CH:15][CH:16]=1)#[CH:23]
Reactant: C#Cc1cccc(CO)c1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C#Cc1cccc(COc2ccc(Cc3cc(-c4ccc(N)nc4N)on3)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
To a tetrahydrofuran (10 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (150 mg, 0.53 mmol) described in Manufacturing Example 18-1-1, (3-ethynyl-phenyl)-methanol (91 mg, 0.69 mmol) described in Manufacturing Example 214-1-2, and triphenylphosphine (180 mg, 0.69 mmol) was added diethyl azodicarboxylate (300 mg, 0.69 mmol, 40% toluene solution), which was stirred for 30 minutes at room temperature. NH silica gel was added to the reaction solution, and the solvent was evaporated under a reduced pressure. The crude product that had adsorbed to the NH silica gel was purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1, then 1:1, then ethyl acetate) to obtain the title compound (110 mg, 51%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.[OH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:14][C:13](=[O:21])[CH:12]=1.C1CCC(N=C=NC2CCCCC2)CC1.[Na].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([C:12]1[C:13](=[O:21])[O:14][C:15]2[C:20]([C:11]=1[OH:10])=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:9]
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: O=C(O)Cc1ccco1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Product: O=C(Cc1ccco1)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.55 g (12.3 mmol) of the furanacetic acid, 1.99 g (12.3 mmol) of 4-hydroxycoumarin and 2.83 g (13.7 mmol) of DCC were suspended in 50 ml of toluene, then 149 mg (1.22 mmol) of DMAP added and stirring carried out overnight at 60° C. The reaction liquid was then cooled to room temperature and the insoluble material filtered off. The mother liquor was concentrated and the residue purified by column chromatography. The solid obtained was recrystallized from methanol and Compound 9. (594 mg, 2.20 mmol, 18%) obtained. This was converted to the sodium salt with an equivalent amount of sodium hydrogen carbonate.
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:4]([CH3:17])[C:3]=1[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1)=[O:19].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1>>[CH3:17][N:4]1[C:3]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])=[C:2]([C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)[N:6]=[C:5]1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1
Reactant: Cn1c(-c2cccc(C(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1cccnc1
Product: Cn1c(-c2cccc(C(F)(F)F)c2)nc(-c2cccnc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [5-iodo-3-methyl-2-(3-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 36) was reacted with pyridine-3-yl-boronic acid to give the title compound as colorless oil. MS: 484.4 (MH+).
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([O:51][CH2:52][C:53]([F:56])([F:55])[F:54])=[N:40][C:41]([CH3:50])=[CH:42][C:43]=2[O:44][CH2:45][C:46]([F:49])([F:48])[F:47])=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[Cl:67][C:68]1[CH:69]=[C:70]([CH:79]([CH3:81])[CH3:80])[C:71]2[O:75][C:74]([SH:76])=[N:73][C:72]=2[C:77]=1[CH3:78]>>[Cl:67][C:68]1[CH:69]=[C:70]([CH:79]([CH3:81])[CH3:80])[C:71]2[O:75][C:74]([S:76][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]4[C:39]([O:51][CH2:52][C:53]([F:54])([F:55])[F:56])=[N:40][C:41]([CH3:50])=[CH:42][C:43]=4[O:44][CH2:45][C:46]([F:48])([F:47])[F:49])=[O:36])[CH2:30][CH2:29]3)=[N:73][C:72]=2[C:77]=1[CH3:78]
Reactant: Cc1c(Cl)cc(C(C)C)c2oc(S)nc12
Reactant: Cc1cc(OCC(F)(F)F)c(NC(=O)CN2CCN(CCO)CC2)c(OCC(F)(F)F)n1
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: Cc1cc(OCC(F)(F)F)c(NC(=O)CN2CCN(CCSc3nc4c(C)c(Cl)cc(C(C)C)c4o3)CC2)c(OCC(F)(F)F)n1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide, and 2-mercaptobenzimidazole was replaced by 5-chloro-7-isopropyl-2-mercapto-4-methylbenzoxazole, to thereby yield the title compound as a colorless crystalline powder.
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:5][CH:4]([CH2:6][OH:7])[CH2:3]1.ClCCl.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>O>[CH3:19][S:20]([O:7][CH2:6][CH:4]1[CH2:5][C:2]([F:8])([F:1])[CH2:3]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CC(F)(F)C1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107 %

Procedure:
1.35 g (11.06 mmol) of (3,3-difluorocyclobutyl)methanol were initially charged in 41.8 ml of abs. dichloromethane, 3.08 ml (22.11 mmol) of triethylamine and 1.03 ml (13.27 mmol) of methanesulphonyl chloride were added and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and filtered, and the filtrate was concentrated. This gave 2.37 g (quantitative yield) of the target compound.