Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([O:18][CH2:19][CH2:20]Cl)[C:12]=2[NH2:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:23]=[N+:24]=[N-:25].[Na+]>CS(C)=O.O>[N:23]([CH2:20][CH2:19][O:18][C:13]1[CH:14]=[C:15]([F:17])[CH:16]=[C:11]([CH2:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[C:12]=1[NH2:22])=[N+:24]=[N-:25]
Reactant: Nc1c(CS(=O)(=O)c2ccccc2)cc(F)cc1OCCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCOc1cc(F)cc(CS(=O)(=O)c2ccccc2)c1N
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 2-benzenesulfonylmethyl-6-(2-chloro-ethoxy)-4-fluorophenylamine (1.67 g, 4.87 mmoles) and sodium azide (0.38 g, 5.84 mmoles) in DMSO (20 mL) was stirred together in a round bottom flask under nitrogen at 90° C. for 3 hours. Reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAC, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (1.44 g, 4.14 mmoles).
Reaction SMILES: CN(C)C=O.[C:6]([CH2:9][N:10]1[C:14](=[O:15])[C:13](=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:12][C:11]1=[S:23])([OH:8])=[O:7].[OH-].C[N+](C)(C)C.[CH2:30](Br)[CH3:31]>CO>[C:6]([CH2:9][N:10]1[C:14](=[O:15])[C:13](=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:12][C:11]1=[S:23])([O:8][CH2:30][CH3:31])=[O:7]
Reactant: O=C(O)CN1C(=O)C(=Cc2ccccc2)SC1=S
Reactant: CCBr
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CCOC(=O)CN1C(=O)C(=Cc2ccccc2)SC1=S
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Under an atmosphere of nitrogen, 4.2 ml of anhydrous N,N-dimethylformamide was added dropwise to 0.279 g of 3-carboxymethyl-5-benzylidenerhodanine (prepared as described in Example 1) at room temperature, and then 1.14 ml of methanol solution of 91.15 mg of tetramethylammonium hydroxide was added dropwise. After the mixture was stirred at room temperature for 20-30 minutes, 0.075 ml of ethyl bromide was added dropwise to the reaction mixture. The mixture was stirred at the same temperature for about 2 hours, and then concentrated under reduced pressure. The residue was diluted with 15 ml of water and extracted with ethyl acetate. The extract was washed with 50 ml of aqueous solution of sodium bicarbonate, 50 ml of water and 50 ml of aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate and n-hexane (1:3) to obtain 14 mg of the titled compound.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH:13][CH2:14][C:15](=[O:17])[CH3:16].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:1]([O:13][CH2:14][C:15](=[O:17])[CH3:16])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: CC(=O)CO
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)OCC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Monohydroxyacetone was distilled prior to use. Chloroform was distilled from phosphorus pentoxide prior to use. Decanoyl chloride (65 cm3, 0.3146 mole) was added dropwise to stirred solution of monohydroxyacetone (21.8 cm3, 0.3146 mole) and anydrous pyridine (25.4 cm3, 0.3146 mole) in anhydrous chloroform (500 cm3). During the addition the solution was maintained in an ice bath. The mixture was then stirred at room temperature overnight. The solution was washed with water (4×200 cm3) and saturated sodium chloride solution (200 cm3). The organic phase was dried over sodium sulphate and evaporated in vacuo. The resulting oil was distilled to yield 1-decanoyloxypropan-2-one as a mobile liquid, bp 154°-60° (1 mm) (52.4 g, 0.230 mole, 73%),ir (neat) 2860, 1700, 1400, 1340, 1150, 1110 and 1050 cm-1 ; pmr (CDCI3) δ 4.6 (s, 2 H), 2.4 (t, 2 H), 2.1 (s, 3 H), 1.8-1.0 (bm, 14 H) and 0.9 (t, 3 H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1.Cl.C(=O)([O-])O.[Na+].[N:25]#[C:26][NH2:27]>C(O)C.C(OCC)(=O)C>[NH2:27][C:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1)=[NH:25]
Reactant: N#CN
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)Nc1nc(CCc2ccc(NC(=N)N)cc2)cs1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
To a suspension of N-(4-(2-(4-aminophenyl)ethyl)-1,3-thiazol-2-yl)acetamide (26 g) in ethanol (500 ml) was added 4N hydrogen chloride in ethyl acetate (25 ml) and cyanamide (6.3 g). The mixture was refluxed for 26 hours. The reaction mixture was cooled to ambient temperature and poured into a mixture of ethyl acetate (500 ml) and saturated sodium hydrogen carbonate solution (500 ml). The resulted precipitate was collected by filtration and washed with water (300 ml) and ethanol (300 ml) to give N-{4-[2-(4-{[amino(imino)methyl]-amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide (18 g) as white crystals.
Reaction SMILES: [OH:1][CH:2]1[C:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][N:21]=[C:20]([C:24]([O:26]CC)=[O:25])[CH:19]=3)[CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.O.[OH-].[Na+]>C1COCC1>[O:1]=[C:2]1[C:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][N:21]=[C:20]([C:24]([OH:26])=[O:25])[CH:19]=3)[CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: CCOC(=O)c1cc(N2CCC(C3=Cc4ccccc4NC3O)CC2)ncn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(N2CCC(c3cc4ccccc4[nH]c3=O)CC2)ncn1

Procedure:
1.10 g (2.91 mmol) ethyl 6-[4-(2-hydroxy-1,2-dihydro-quinolin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylate were stirred overnight at RT in 20 mL THF, 1.5 mL water and 1.5 mL of a 4 M NaOH solution. The organic solvent was eliminated by rotary evaporation and the precipitated solid was suction filtered. The filtrate was acidified with a 4 M HCl solution and the precipitated solid was suction filtered and dried.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[H-].[Na+].Br[CH2:10][CH2:11][CH2:12][C:13]1[CH:23]=[CH:22][CH:21]=[C:15]2[C:16]([NH:18][C:19](=[O:20])[C:14]=12)=[O:17]>C1(C)C(C)=CC=CC=1>[N:2]1([O:1][CH2:10][CH2:11][CH2:12][C:13]2[CH:23]=[CH:22][CH:21]=[C:15]3[C:16]([NH:18][C:19](=[O:20])[C:14]=23)=[O:17])[CH:6]=[CH:5][CH:4]=[N:3]1
Reactant: O=C1NC(=O)c2c(CCCBr)cccc21
Reactant: On1cccn1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=C1NC(=O)c2c(CCCOn3cccn3)cccc21
Reaction time: 1 h
Yield: 101.3 %

Procedure:
26 g of 1-hydroxypyrazole are added to a suspension of 10 g of sodium hydride (80 percent strength in oil) in 500 ml of xylene. The mixture is stirred for 1 hour, after which 84 g of 3-bromopropylphthalimide are added and the mixture is refluxed for 2 hours. After cooling, the mixture is filtered, the filtrate is evaporated down, the crystalline residue is suspended in diethyl ether and the product is filtered off under suction. 85 g of the title compound of melting point 116°-118° C. are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH:34]([F:36])[F:35])=[N:32][CH:33]=1>C(#N)C.O>[F:35][CH:34]([F:36])[C:31]1[N:32]=[CH:33][C:28]([CH2:27][O:1][C:2]2[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=2[O:17][CH3:18])=[CH:29][CH:30]=1
Reactant: COc1cc(CNC(=O)OC(C)(C)C)ccc1O
Reactant: FC(F)c1ccc(CCl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(CNC(=O)OC(C)(C)C)ccc1OCc1ccc(C(F)F)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.7 %

Procedure:
To a stirred solution of tert-butyl 4-hydroxy-3-methoxybenzylcarbamate (4.70 g, 18.56 mmol) and potassium carbonate (7.64 g, 55.28 mmol) in acetonitrile (50 mL) was added 5-(chloromethyl)-2-(difluoromethyl)pyridine hydrochloride (4.58 g, 21.40 mmol). The mixture was heated to reflux. After 3 h, the off-white suspension was allowed to cool to room temperature and was diluted with water (200 mL). The mixture was extracted with dichloromethane (3×75 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 7.74 g (>100%) of tert-butyl 4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxybenzylcarbamate as a waxy yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH:9]([CH3:11])[CH3:10])([CH2:7]O)[CH2:5][OH:6].[CH3:12][O:13][CH2:14][CH:15]=[O:16].C1CCCCC1>O>[CH3:12][O:13][CH2:14][CH:15]1[O:6][CH2:5][C:4]([CH2:3][O:2][CH3:1])([CH:9]([CH3:11])[CH3:10])[CH2:7][O:16]1
Reactant: COCC=O
Reactant: COCC(CO)(CO)C(C)C
Solvent: O
Solvent: C1CCCCC1
Product: COCC1OCC(COC)(C(C)C)CO1
Yield: 83 %

Procedure:
A mixture of 486 g (3 moles) of 2-methoxymethyl-2-isopropyl-1,3-propanediol, 287 g (3.3 moles) of 85% strength methoxyacetaldehyde and 250 ml of cyclohexane was heated with 5 g of the ion exchanger Lewasorb AC 10 under a water separator until water no longer separated off. The ion exchanger was filtered off, the solvent was stripped off under reduced pressure and the residue was subjected to fractional distillation under reduced pressure. 543 g (83% yield) of 2,5-dimethoxymethyl-5-isopropyl-1,3-dioxane of boiling point 95° C./1 mbar obtained.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:26][O:27][CH2:28][CH2:29]Br.[H-].[Na+]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@@H:20]([CH3:25])[CH2:21][N:22]([CH2:29][CH2:28][O:27][CH3:26])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COCCBr
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@@H](C)CNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: COCCN1C[C@H](C)n2c(cc3cc(OC4CCN(C(C)C)CC4)ccc32)C1=O
Yield: 50 %

Procedure:
The title compound was synthesized in analogy to example 17, from (S)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 11), 2-bromoethyl methyl ether and sodium hydride, to give the desired product as a colorless oil (50%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[C:31]([CH2:36][CH3:37])=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:36]([C:31]1[C:30]([C:26]2[CH:25]=[C:24]([C:22]3[CH2:21][C:20](=[O:38])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:17])([F:16])[F:18])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:35][CH:34]=[CH:33][N:32]=1)[CH3:37]
Reactant: CCc1ncccc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(C)cc2NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1ncccc1-c1cccc(C2=Nc3cc(C)c(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (2-{3-[3-(2-ethyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M214) (312 mg, 0.58 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (190 mg, 77%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:12])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.[C:13]([N:17]=[C:18]=S)([CH3:16])([CH3:15])[CH3:14]>>[C:13]([NH:17][C:18]1[N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[N:12]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)N=C=S
Reactant: CNc1ccc([N+](=O)[O-])cc1N
Product: Cn1c(NC(C)(C)C)nc2cc([N+](=O)[O-])ccc21

Procedure:
N1-methyl-4-nitro-benzene-1,2-diamine (2.0 g, 12.0 mmol) and tert-butyl isothiocyanate (1.67 ml, 13.2 mmol) were coupled using the procedure of intermediate example one part B to give the title compound as a yellow solid. 1H NMR (300 MHz, d6-DMSO) d 8.01 (d, J=2.1 Hz, 1H), 7.90 (dd, J=8.7 and 2.1 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 6.41 (s, 1H), 3.58 (s, 3H), 1.48 (s, 9H) ppm.
Reaction SMILES: Cl.Cl.[O:3]=[C:4]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:20]=[N:21][CH:22]=[C:23]([CH:27]=3)[C:24]([OH:26])=[O:25])[CH:17]=2)[O:12][C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5]1.[CH:28]1([C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:40]=2[N:39]=[C:38]([C:41](N2C=CN=C2)=[O:42])[CH:37]=[C:36]3[O:48][CH3:49])[CH2:30][CH2:29]1.Cl>CN(C=O)C.O>[CH:28]1([C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:40]=2[N:39]=[C:38]([C:41]([N:9]2[CH2:10][CH2:11][C:6]4([CH2:5][C:4](=[O:3])[C:18]5[C:13](=[CH:14][CH:15]=[C:16]([C:19]6[CH:20]=[N:21][CH:22]=[C:23]([CH:27]=6)[C:24]([OH:26])=[O:25])[CH:17]=5)[O:12]4)[CH2:7][CH2:8]2)=[O:42])[CH:37]=[C:36]3[O:48][CH3:49])[CH2:29][CH2:30]1
Reactant: COc1cc(C(=O)n2ccnc2)nc2c(C3CC3)cccc12
Reactant: O=C(O)c1cncc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(=O)O)c4)ccc2O3)nc2c(C3CC3)cccc12
Temperature: 70 °C
Reaction time: 19 h

Procedure:
5-{4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinic acid di-hydrochloride (4.93 g, 12.0 mmol), TEA (5.14 mL, 36.9 mmol) were suspended in DMF (49 mL) and (8-cyclopropyl-4-methoxy-quinolin-2-yl)-imidazol-1-yl-methanone (2.70 g, 9.22 mmol) was added thereto at room temperature, and the reaction mixture was stirred at 70° C. for 19 h. After cooled to room temperature, the mixture was poured into 1N HCl aq. (27.7 mL, 27.7 mmol) in H2O (367 mL) solution and the suspension was stirred for 2 h. The resulting precipitate was filtered, washed with H2O to give crude intended compound as a pale brown solid. This solid was washed with EtOAc-MeOH (1:1), then EtOH, and dried to afford the intended compound as a colorless solid. 1H-NMR (400 MHz, DMSO-d6) δ: 9.08 (1.0H, d, J=2.4 Hz), 9.03 (1.0H, d, J=2.0 Hz), 8.41 (1.0H, dd, J=2.0, 2.4 Hz), 8.07-8.03 (2.0H, m), 7.94 (1.0H, dd, J=8.3, 1.5 Hz), 7.49 (1.0H, dd, J=8.3, 7.6 Hz), 7.30-7.23 (2.0H, m), 7.20 (1.0H, s), 4.40-4.33 (1.0H, m), 4.07 (3.0H, s), 3.94-3.87 (1.0H, m), 3.57-3.48 (1.0H, m), 3.39-3.24 (1.0H, m), 3.11-3.04 (1.0H, m), 2.98 (2.0H, s), 2.15-2.07 (1.0H, m), 2.03-1.79 (3.0H, m), 1.10-1.04 (2.0H, m), 0.87-0.72 (2.0H, m). MS [M+H]+=564.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].C(O[CH:9]1[NH:12][C:11](=[O:13])[CH:10]1[CH3:14])(=O)C>[OH-].[Na+].O.CC(C)=O>[C:1]([S:3][CH:9]1[NH:12][C:11](=[O:13])[CH:10]1[CH3:14])(=[O:4])[CH3:2]
Reactant: CC(O)=S
Reactant: CC(=O)OC1NC(=O)C1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)SC1NC(=O)C1C

Procedure:
A solution of 1.5 ml of thioacetic acid in 20.5 ml of 1N sodium hydroxide solution is added dropwise at room temperature, under nitrogen, to a solution of 2 g of 4-acetoxy-3-methyl-azetidin-2-one (produced according to K. Clauss et. al., Lieb. Ann. Chem., 1974, 539; racemic mixture of cis- and trans-isomer in a ratio of 3:1, Mp. 53°-65°) in 5.16 ml of water and 1.25 ml of acetone, and the mixture is stirred at the same temperature for 3 hours. The reaction mixture is exhaustively extracted with methylene chloride. The combined organic phases are dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed over 150 g of silica gel with toluene/ethyl acetate (9:1) and yields the almost pure trans-isomer of the title compound with the following physico-chemical properties:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:13])[C:10]=1[O:11]C)[C:5]([OH:7])=O.[NH2:14][C:15]1[CH:20]=[C:19]([O:21]C)[CH:18]=[C:17]([Br:23])[C:16]=1O>>[Br:23][C:17]1[C:16]2[O:7][C:5]([C:4]3[CH:8]=[C:9]([F:13])[C:10]([OH:11])=[C:2]([F:1])[CH:3]=3)=[N:14][C:15]=2[CH:20]=[C:19]([OH:21])[CH:18]=1
Reactant: COc1cc(N)c(O)c(Br)c1
Reactant: COc1c(F)cc(C(=O)O)cc1F
Product: Oc1cc(Br)c2oc(-c3cc(F)c(O)c(F)c3)nc2c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 21, from 3,5-difluoro-4-methoxybenzoic acid, and 2-amino-6-bromo-4-methoxyphenol, and was obtained as a white solid, m.p. 270-272° C.; MS m/e 340 (M−H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[N:3]=1.[Br:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[Br:18][C:19]1[CH:24]=[C:23]([C:2]2[N:7]=[C:6]([C:8]3[S:9][C:10]([Cl:13])=[CH:11][CH:12]=3)[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[N:3]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)s2)nc(Cl)n1
Reactant: OB(O)c1cccc(Br)c1
Product: FC(F)(F)c1cc(-c2ccc(Cl)s2)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(5-chloro-thiophen-2-yl)-6-trifluoromethyl-pyrimidine (example A.1) (1.2 g, 4.0 mmol) and commercially available 3-bromo-benzene-boronic acid (0.88 g, 4.38 mmol) according to the general procedure IIb. Obtained as a white solid (0.73 g, 43%). MS (EI) 419.9 [(M)+]; mp 124° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19](O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:20]1[O:21][C:16]([CH3:17])([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][CH:13]=2)[O:18][CH2:19]1
Reactant: CC(=O)Cc1ccc(OCc2ccccc2)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(Cc2ccc(OCc3ccccc3)cc2)OCCO1

Procedure:
A solution of 1-(4-benzyloxyphenyl) propan-2-one (5 g), ethylene glycol (1.4 g) and a trace amount of 4-toluenesulphonic acid, in benzene (100 ml) was heated under reflux with azetropic removal of water for 2 hours. The solvent was evaporated, the residue dissolved in ethyl acetate, washed with 1.2 N sodium bicarbonate solution, dried (MgSO4) and evaporated to give a light brown oil which crystallised on standing (6.1 g) m.p. 58°-62°.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20](Cl)=[O:21]>C(Cl)Cl>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)=[O:21]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(NC(=O)c3c(F)cccc3F)cc2)OC1(C)C
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a stirred solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (5.2 g, 24 mmol), TEA (5 mL) in dry DCM (50 mL) at 0° C. was added 2,6-difluoro-benzoyl chloride (3.0 mL, 24 mmol) dropwise. The mixture was allowed to warm to to room temperature over 2 h before it was washed with water (2×100 mL) and dried. Removal of solvents gave 2,6-difluoro-N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (8.4 g, 23 mmol) as white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[CH:34]=[CH:33][O:32][CH:31]=1)(=[O:29])=[O:28].[OH-].[NH4+:36]>>[NH2:36][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:9][C:8]=2[C:7]2[C:2]([Cl:1])=[C:3]([NH:26][S:27]([C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)(=[O:28])=[O:29])[CH:4]=[CH:5][CH:6]=2)[CH:18]=[CH:17][N:16]=1
Reactant: [NH4+]
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1ccoc1
Agent: [OH-]
Product: Nc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2Cl)n1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide (95 mg, 0.177 mmol) and ammonium hydroxide (4 mL), the title compound was obtained as an off-white solid (59 mg, 61% yield). MS (ESI): 519 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([CH2:12][OH:13])=[CH:10][CH:11]=1.COC(=O)CCl.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH3:34]>CO>[OH:13][CH2:12][C:9]1[N:8]=[CH:7][C:6]([O:5][CH2:4][C:3]([NH2:34])=[O:2])=[CH:11][CH:10]=1
Reactant: N
Reactant: COC(=O)COc1ccc(CO)nc1
Agent: COC(=O)CCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CO
Product: NC(=O)COc1ccc(CO)nc1
Yield: 100 %

Procedure:
1.25 g (6.35 mmol) of (6-Hydroxymethyl-pyridin-3-yloxy)-acetic acid methyl ester (prepared from 6-methyl-pyridin-3-ol by reaction with: 1) Chloro-acetic acid methyl ester, 2) m-Cl-perbenzoic acid and 3) trifluoroacetic acid anhydride) was treated with 31 ml 7M NH3 in MeOH for 2.5 h at RT. The suspension was evaporated to give 1.19 g (100%) of the title compound as a white solid. MS: 183.3 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:12]2[C:20]3[CH:19]=[C:18]4[O:21][CH2:22][CH2:23][O:24][C:17]4=[CH:16][C:15]=3[N:14]([CH2:25][C:26]3[O:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=3)[C:13]2=[O:35])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[C:36]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[F:32][C:31]([F:34])([F:33])[C:28]1[O:27][C:26]([CH2:25][N:14]2[C:15]3[CH:16]=[C:17]4[O:24][CH2:23][CH2:22][O:21][C:18]4=[CH:19][C:20]=3[C:12]3([C:3]4=[CH:4][C:5]5[O:10][CH2:9][CH2:8][O:7][C:6]=5[CH:11]=[C:2]4[O:1][CH2:36]3)[C:13]2=[O:35])=[CH:30][CH:29]=1
Reactant: O=C1C(c2cc3c(cc2O)OCCO3)c2cc3c(cc2N1Cc1ccc(C(F)(F)F)o1)OCCO3
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cc3c(cc2C12COc1cc4c(cc12)OCCO4)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 8-(7-hydroxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-((5-(trifluoromethyl)furan-2-yl)methyl)-6,8-dihydro-2H-[1,4]dioxino[2,3-f]indol-7(3H)-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 6-((5-(trifluoromethyl)furan-2-yl)methyl)-2,3,3′,7-tetrahydro-2′H-spiro[[1,4]dioxino[2,3-f]indole-8,8′-benzofuro[5,6-b][1,4]dioxin]-7(6H)-one was obtained (76%) as a colorless solid: mp 176-178° C.; 1H NMR (300 MHz, CDCl3) δ 6.75-6.67 (m, 2H), 6.49-6.43 (m, 2H), 6.37-6.31 (m, 1H), 6.22-6.16 (m, 1H), 4.87 (ABq, 2H), 4.69 (ABq, 2H), 4.26-4.04 (m, 8H); 13C NMR (75 MHz, CDCl3) δ 177.2, 155.0, 152.0, 151.9, 144.6, 144.0, 140.1, 138.3, 135.2, 124.3, 120.9, 113.7, 112.6, 112.6, 111.5, 109.1, 99.3, 98.9, 80.0, 64.6, 64.5, 64.0, 63.9, 57.8, 37.0; MS (ES+) m/z 501.9 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[H-].[Na+].[CH3:11]I>CN(C)C=O.C(Cl)(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][N:5]([CH3:11])[C:4](=[O:8])[CH:3]=1
Reactant: O=c1cc(I)cc[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cn1ccc(I)cc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
A solution of 4-iodo-2-pyridone (500 mg), sodium hydride (109 mg) and methyl iodide (482 mg) in dimethylformamide (5.0 mL) was stirred at room temperature for 4 hr. Additional sodium hydride (109 mg) and methyl iodide (482 mg) were added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform and washed with saturated aqueous sodium hydrogen carbonate solution. After extraction with chloroform, the organic phase was dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by column chromatography (silica gel cartridge, chloroform:methanol=98:2-96:4) to afford the title compound (341 mg).