Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC(N)=S.[CH3:5][N:6]([CH3:19])[S:7]([C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=1[OH:18])(=[O:9])=[O:8].[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]=[C:28]=[S:29]>>[Cl:16][C:15]1[CH:14]=[CH:13][C:12]([NH:17][C:28]([NH:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH3:20])=[S:29])=[C:11]([OH:18])[C:10]=1[S:7]([N:6]([CH3:19])[CH3:5])(=[O:9])=[O:8]
Reactant: Cc1ccccc1N=C=S
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Agent: NC(N)=S
Product: Cc1ccccc1NC(=S)Nc1ccc(Cl)c(S(=O)(=O)N(C)C)c1O
Yield: 69.6 %

Procedure:
Following the general procedure for thiourea formation outlined in example 12, N,N-dimethyl-3-amino-6chloro-2-hydroxybenzenesulfonamide (500 mg, 2 mmol) and 2-methylphenylisothiocyanate (298.4 mg, 2 mmol) were coupled to form the desired thiourea (557 mg, 70%). EI-MS m/z 400.0 (M30 ).
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[C:12](I)=[CH:11][C:10]([Cl:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].Cl>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].O>[Cl:3][C:4]1[C:12]([OH:1])=[CH:11][C:10]([Cl:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cc(Cl)cc(I)c1Cl
Reactant: [OH-]
Agent: [Cu+2]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: O=C(O)c1cc(Cl)cc(O)c1Cl
Temperature: 100 °C
Yield: 65 %

Procedure:
To a flask containing 1100 mL of water was added 97.20 grams (2.43 moles) of sodium hydroxide. When the sodium hydroxide was completely dissolved, 51.34 grams (0.162 mole) of 2,5-dichloro-3-iodobenzoic acid was added, turning the solution black. To this black solution was added 26.29 grams (0.105 mole) of copper(II) sulfate pentahydrate. The reaction mixture was heated to 100° C. and maintained at this temperature for three hours. At the-conclusion of this period, the reaction mixture was cooled in an icewater bath and then acidified with concentrated hydrochloric acid. This mixture was extracted with ethyl acetate, and the extract was washed four times with water and once with a saturated aqueous solution of sodium chloride. The extract was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure, leaving 21.79 grams of 2,5-dichloro-3-hydroxybenzoic acid as a black solid.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:8]([CH2:10][OH:11])[N:9]=1)(=O)C.[ClH:19]>C(O)C>[ClH:19].[ClH:19].[NH2:4][C:5]1[S:6][C:7]([S:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:8]([CH2:10][OH:11])[N:9]=1
Reactant: CC(=O)Nc1nc(CO)c(Sc2ccncc2)s1
Agent: Cl
Solvent: CCO
Product: Nc1nc(CO)c(Sc2ccncc2)s1
Yield: 75.3 %

Procedure:
A mixture of 2-acetylamino-4-hydroxymethyl-5-(4-pyridylthio)thiazole (3.0 g) in a mixture of concentrated hydrochloric acid (8 ml) and ethanol (100 ml) was refluxed for 2.5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was triturated with acetone. The precipitates were collected by filtration, washed with isopropyl ether and were recrystallized from a mixture of ethanol and isopropyl ether to give 2-amino-4-hydroxymethyl-5-(4-pyridylthio)thiazole dihydrochloride (2.5 g, yield: 75.3%). mp: 231°-237° C. (dec.) IR (Nujol) 3350, 2300, 1610, 1560 cm-1
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:8]=1[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:6])=[O:5])([CH3:3])[CH3:2]>[Pd].CO>[NH2:23][C:20]1[CH:21]=[CH:22][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[C:8]([CH:19]=1)[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1CN(C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)S(=O)(=O)c1ccc(N)cc1CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
To a 500 mL round-bottomed flask was added tert-butyl 2-(isopropylsulfonyl)-5-nitrobenzyl(methyl)carbamate (2.6 g, 6.98 mmol, see WO 2008/079836 for preparation) and MeOH (200 ml) to give a colorless solution. Pd/C (0.074 g, 0.698 mmol) was added. The mixture was stirred under a hydrogen balloon at rt overnight. Pd/C was removed by filtration and the filtrate was concentrated to give 8A (2.18 g, 91% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:27]=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=4)([C:20]4[N:21]([CH3:25])[CH:22]=[N:23][CH:24]=4)O)[CH:16]=3)[N:11]=[C:10]([O:33]C)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:39][O:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][NH2:46])=[CH:43][CH:42]=1>C1(C)C=CC=CC=1.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:27]=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=4)([NH:46][CH2:45][C:44]4[CH:47]=[CH:48][C:41]([O:40][CH3:39])=[CH:42][CH:43]=4)[C:20]4[N:21]([CH3:25])[CH:22]=[N:23][CH:24]=4)[CH:16]=3)[NH:11][C:10](=[O:33])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)nc3)c3cncn3C)ccc2n1
Reactant: COc1ccc(CN)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COc1ccc(CNC(c2ccc(Cl)nc2)(c2ccc3[nH]c(=O)cc(-c4cccc(Cl)c4)c3c2)c2cncn2C)cc1
Temperature: 85 °C
Reaction time: 3 h
Yield: 36.6 %

Procedure:
To [4-(3-chloro-phenyl)-2-methoxy-quinolin-6-yl]-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methanol (1.08 g, 2.21 mmol) in toluene (8.5 ml) under an atmosphere of dry N2 was added thionyl chloride (1.61 ml, 22.06 mmol) dropwise. The reaction mixture was heated at 85° C. for 15 hours. Solvent and the excess thionyl chloride were removed under reduced pressure. The crude chloride was taken up in toluene and concentrated under vacuum. The resulting solid was dissolved in THF (10 ml) and to this solution at −78° C. was added p-methoxybenzylamine (1.44 ml, 11.03 mmol) in THF (2 ml). The reaction mixture was stirred at −78° C. for 3 hours under an atmosphere of N2 for 3 hours. After removal of THF, the product mixture was partitioned between CHCl3 and water. The organic layer was washed, dried over MgSO4 and concentrated under vacuum to give the crude product. It was chromatographed on silica gel with MeOH—CHCl3—NH4OH (2:98:0.1) as eluents to afford the titled compound of Example 46A (0.482 g, 52% yield).
Reaction SMILES: [C:1]([CH2:9][C:10](=O)[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>C(OCC)(=O)C>[N:13]1(/[C:10](/[CH3:11])=[CH:9]\[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCNC1
Reactant: CC(=O)CC(=O)c1ccccc1
Solvent: CCOC(C)=O
Product: C/C(=C/C(=O)c1ccccc1)N1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.2 %

Procedure:
To a solution of 17.4 g of benzoylacetone in 100 ml of ethyl acetate is added a solution of 7.35 g of pyrrolidine in 50 ml of ethyl acetate. The reaction mixture is stirred at room temperature for 16 hours. The precipitated compound is collected by filtration to give 20.30 g of 3-(1-pyrrolidinyl)crotonophenone.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14]/[CH:15]=[CH:16]/[C@@H:17]2[CH2:22][O:21][CH2:20][CH2:19][N:18]2C(OC(C)(C)C)=O)[CH2:10][C@H:9]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([CH3:38])[CH:32]=1)=[O:7].[ClH:48]>C(OCC)(=O)C.CCCCCC>[ClH:48].[ClH:48].[F:45][C:42]([F:43])([F:44])[C:40]1[CH:39]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:47])[F:46])[CH:41]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14]/[CH:15]=[CH:16]/[C@@H:17]2[CH2:22][O:21][CH2:20][CH2:19][NH:18]2)[CH2:10][C@H:9]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([CH3:38])[CH:32]=1)=[O:7]
Reactant: Cc1ccc(C[C@@H]2CN(C/C=C/[C@@H]3COCCN3C(=O)OC(C)(C)C)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(C[C@@H]2CN(C/C=C/[C@@H]3COCCN3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reaction time: 5 h

Procedure:
A solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[(2E)-3-[(3R)-4-(tert-butoxycarbonyl)morpholin-3-yl]-2-propenyl]-2-(3,4-dimethylbenzyl)piperazine (1.36 g) in ethyl acetate (13 ml) was treated 4N hydrogen chloride in ethyl acetate (3.12 ml) at room temperature for 18 hours and then at 40° C. for 5 hours. The solution was diluted with hexane and stirred for 1 hour. The resulting precipitate was collected by filtration and dried under reduced pressure to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[(2E)-3-[(3R)-3-morpholinyl]-2-propenyl]piperazine dihydrochloride (1.11 g) as a white powder.
Reaction SMILES: [C:1]([CH:3]=[CH:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[F:22])=[O:13])[CH:8]([CH2:23][OH:24])[CH2:7]1)#[N:2].[NH:25]1[CH:29]=[C:28]([C:30]2[C:31]3[CH:38]=[CH:37][N:36](COCC[Si](C)(C)C)[C:32]=3[N:33]=[CH:34][N:35]=2)[CH:27]=[N:26]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([CH2:3][CH:4]([N:25]1[CH:29]=[C:28]([C:30]2[C:31]3[CH:38]=[CH:37][NH:36][C:32]=3[N:33]=[CH:34][N:35]=2)[CH:27]=[N:26]1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[F:22])=[O:13])[CH:8]([CH2:23][OH:24])[CH2:7]1)#[N:2]
Reactant: N#CC=CCN1CCN(C(=O)c2ccc(C#N)cc2F)C(CO)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCC(CN1CCN(C(=O)c2ccc(C#N)cc2F)C(CO)C1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 8 h

Procedure:
4-{[4-[3-cyanoprop-2-en-1-yl]-2-(hydroxymethyl)piperazin-1-yl]carbonyl}-3-fluorobenzonitrile (46 mg, 0.14 mmol, as a mixture of E- and Z-mixtures from Step 2) was combined with 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (29 mg, 0.093 mmol, prepared as described in WO 2007/070514 Example 65) in DMF (0.14 mL) and potassium carbonate (0.0414 g, 0.299 mmol) was added. The reaction mixture was stirred overnight. The mixture was then filtered and the filtrate was diluted with EtOAc. This solution was washed with water (thrice), brine; dried over sodium sulfate, decanted and concentrated. The crude was then stirred in 1:1 DCM:TFA (4 mL) for 1 h and the solvent removed in vacuo. The residue was then stirred with 0.2 mL ethylenediamine in 1.5 mL MeOH for 30 min. Preparative HPLC-MS (C18, eluting with a gradient of H2O/MeCN containing 0.15% NH4OH) was used to purify product—a mixture of diastereomers (24 mg, 50%). 1H NMR (400 MHz, DMSO-d6, mixture of diastereomers and rotamers): δ 12.12 (br s, 2H), 8.81, 8.80, 8.78, 8.78 (4s, 2H), 8.68, 8.67 (2s, 2H), 8.37, 8.37, 8.36 (3s, 2H), 7.99-7.91 (m, 2H), 7.80-7.72 (m, 2H), 7.63-7.50 (m, 4H), 6.99-6.95 (m, 2H), 5.07-1.84 (m, 28H); LCMS (M+H)+: 514.2.
Reaction SMILES: CS(C)=O.[CH2:5]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([NH:16][S:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]([CH:30]([OH:32])[CH3:31])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:12][CH2:11]1)=[O:9])[CH3:6].C(N(CC)CC)C>C(Cl)Cl>[CH2:5]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([NH:16][S:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]([C:30](=[O:32])[CH3:31])=[CH:22][CH:21]=2)(=[O:18])=[O:19])[CH2:12][CH2:11]1)=[O:9])[CH3:6]
Reactant: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(C(C)O)c3ccccc23)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(C(C)=O)c3ccccc23)CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 25.1 %

Procedure:
To a −78° C. solution of oxalyl dihcloride (85 mg, 0.665 mmol) in CH2Cl2 (10 mL) was added DMSO (104 mg, 1.33 mmol). After stirred at -78° C. for 10 min, a solution of 4-[4-(1-hydroxy-ethyl)-naphthalene-1-sulfonylamino]-piperidine-1-carboxylic acid ethyl ester 38 (180 mg, 0.443 mmol) in CH2Cl2 was added into the mixture by dropwise. The resultant mixture was stirred at −78° C. for another 30 min, then was added triethyl amine (224 mg, 2.22 mmol). The reaction mixture was warmed up to room temperature and stirred for 2 h. The resultant mixture was quenched with saturated ammonium chloride solution and the aqueous layer was extracted with CH2Cl2. The organic extracts were combined, washed with brine and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude product. The crude material was purified by Flash column chromatography (CH2Cl2: MeOH) to provide 45 mg of 4-(4-acetyl-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid ethyl ester 39 in 25% yield. LC/MS showed m/z: 409 (M+H)+.
Reaction SMILES: [O:1]([C:13]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([CH:21]=O)=[CH:15][C:14]=1[O:23][CH3:24])[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[I-:25].[CH3:26][N+:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[CH3:37].C([O-])(=O)C.[NH4+]>C(O)C>[I-:25].[C@@H:2]1([O:1][C:13]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([CH:21]=[CH:37][C:28]3[CH:29]=[CH:30][C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[N+:27]=3[CH3:26])=[CH:15][C:14]=2[O:23][CH3:24])[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: Cc1ccc2ccccc2[n+]1C
Reactant: COc1cc(C=O)cc(OC)c1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: CC(=O)[O-]
Agent: [I-]
Agent: [NH4+]
Solvent: CCO
Product: COc1cc(C=Cc2ccc3ccccc3[n+]2C)cc(OC)c1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Temperature: 60 °C
Reaction time: 5 h
Yield: 59.5 %

Procedure:
A suspension of 4-formyl-2,6-dimethoxyphenyl β-D-galactopyranoside (0.19 g, 0.55 mmol), 1,2-dimethylquinolinium iodide (0.16 g, 0.55 mmol) in ethanol (20 ml) containing ammonium acetate (0.13 g, 1.7 mmol) was stirred at about 60° C. for 5 h. The dark orange precipitate which formed during the reaction was then filtered off and washed with ethanol followed by acetone to give (22c)(0.2 g, 86%) as an orange powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Br[CH:21]([CH2:25]Br)[C:22]([NH2:24])=[O:23]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:21]([C:22]([NH2:24])=[O:23])[CH2:25]1
Reactant: COc1ccccc1NCCNCc1ccccc1
Reactant: NC(=O)C(Br)CBr
Product: COc1ccccc1N1CCN(Cc2ccccc2)C(C(N)=O)C1

Procedure:
In a manner similar to Preparation 1, react N-(2-methoxyphenyl)-N'-(phenylmethyl)-1,2-ethanediamine (15.4 g, 60.2 mmol) with 2,3-dibromopropanamide (27.7 g, 0.12 mol) to give the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]([CH3:14])=[C:12]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C:16]2=[O:28])[N:11]=[N:10]1>O1CCOCC1>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]([CH3:14])=[C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]2=[O:28])[N:11]=[N:10]1
Reactant: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2=O)nnn1-c1ccccc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(N2CCNCC2=O)nnn1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
4N Hydrochloric acid solution in dioxane (10 ml) was added to 150 mg of tert-butyl 4-[1-(2-chlorophenyl)-5-methyl-1H-[1,2,3]-triazol-4-yl]-3-oxopiperazine-1-carboxylate prepared in Example 26, the mixture was stirred at room temperature for 3 hours and the solvent was evaporated in vacuo to give 110 mg of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11]CC2)=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:14]1[CH:19]=[C:18](B(O)O)[CH:17]=[N:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>Cl[Pd]Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[N:14]1[CH:19]=[C:18]([C:5]2[CH:4]=[CH:3][C:2]3[O:11][CH2:12][CH2:13][NH:8][C:7]=3[CH:6]=2)[CH:17]=[N:16][CH:15]=1
Reactant: Brc1ccccc1N1CCOCC1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: c1ncc(-c2ccc3c(c2)NCCO3)cn1

Procedure:
In a manner similar to those previously described (Examples 15-17, 67), 6-bromophenyl morpholine (67C) was treated with pyrimidine-5-boronic acid, PdCl2(dppf, and K2CO3, to provide compound 6-(pyrimidin-5-yl)-benzomorpholine, which was further converted to the title compound 68. MS m/z 294 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([P:8]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.OO.S([O-])([O-])=[O:25].[Na+].[Na+]>C(OCC)(=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](=[O:25])([C:15]2[CH:16]=[CH:17][C:18]([Br:21])=[CH:19][CH:20]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(P(c2ccccc2)c2ccc(Br)cc2)cc1
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=P(c1ccccc1)(c1ccc(Br)cc1)c1ccc(Br)cc1
Temperature: 5 °C
Reaction time: 12 h

Procedure:
10.05 g (24 mmol) of bis(4-bromophenyl)phenylphosphine were dissolved in 200 ml of ethyl acetate in a 500 ml four-necked flask with internal thermometer, mechanical stirrer, reflux condenser and dropping funnel and cooled to an internal temperature of 5° C. A solution of 2.25 ml (26.4 mmol) of H2O2 (35%) in 17.5 ml of water was added dropwise over the course of 30 min., and the mixture was stirred at room temperature for a further 12 h. 25 ml of saturated sodium sulfite solution were subsequently added, the organic phase was separated off, washed twice with saturated sodium sulfite solution and dried over sodium sulfate. The solvent was removed under reduced pressure. The purification was carried out firstly by column chromatography on silica using a solvent mixture of initially hexane:ethyl acetate 2:1 to hexane:ethyl acetate 1:1. Further purification was carried out by recrystallisation from heptane/toluene, giving 6.5 g of product in a purity of 99.7% (according to HPLC). 1H-NMR (500 MHz, CDCl3): [ppm] 7.46-7.66 (m). 31P-NMR (CDCl3): [ppm] 28.40.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:29]=[CH:28][C:22]4[CH:23]=[CH:24][C:25](=[O:27])[O:26][C:21]=4[CH:20]=3)[O:9][C:8]=2[CH:30]=1.CI.[CH:33](N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([CH2:13][N:14]([CH3:33])[CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:29]=[CH:28][C:22]4[CH:23]=[CH:24][C:25](=[O:27])[O:26][C:21]=4[CH:20]=3)[O:9][C:8]=2[CH:30]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc2c(c1)OC(CNCCCOc1ccc3ccc(=O)oc3c1)CO2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc2c(c1)OC(CN(C)CCCOc1ccc3ccc(=O)oc3c1)CO2
Temperature: 80 °C
Yield: 9.7 %

Procedure:
7-[3-[[(2,3-Dihydro-7-methoxy-1,4-benzodioxin-2-yl)methyl]amino]propoxy]-2H-1-benzopyran-2-one hydrochloride (2.2 g, 5.0 mmole) was dissolved in 100 ml of DMF and 700 mg (5.0 mmole) of methyl iodide added, followed by 2.6 g (20 mmole) of diisopropylethylamine. The mixture was heated at 80° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed in vacuum and replaced with 300 ml of dichloromethane. The mixture was washed with 300 ml portions of saturated aqueous sodium bicarbonate, saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography on 100 g of silica gel using chloroform as eluant and crystallized from isopropanol with addition of 2.5 ml of 4N isopropanolic HCl to give 0.20 g of the title compound as a monohydrochloride, m.p. 176°-178° C.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH:9]([CH2:11][CH2:12][CH3:13])[S:8](=[O:15])(=[O:14])[C:7]2[S:16][C:17]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:18][C:6]1=2)(=O)[CH3:2].S(C)C.Cl>O1CCCC1>[CH2:1]([NH:4][C@H:5]1[CH2:10][C@H:9]([CH2:11][CH2:12][CH3:13])[S:8](=[O:15])(=[O:14])[C:7]2[S:16][C:17]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:18][C:6]1=2)[CH3:2]
Reactant: CCCC1CC(NC(C)=O)c2cc(S(N)(=O)=O)sc2S1(=O)=O
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Product: CCC[C@H]1C[C@H](NCC)c2cc(S(N)(=O)=O)sc2S1(=O)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A flask fitted with a short path distillation head was charged with a solution of 7 (53.3 g, 0.145 mol) in 1000 ml of tetrahydrofuran. After blanketing the system with argon, the solution was treated with 10.0M BH3.(CH3)2S (51 ml, 0.5 mol) at a rate sufficient to maintain reasonable gas evolution. Upon addition, the flask was gently warmed to collect (CH3)2S. After equilibrating to room temperature overnight, the solution was chilled to 0° C. and was then treated with 80 ml of absolute ethanol followed by equilibrating to room temperature. The resulting amber solution was concentrated to remove solvents. The dry solids were solublilzed in 500 ml of tetrahydrofuran and treated with 60 ml (0.36 mol) of 6N aqueous hydrochloric acid. The mixture was allowed to reflux for 1 hour, followed by stirring at room temperature for 2 hours. The solution was concentrated to remove tetrahydrofuran, and the resulting oil was treated with 500 ml of ethyl acetate and 200 ml of water. The aqueous phase was buffered to pH 8, and washed with an additional 50 ml of ethyl acetate. All organic extracts were then washed with 100 ml of saturated aqueous sodium chloride. The dried (Na2SO4) organic phase was filtered and concentrated to yield 45.12 g (0.128 mol, 88.3%) of 8 and 9 as a cis/trans isomeric mixture. The mixture was dissolved in 1500 ml ethyl acetate and treated with a solution of 5.6 g (0.134 mol) of maleic acid in 400 ml of hot ethyl acetate. A sufficient amount of hot methanol was added to solubilize all solids, and the solution was allowed to stand for 72 hours. The resulting white solid was collected and dried to give 12.50 g of the maleate salt. A second crop gave 2.26 g. The remaining liquor was concentrated and oil was solubilized in ethyl acetate and triturated slowly with diethyl ether to selectively give the trans isomer. The precipitation was repeated several times to give a total of 12.88 g of white solid. The total amount of pure trans maleate was 27.64 g (46.1% of 8). The remaining cis isomer enriched oil 9 was chromatographed (silica gel, 95:5:0.5, CHCl3 /MeOH/NH4OH followed by 90:10:1.0, CHCl3 /MeOH/NH4OH)) to give 0.9 g of 8. A total yield of 21.70 g (48.4% yield)* of 8 was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[OH:16].C(=O)([O-])[O-].[K+].[K+].Cl[C:25]([F:31])([F:30])C(OC)=O.O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([C:12]([F:14])([F:13])[F:15])=[CH:6][C:5]=1[O:16][CH:25]([F:31])[F:30]
Reactant: COC(=O)c1c(O)cc(C(F)(F)F)cc1OC
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(OC)cc(C(F)(F)F)cc1OC(F)F
Temperature: 65 °C

Procedure:
To a solution of 35 mg (0.140 mmol) 2-hydroxy-6-methoxy-4-trifluoromethyl-benzoic acid methyl ester in 350 ul N,N-dimethylformamide under nitrogen at room temperature, was added 29 mg (0.210 mmol) potassium carbonate, followed dropwise by 18.1 ul (0.168 mmol) methyl chlorodifluoroacetate. The reaction mixture was heated in a 65° C. oil bath for 22 hours. Water and ethyl acetate were added. Both phases were separated and the organic layer was washed 3 times with water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude brown oil (49 mg) was purified with flash column chromatography on silica (10 g) eluting with a gradient formed from n-heptane and ethyl acetate (0%=>10% in 15 minutes) to provide 16 mg (y: 38.1%) of the title compound as a light yellow oil.