Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]1([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH2:9][CH2:8][CH2:7][C@@:4]2([O:6][CH2:5]2)[CH2:3]1.C(O)(C(F)(F)F)=[O:23].C(Cl)Cl.[OH-].[Na+]>O>[OH:6][C@@:4]1([CH2:5][OH:23])[CH2:7][CH2:8][CH2:9][C@@:2]([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)([CH3:1])[CH2:3]1
Reactant: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@]2(CO2)C1
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@@](O)(CO)C1
Temperature: 18 °C
Reaction time: 2.5 h

Procedure:
To a 3 L flask was added 1-{[(3R,5S)-5-methyl-1-oxaspiro[2.5]oct-5-yl]methyl}-1H-benzimidazole-6-carbonitrile (94.7 g, 337 mmol). The material was azeotroped two times with EtOAc to remove any trace amounts of MeOH from the SFC. Next, to the residue was added DMF (731 mL) and water (731 mL). The solution was cooled to ˜18° C. (with an ice water bath). Next, a solution of TFA (51.9 mL, 673 mmol) in water (731 mL) added (pre-cooled to ˜10° C.). The entire solution was then cooled with an ice water bath to ˜10° C. The temperature was held around 10° C. for about 2.5 h then allowed to warm to RT and stir overnight. The next day, DCM (500 mL) was added, and the solution was made basic by slowly adding 6N NaOH. The mixture was added to a separatory funnel, the DCM separated and the aqueous layer diluted with 6N NaOH (300 mL), and then extracted with DCM (8×250 mL). The combined organic extracts were concentrated under reduced pressure to remove as much DMF as possible. The residue was dissolved in DCM (250 mL) and stirred at RT to crystallize the trans diol. After stirring overnight, the solution was cooled to ˜10° C., and the solids were filtered off, washed with DCM and dried under reduced pressure. This yielded 49.15 g of 1-{[(1S,3S)-3-hydroxy-3-(hydroxymethyl)-1-methylcyclohexaneyl]methyl}-1H-benzimidazole-6-carbonitrile (trans diol) as a white solid. The filtrate (˜60 g material, a mixture of cis-diol, trans-diol, and elimination side products) was concentrated, loaded onto silica gel and split into 3 equal portions and purified on the ISCO RF (3×330 g column): 0-5% MeOH/DCM over 15 min, hold at 5% for 10 min, then 5-25% over 10 min, then hold at 25%. The trans diol product was combined with the solids from the crystallization and used without further purification. MS (m/z) 300.2 (M+H+).
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3][NH:2]1)[CH2:9]2.[Cl:12][CH2:13][C:14](Cl)=[O:15]>ClCCl.O>[Cl:12][CH2:13][C:14]([N:2]1[CH2:3][CH:4]2[CH2:10][CH:8]3[CH2:7][CH:6]([CH2:11][CH:1]1[CH2:9]3)[CH2:5]2)=[O:15]
Reactant: C1NC2CC3CC1CC(C3)C2
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: O
Product: O=C(CCl)N1CC2CC3CC(C2)CC1C3
Yield: 73.1 %

Procedure:
To a solution of 2-azatricyclo[4.3.1.14,8 ]undecane (0.30 g) in dichloromethane (4 ml) and water (0.4 ml) was added dropwise a solution of chloroacetyl chloride (0.26 g) in dichloromethane (2 ml) under stirring at cooling in an ice-bath. The mixture was stirred 2 hours under the same condition and then at ambient temperature overnight. The reaction mixture was washed with IN hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, and dried over sodium sulfate. Removal of the solvent gave N-chloromethylcarbonyl-2-azatricyclo-[4.3.1.14,8 ]undecane (0.33 g), which was used in a following reaction step without further purification.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[N:17]=[CH:16][N:15]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=4[OH:28])[CH:13]=3)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C=O)C.O>[CH2:35]([O:28][C:19]1[CH:20]=[C:21]([C:24]([F:25])([F:27])[F:26])[CH:22]=[CH:23][C:18]=1[C:14]1[N:15]=[CH:16][N:17]=[C:12]([O:11][C:8]2[CH:9]=[C:10]3[C:5]([CH:4]=[CH:3][CH:2]=[N:1]3)=[CH:6][CH:7]=2)[CH:13]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc(-c2cc(Oc3ccc4cccnc4c3)ncn2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenol, (Example 191), (50 mg, 0.13 mmol) and K2CO3 (54 mg, 0.39 mmol) in DMF (2.0 mL) was added benzyl bromide (17 μL, 0.14 mmol, Aldrich) and the reaction mixture was stirred at room temperature for 4 h. The resulting mixture was diluted with water and extracted with CH2Cl2. The combined extracts were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuum. Purification by silica gel chromatography (gradient: 0% to 3.0% MeOH/CH2Cl2) provided the title compound as a light-yellow amorphous solid. MS (ESI, pos. ion) m/z: 474 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:14]([Li])CCC.CI.[Cl-].[NH4+]>CCOCC>[CH3:13][O:12][C:3]1[C:2]([CH3:14])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=1
Reactant: COc1ncc(C(F)(F)F)cc1Br
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CI
Product: COc1ncc(C(F)(F)F)cc1C
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A solution of 5.12 g (0.020 mol) of 3-bromo-2-methoxy-5-(trifluoromethyl)pyridine in 60 ml of ether was cooled to -70° C. and blanketed with nitrogen. A solution containing 0.021 mole of butyl lithium (8.4 ml of 2.5 M) was added slowly with stirring keeping the temperature below about -65° C. and the mixture allowed to react for another 30 min. Methyl iodide (0.62 ml, 0.01 mol) was added to the mixture and stirring continued at -70° C. for about 30 min. The mixture was allowed to warm to about 20° C. and was then poured onto a mixture of ice and saturated aqueous ammonium chloride. The organic layer that formed was recovered. The aqueous layer was extracted with ether and the extract added to the organic layer. The combined organic materials were dried over sodium sulfate and concentrated by evaporation under reduced pressure. The residue was distilled to obtain 2.1 g (54 percent of theory) of the title compound as a colorless oil boiling at 67°-69° C. at 24 mm pressure. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[O:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[CH2:11][OH:12].C(N(CC)CC)C>O1CCCC1>[CH3:4][S:1]([O:12][CH2:11][CH:7]1[CH2:8][CH2:9][CH2:10][O:6]1)(=[O:3])=[O:2]
Reactant: OCC1CCCO1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCCO1
Reaction time: 2 h

Procedure:
Mesyl chloride (6.17 g) was dropwise added to a solution of 5.0 g of (tetrahydro-2furanyl)methanol, 2.18 g of triethylamine and 30 ml of tetrahydrofuran under ice-cooling over 30 minutes, followed by stirring at the same temperature for 2 hours. After the completion of reaction, the insolubles were filtered, and the filtrate was then concentrated under a reduced pressure to obtain (tetrahydro-2-furanyl)methyl methanesulfonate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].C([O-])([O-])=[O:22].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH2:12])=[O:22])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:17]([F:18])([F:19])[F:20]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of 4-[4-chloro-3-(trifluoromethyl)phenoxy]benzonitrile (Preparation 47, 48 g, 161 mmol) in DMSO (500 ml) was added K2CO3 (45 g, 323 mmol) followed by dropwise addition of a 30 wt % aqueous hydrogen peroxide solution (27 ml, 806 mmol) at 15° C. The reaction mixture was stirred for 1 hour at room temperature and the mixture was poured into water (500 ml) to afford a preciptate. The precipitated solid was collected by filtration, azeotroped with toluene, and dried over in vacuo to give 51 g of titled compound.
Reaction SMILES: O.NN.C1(=O)[N:8]([CH2:9][C:10]#[C:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])C(=O)C2=CC=CC=C12>C(O)C>[NH2:8][CH2:9][C:10]#[C:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: O=C(O)CCCC#CCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: NCC#CCCCC(=O)O
Temperature: 5 °C
Yield: 66.4 %

Procedure:
Hydrazine hydrate (0.1 ml) was added to a solution of 7-phthalimidohept-5-ynoic acid (0.55 g) in ethanol (25 ml). The mixture was refluxed for 3.5 hours and then the solvent was removed under reduced pressure. The residue was suspended in water (20 ml), the pH of the solution was adjusted to 5, and the solid was collected by filtration. The filtrate was evaporated to dryness and the residue was extracted with ethanol (3×5 ml). The ethanol extracts were cooled (5° C.) and the resulting precipitate was collected to give the title compound (0.19 g) m.p. 180°-183° C.
Reaction SMILES: O.[NH2:2]N.C(O)(=O)C.[Br:8][C:9]1[CH:21]=[CH:20][C:12]([C:13](/[N:15]=[CH:16]/[N:17](C)C)=O)=[CH:11][CH:10]=1>>[Br:8][C:9]1[CH:21]=[CH:20][C:12]([C:13]2[NH:2][N:17]=[CH:16][N:15]=2)=[CH:11][CH:10]=1
Reactant: CN(C)/C=N/C(=O)c1ccc(Br)cc1
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: Brc1ccc(-c2ncn[nH]2)cc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 66.5 %

Procedure:
To a solution of hydrazine hydrate (1.96 mL, 40.4 mmol) in acetic acid (91.9 mL, 36.8 mmol) was added (E)-4-bromo-N-((dimethylamino)methylene)benzamide (9.38 g, 36.8 mmol) and the mixture stirred at 90° C. for 1.5 hours. The reaction mixture was concentrated to about 10 mL and diluted with ether (50 mL). The resulting white solid was collected by vacuum filtration, rinsing with excess ether, and dried to afford 5-(4-bromophenyl)-1H-1,2,4-triazole (5.48 g, 66%) which was carried on without further purification. LCMS (APCI+) m/z 224, 226 [M+H]+.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]=[C:12]([SH:14])[NH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:16][C:17](=O)[CH3:18].CCOCC.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([S:8][C:9]1[N:13]=[C:12]2[S:14][CH:16]=[C:17]([CH3:18])[N:11]2[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Sc1nc(SCc2ccccc2)n[nH]1
Reactant: CC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: Cc1csc2nc(SCc3ccccc3)nn12
Yield: 92.3 %

Procedure:
The product of stage (a) (22.3 g) and chloroacetone (9.6 g) were heated in ethanol (120 ml) under reflux for 22 hours. The solution was then reduced under vacuum, and the residue was stirred with a mixture of ether and aqueous sodium bicarbonate. The ether solution was separated, washed with water, dried over magnesium sulphate, and reduced under vacuum to give 24.1 g of the desired product as an orange oil.
Reaction SMILES: [CH3:1][C:2]([S:7][CH3:8])([CH3:6])[CH:3]=[N:4][OH:5].[CH3:9][N:10]=[C:11]=[O:12]>O>[CH3:1][C:2]([S:7][CH3:8])([CH3:6])[CH:3]=[N:4][OH:5].[CH3:9][NH:10][C:11]([O:5][N:4]=[CH:3][C:2]([CH3:6])([S:7][CH3:8])[CH3:1])=[O:12]
Reactant: CN=C=O
Agent: CSC(C)(C)C=NO
Solvent: O
Product: CNC(=O)ON=CC(C)(C)SC

Procedure:
The carbamoylation step of the process of this invention can be conducted by mixing 2-methyl-2-(methylthio) propionaldehyde oxime with water at a preferred temperature of from about 0° C. to about 30° C. after which a catalyst is optionally added to the mixture. While maintaining the reaction temperature between about 0° C. and 30° C., methyl isocyanate is added with vigorous stirring over a sufficient period of time to provide for substantially complete conversion of 2-methyl-2-(methylthio) propionaldehyde oxime to 2-methyl-2-(methylthio) propionaldehyde O-(methylcarbamoyl) oxime. The carbamoylation step of the process of this invention can provide 2-methyl-2-(methylthio) propionaldehyde O-(methylcarbamoyl) oxime on a yield basis in excess of 90 percent based on the weight of 2-methyl-2-(methylthio) propionaldehyde oxime.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[C:9](C1NC=CN=1)(C1NC=CN=1)=[S:10]>C(#N)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]=[C:9]=[S:10])=[N:3][CH:4]=1
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Nc1ccc(Cl)cn1
Solvent: CC#N
Product: S=C=Nc1ccc(Cl)cn1
Yield: 36.6 %

Procedure:
2-Amino-5-chloropyridine (10.28 g) was added in portions, with stirring, over a period of 25 minutes to a solution of thiocarbonyl diimidazole (14.26 g) in acetonitrile (100 ml) at ambient temperature. The stirring was continued and the solution/suspension was left at ambient temperature for a few hours. The precipitate was filtered and washed with acetonitrile (3×25 ml). The solid residue was dissolved in hot acetone and filtered. The acetone solution was evaporated in vacuo, the residue was dissolved in hot ethyl acetate and filtered through a pad of silica (diam. 7 cm×3 cm). The silica was washed with another portion of hot ethyl acetate. The combined solutions were evaporated in vacuo to yield a crude product (5 g) of the titled product.
Reaction SMILES: [NH2:1][OH:2].[C:3]12([CH2:13][C:12](=[O:14])[O:11][C:9](=[O:10])[CH2:8]1)[CH2:7][CH2:6][CH2:5][CH2:4]2>>[OH:2][N:1]=[C:9]([OH:10])[CH2:8][C:3]1([CH2:13][C:12]([OH:11])=[O:14])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C1CC2(CCCC2)CC(=O)O1
Reactant: NO
Product: O=C(O)CC1(CC(O)=NO)CCCC1

Procedure:
In a manner analogous to that described in Example 1, by the reaction of hydroxylamine with 1,1-cyclopentane-diacetic anhydride, there was obtained 1,1-cyclopentane-diacetic acid N-hydroxyimide (m.p. 70°-74° C.) which, by acylation with benzene-sulphonyl chloride, was converted into benzene-sulphonyloxy-1,1-cyclopentane-diacetic acid imide (m.p. 133°-136° C.).
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([C:16]([CH3:23])([CH3:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=[C:12]([CH2:24]Cl)[C:11]=2[OH:26])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:27]([OH:32])[CH2:28][CH:29]([CH3:31])[CH3:30].[H-].[Na+]>>[N:1]1[N:2]([C:10]2[CH:15]=[C:14]([C:16]([CH3:23])([CH3:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=[C:12]([CH2:24][O:32][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[C:11]=2[OH:26])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)CC(C)(C)c1cc(CCl)c(O)c(-n2nc3ccccc3n2)c1
Reactant: CC(C)CCO
Agent: [H-]
Agent: [Na+]
Product: CC(C)CCOCc1cc(C(C)(C)CC(C)(C)C)cc(-n2nc3ccccc3n2)c1O
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 64.7 %

Procedure:
2-(2H-Benzotriazol-2-yl)-6-chloromethyl-4-(1,1,3,3-tetramethyl-butyl)-phenol (5.0 g, 13.5 mmol) is suspended in isoamyl alcohol (20.0 g, 227 mmol) and stirred at 80° C. for 15 minutes. Sodium hydride (0.2 g, 4.3 mmol, 60% in mineral oil) is added. The orange reaction mixture is stirred at 80° C. for 15 minutes and evaporated to dryness. The residue is dissolved in ethyl acetate and extracted with aqueous citric acid (5%) and brine. The organic layer is dried over sodium sulphate, filtered and evaporated to dryness. The crude product is purified by column chromatography (ethyl acetate/heptane 1:12) to yield 3.7 g of 2-(2H-Benzotriazol-2-yl)-6-(3-methyl-butoxymethyl)-4-(1,1,3,3-tetramethyl-butyl)-phenol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([F:26])=[C:16]([C@@:18]4([CH3:25])[NH:23][C:22](=S)[CH2:21][O:20][CH2:19]4)[CH:17]=3)[CH2:7][CH2:8][C:9]=2[CH:10]=1.C(OO)(C)(C)C.[NH3:33]>CO>[NH2:33][C:22]1[CH2:21][O:20][CH2:19][C@:18]([C:16]2[CH:17]=[C:12]([NH:11][CH:6]3[C:5]4[N:4]=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=4[CH2:8][CH2:7]3)[CH:13]=[CH:14][C:15]=2[F:26])([CH3:25])[N:23]=1
Reactant: C[C@@]1(c2cc(NC3CCc4cc(Cl)cnc43)ccc2F)COCC(=S)N1
Reactant: N
Agent: CC(C)(C)OO
Solvent: CO
Product: C[C@@]1(c2cc(NC3CCc4cc(Cl)cnc43)ccc2F)COCC(N)=N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a pressure tube (R)-5-[5-((RS)-3-chloro-6,7-dihydro-5H-[1]pyrindin-7-ylamino)-2-fluoro-phenyl]-5-methyl-morpholin-3-thione (58 mg, 0.15 mmol) was dissolved in a solution of ammonia in methanol (7M, 0.5 ml). Then tert-butyl hydroperoxide (70% in water) (0.07 ml, 0.74 mmol) was added. The tube was sealed and the mixture stirred for 4 hours at room temperature. For the workup, the solution was evaporated at reduced pressure. NMR analysis showed still starting material. The residue was redissolved in a solution ammonia in methanol (7M, 0.5 ml) and heated to 50° C. for 3 days. Thereafter, another 0.5 ml were added, then after 1 day another 0.071 ml (0.74 mmol) of tert-butyl hydroperoxide. After stirring at room temperature for 4.5 hours the reaction mixture was quenched with a saturated aqueous solution of sodium carbonate, thereafter extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate, then evaporated at reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 0:100 as the eluent. The [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-((RS)-3-chloro-6,7-dihydro-5H-[1]pyrindin-7-yl)-amine was obtained as a white foam (33 mg, 60%); (calculated) C19H20ClFN4O [374.85]; (found) [M+H]+=375.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[S:13][C:14]=1[Cl:15]>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:16]([C:12]1[S:13][C:14]([Cl:15])=[C:10]([Cl:9])[CH:11]=1)(=[O:18])=[O:17]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)s1
Product: Cc1noc(NS(=O)(=O)c2cc(Cl)c(Cl)s2)c1Br
Yield: 42 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-4,5-dichlorothiophene-2-sulfonamide was prepared in the same manner as described in Example 1 from 5-amino-4-bromo-3-methylisoxazole and 4,5-dichlorothiophene-2-sulphonyl chloride in 42% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 135-138° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[CH3:33][N:34]([CH3:44])[C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([N:34]([CH3:44])[CH3:33])[CH:40]=2)=[CH:4][N:3]=1
Reactant: CN(C)c1cccc(B(O)O)c1
Reactant: COc1cc(-c2csc3c(I)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2csc3c(-c4cccc(N(C)C)c4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reaction time: 0.42 h
Yield: 20.3 %

Procedure:
A mixture of 1-Methyl-1H-indole-2-carboxylic acid [4-(4-amino-7-iodo-thieno[3,2-c]pyridin-3-yl)-2-methoxy-phenyl]-amide (0.100 g, 0.18 mmol) in 1,2-dimethoxyethane (3 mL) and water (1.5 mL) was reacted with 3-(dimethylamino)phenylboronic acid (0.045 g, 0.27 mmol), sodium carbonate (0.06 g, 0.54 mmol) and tetrakis triphenylphosphine palladium (0) (0.017 g, 0.01 mmol) at reflux for two hours. The solvent was removed in vacuo and the residue was purified by preparative RP-HPLC (Hypersil-HS 100 A, C18, 8 μm, 100 Å, 25 cm; 5% acetonitrile—0.1M ammonium acetate 5–100% acetonitrile—0.1M ammonium acetate over 25 min, 21 ml/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyophilized to provide the title compound (20 mg) as an off-white powder. 1H NMR (DMSO-d6, 400 MHz) δ 9.52 (s, 1H), 8.01 (t, 1H), 7.94 (s, 1H), 7.72 (d, 1H), 7.58 (m, 2H), 7.34 (m, 3H), 7.23 (s, 1H), 7.16 (t, 1H), 7.10 (d, 1H), 6.97 (s, 1H), 6.95 (d, 1H), 6.79 (d, 1H), 5.56 (bs, 2H), 4.04 (s, 3H), 3.92 (s, 3H), 2.97 (s, 6H); LCMS (Conditions b), Rt=6.22 min, MS m/e: 548 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:22]=[CH:21][C:7]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH3:19])=[CH:11][C:10]2=[O:20])=[CH:6][CH:5]=1.[C:23](OCC)(=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].CCOCC>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH2:19][C:23](=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:11][C:10]2=[O:20])=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cc(=O)n(Cc2ccc(Cl)cc2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)Cc1cc(=O)n(Cc2ccc(Cl)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Sodium hydride (18g.; 60% w/w dispersion in oil, washed as described in Example 1) was stirred in dry dimethylformamide (300 ml.), and 1-(4-chlorobenzyl)-1,2-dihydro-4-methyl-2-oxoquinoline (64.7 g.) was added, followed by diethyl oxalate (55 g.). The mixture was stirred at room temperature for 2.5 hours with occasional external cooling to keep the temperature below 25° C. Ether (2 1.) was added, and the mixture was filtered. The solid residue was washed with ether (500 ml.), and then suspended in dimethylformamide (200ml.) nd acidified to pH 2 by the addition of concentrated hydrochloric acid. The resultant mixture was added to water (3 1.), and the mixture filtered, and the solid residue washed with water (2 1.), drained well, and crystallised from ethanol to give ethyl 1-(4-chlorobenzyl)-1,2-dihydro-2-oxoquinol-4-ylpyruvate, m.p. 180°-182° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].[C:10]1([CH:16]([CH3:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>C(=S)=S>[CH:16]([C:10]1[CH:15]=[CH:14][C:13]([C:1](=[O:4])[CH2:2][CH3:3])=[CH:12][CH:11]=1)([CH3:18])[CH3:17]
Reactant: CCC(=O)Cl
Reactant: CC(C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O
Product: CCC(=O)c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 112.1 %

Procedure:
Propionyl chloride (11.6 g, 125 mmol) was dropwise added to a suspension of aluminium chloride (16.7 g, 125 mmol) and cumene (18.0 g, 150 mmol) in carbon disulfide (30 mL) at −5° C., and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into water with ice, and the organic layer was separated, washed with an aqueous saturated sodium hydrogencarbonate and water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 1-(4-isopropylphenyl)propan-1-one (24.7 g). Sodium borohydride (1.29 g, 34.2 mmol) was added to a solution of the thus-obtained compound (13.0 g, 68.4 mmol) in ethanol (80 mL) with cooling with ice, and the mixture was stirred for 30 minutes at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (11.5 g, yield 79%). This was oily.