Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[CH2:16][CH2:17][C:18]2[O:19][C:20]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])=[N:21][N:22]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[NH:23][C:20]1[O:19][C:18]([CH2:17][CH2:16][C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:32])=[N:22][N:21]=1
Reactant: O=C(CCc1nnc(Nc2ccc(F)cc2F)o1)NC1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C(CCc1nnc(Nc2ccc(F)cc2F)o1)NC1CCNCC1
Yield: 41.5 %

Procedure:
N-(1-Benzylpiperidin-4-yl)-3-{5-[(2,4-difluorophenyl)amino]-1,3,4-oxadiazol-2-yl}propanamide (8.14 g, 18.4 mmol) was dissolved in ethanol and hydrogenated over a Pd/C catalyst at 3 bar until the reaction had gone to completion. The reaction mixture was filtered and the filtrate was evaporated to dryness, leaving an off-white solid which was triturated in ether, filtered and then dried in air to leave the subtitle compound (2.68 g, 41%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]([OH:14])=[O:13])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]([O:14][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:13])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: BrCc1ccccc1
Reactant: O=C(O)Cc1ccc2c(c1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccc2c(c1)OCCO2)OCc1ccccc1
Reaction time: 3 h
Yield: 96.7 %

Procedure:
To a solution of 1,4-benzodioxane-6-acetic acid (5.0 g) and potassium carbonate (2.13 g) in dimethylformamide (20 ml) was added benzyl bromide (4.84 g) at room temperature. After being stirred at the same temperature for 3 hours, the mixture was poured into water (200 ml) and extracted with diethyl ether (150 ml). The organic layer was washed with 5% hydrochloric acid solution, 1M aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo to afford benzyl 1,4-benzodioxane-6-acetate (7.08 g) as an oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]([CH3:27])([CH2:25][OH:26])[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[O:14].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:25]([C:12]([CH3:27])([CH3:11])[C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)=[O:14])=[O:26]
Reactant: COc1ccc(COC(=O)C(C)(C)CO)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1ccc(COC(=O)C(C)(C)C=O)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of 0.2 mL (2.2 mmol) of oxalyl chloride in 4 mL of CH2Cl2 at −78° C. was treated with 0.32 mL (4.5 mmol) of DMSO in 0.5 mL of CH2Cl2 maintaining the temperature at less than 60° C. The resulting mixture was stirred cold for 5 min. A solution of 211 mg (0.94 mmol) of 2,2-dimethyl-3-hydroxypropionic acid, para-methoxybenzyl ester (from Step A) in 1 mL of CH2Cl2 was added maintaining the temperature at less than −60° C. The resulting mixture was stirred cold for 15 min. The mixture was treated with 1.6 mL (9.1 mmol) of DIEA maintaining the temperature at less than −60° C. The reaction was warmed to 0° C., stirred for 30 min and quenched with H2O. The mixture was partitioned between 50 mL of CH2Cl2 and 50 mL of H2O and the layers were separated. The aqueous layer was extracted with 50 mL of CH1Cl2. The combined organic phases were washed with 100 mL of brine, dried over Na2SO4 and concentrated to afford the title compound which was used without further purification: RF: 0.43 (4:1 v/v hexanes/EtOAc); 1H-NMR (500 MHz) δ 1.35 (s, 6H), 3.81 (s, 3H), 5.12 (s, 2H), 6.89 (d, J=8.7, 2H), 7.27 (d, J=8.7, 2H), 9.66 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][N:25]([CH3:34])[C:26]([CH2:28][CH2:29][CH2:30][C:31](O)=[O:32])=[O:27]>>[CH3:24][N:25]([CH3:34])[C:26](=[O:27])[CH2:28][CH2:29][CH2:30][C:31]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:32]
Reactant: CN(C)C(=O)CCCC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CCCC(=O)N(C)C

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 4-dimethylcarbamoyl-butyric acid to yield (3aR,4S,7aR)-methyl 4-(5-(dimethylamino)-5-oxopentanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [2M+NH4]=927; RT=1.16 min; UPLC Method I
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH3:12])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1)=[O:4].CO.[BH4-].[Na+]>O>[CH3:12][NH:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([CH:2]([CH3:16])[CH3:1])[OH:4])=[CH:6][C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: CNc1ccc(C(=O)C(C)C)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNc1ccc(C(O)C(C)C)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred solution of 30 parts of intermediate 45, namely 2-methyl-1-[4-(methylamino)-3-nitrophenyl]-1-propanone in 320 parts of methanol were added dropwise 15 parts of sodium tetrahydroborate (the temperature was kept at 20° C.). Upon complete addition, stirring was continued for 30 minutes at room temperature. The reaction mixture was poured into water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated to dry, yielding 30 parts (100%) of 4-(methylamino)-α-(1-methylethyl)-3-nitrobenzenemethanol as an oily residue (interm. 46).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][N:17]=[C:16]4[C:19]5[C:24]([CH2:25][CH2:26][C:15]=34)=[CH:23][C:22]([CH:27]([OH:30])CO)=[CH:21][CH:20]=5)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.I([O-])(=O)(=O)=O.[Na+].[BH4-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][N:17]=[C:16]4[C:19]5[C:24]([CH2:25][CH2:26][C:15]=34)=[CH:23][C:22]([CH2:27][OH:30])=[CH:21][CH:20]=5)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: OCC(O)c1ccc2c(c1)CCc1c-2noc1C1CCC(c2ccc(Cl)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: OCc1ccc2c(c1)CCc1c-2noc1C1CCC(c2ccc(Cl)cc2)CC1
Reaction time: 0.67 h

Procedure:
To a solution of 1-(3-(4-(4-chlorophenyl)cyclohexyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)ethane-1,2-diol (Preparation 27C, 0.05 g, 0.118 mmol) in methanol (1.0 mL) at 0° C. was added a solution of sodium periodate (0.030 g, 0.142 mmol) in water (1.0 mL) dropwise. The white heterogeneous reaction mixture was stirred for 40 mins. at the same temperature and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhyd. sodium sulfate and concentrated. The residue was taken in methanol (2 mL) and treated with sodium borohydride (5.35 mg, 0.142 mmol) at room temperature. After 1 h, the reaction was quenched with saturated. aq. sodium bicarbonate. After stirring for 30 min, the reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhyd. magnesium sulfate and concentrated to yield (3-(4-(4-chlorophenyl)cyclohexyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methanol.
Reaction SMILES: C(=[C:8]1/[CH2:9][CH2:10][C:11]2[C:12]/1=[N:13][CH:14]=[C:15]([Br:17])[CH:16]=2)/C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[OH:38]>C(Cl)Cl>[Br:17][C:15]1[CH:16]=[C:11]2[CH2:10][CH2:9][C:8](=[O:38])[C:12]2=[N:13][CH:14]=1
Reactant: CO
Reactant: Brc1cnc2c(c1)CC/C2=C\c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1CCc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
A solution of (E)-7-benzylidene-3-bromo-6,7-dihydro-5H-cyclopenta[b]pyridine (1.61 g, 5.63 mmol) in MeOH (75 mL) and DCM (75 mL) was cooled to −78° C. and a stream of ozone in oxygen was bubbled through the solution for 10 min until the solution turned light blue. Oxygen was pass through the solution for 10 min until the solution turned colorless. Triphenylphosphine (3.63 g, 13.8 mmol) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 1.5 h and then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (80 g, 30% to 70% EtOAc in heptane) to give 3-bromo-5H-cyclopenta[b]pyridin-7(6H)-one (1.14 g, 5.38 mmol, 96% yield) as a yellow solid. MS m/z=211.9 [M+H]+. Calculated for C8H6BrNO 211.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([OH:19])=O)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][N:23]=1.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][N:23]=2)=[O:19])[N:15]=1)([CH3:8])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)O)cs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)Nc2ccc(Br)cn2)cs1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.6 %

Procedure:
{2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}acetic acid (16 g) obtained in Example 3 and 2-amino-5-bromopyridine (8.7 g) were dissolved in dichloromethane (100 mL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) hydrochloride (14.5 g) and 4-dimethylaminopyridine (DMAP) (9.2 g) was successively added, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) to give the title compound (22 g) as a white solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH2:12])=[CH:9][CH:8]=1)[CH3:5])[CH3:2].[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH2:21])=[CH:18][CH:17]=1.[CH3:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[CH2:30])=[CH:27][CH:26]=1>>[CH2:1]([O:3][CH:4]([O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:11]=[CH2:12])=[CH:13][CH:14]=1)[CH3:5])[CH3:2].[OH:15][CH:30]=[CH:29][C:28]1[CH:31]=[CH:32][CH:25]=[CH:26][CH:27]=1.[CH3:24][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH2:21])=[CH:18][CH:17]=1
Reactant: C=Cc1ccc(O)cc1
Agent: C=Cc1ccc(C)cc1
Agent: C=Cc1ccc(OC(C)OCC)cc1
Product: OC=Cc1ccccc1

Procedure:
A solution of poly(p-tert-butoxystyrene/p-methylstyrene) (70 g) obtained in above (1) and conc. hydrochloric acid (100 ml) in 1,4-dioxane was reacted for 4 hours at 70°-80° C. with stirring. After cooling, the reaction mixture was poured into H2O (5 l) and the polymer was precipitated. The polymer was filtered, washed with H2O and dried under reduced pressure to give 47.6 g of poly(p-hydroxystyrene/p-methylstyrene) as white powder. The polymer was found to have p-hydroxystyrene unit and p-methylstyrene unit in a molar ratio of ca. 95:5 based on 1HNMR. (3) To a solution of poly(p-hydroxystyrene/p-methylstyrene) (15.0 g) obtained in above (2) and ethyl vinyl ether (3.5 g) in 1,4-dioxane (150 ml), a catalytic amount of pyridinium p-toluenesulfonate was added and reacted with stirring at room temperature for 24 hours. The reaction mixture was poured into H2O (5 l) and the polymer was precipitated. The precipitate was filtered, washed with H2O and dried under reduced pressure to afford 11.5 g of poly[p-(1-ethoxyethoxy)styrene/p-hydroxystyrene/p-methylstyrene] as white powder having Mw 20000 (GPC with polystyrene calibration). The polymer was found to have p-(1-ethoxyethoxy)styrene unit, p-hydroxystyrene unit and p-methylstyrene unit in a molar ratio of ca. 35:60:5 based on 1HNMR.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].[F:9][C:10]1[C:15](B(O)O)=[CH:14][C:13]([Br:19])=[CH:12][N:11]=1.B(O)O>C(#N)C.[F-].[K+].C(Cl)Cl.O>[Br:19][C:13]1[CH:14]=[C:15]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[NH2:8])[C:10]([F:9])=[N:11][CH:12]=1
Reactant: Nc1cnccc1I
Reactant: OB(O)c1cc(Br)cnc1F
Agent: OBO
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: Nc1cnccc1-c1cc(Br)cnc1F
Temperature: 95 °C
Yield: 68.8 %

Procedure:
A mixture of 4-iodo-pyridin-3-ylamine (1.027 g, 4.67 mmol), 2-fluoro-5-bromopyridine-3-boronic acid (2.05 g, 9.33 mmol), and [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane (1:1) (191 mg, 0.233 mmol) in acetonitrile (12 mL) and 1N aqueous potassium fluoride solution (12 mL) was heated at 95° C. for 3 h. The reaction mixture was allowed to cool, treated with additional portions of the boronic acid (0.5 eq) and of catalyst (5.0 mol %), and heated under reflux overnight under a nitrogen atmosphere. The mixture was allowed to cool, diluted with DCM and water, and filtered to remove the solids. The filtrate layers were separated and the aqueous phase was extracted into DCM, and the combined organic phase concentrated in vacuo. The resultant residue was redissolved in 20% methanol in DCM and absorbed onto silica gel for purification by flash chromatography (silica, 100 g column, Biotage, 1-20% methanol in DCM) to afford the title compound as a brown solid (861 mg, 69%). 1H NMR (DMSO-D6, 400 MHz): 8.43 (d, J=1.1 Hz, 1H), 8.18 (dd, J=8.3 Hz, 2.5 Hz, 1H) 8.11 (s, 1H), 7.81 (d, J=4.8 Hz, 1H), 7.01 (d, J=4.8 Hz, 1H), 5.37 (s, 2H). LCMS (Method B): RT=0.95 min, M+H+=268/270.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([N:6]([CH3:8])[CH3:7])=[CH:4][CH:3]=1.[Mg].C[O:13][B:14]([O:17]C)[O:15]C.S(=O)(=O)(O)O>O1CCCC1>[CH3:7][N:6]([CH3:8])[C:5]1[CH:9]=[CH:10][C:2]([O:13][B:14]([OH:17])[OH:15])=[CH:3][CH:4]=1
Reactant: COB(OC)OC
Reactant: CN(C)c1ccc(Br)cc1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: CN(C)c1ccc(OB(O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A solution of the corresponding Grignard compound is prepared from 16.8 g 4-bromo-N,N-dimethyl-aniline and 2.04 g of magnesium in 150 ml of tetrahydrofuran. This is now slowly added dropwise while stirring at -60° to a solution of 9.4 ml of trimethylborate in 50 ml of tetrahydrofuran under argon. Subsequently, the mixture is stirred at room temperature overnight. The mixture is poured on to ice-water, adjusted to pH 3-4 with dilute sulphuric acid and extracted with diethyl ether. The extract is dried, evaporated and the residue is recrystallized from water. 5.6 g (40%) of 4-dimethylamino-phenylboric acid are obtained. Mass spectrum: peaks inter alia at m/e: 164 (M±H, 100%).
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([NH:10][C:11]2[N:12]=[C:13](Br)[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:9])=[CH:3][CH:2]=1.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([NH:10][C:11]2[N:12]=[C:13]([C:33]3[CH:32]=[CH:31][C:30]([C:29]([F:40])([F:39])[F:28])=[CH:35][CH:34]=3)[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:9])=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccc(-c2ccccc2)cc1)Nc1cc2ccccc2c(Br)n1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(Cc1ccc(-c2ccccc2)cc1)Nc1cc2ccccc2c(-c2ccc(C(F)(F)F)cc2)n1
Yield: 86.4 %

Procedure:
A mixture of Example 14 (0.1 g, 0.24 mmol), 3-trifluoromethylphenylboronic acid (0.14 g, 0.72 mmol), Pd(PPh3)4 (0.028 g, 0.024 mmol) and 2N Na2CO3 solution (0.1 ml) in DME was heated at 75° C. for 12 h under nitrogen. The reaction mixture was cooled, and the solvent was evaporated. The resulting residue was purified by flash column chromatography (SiO2, 10% ethyl acetate in hexane) to provide the title compound (0.1 g, 87%) as a light yellow solid.
Reaction SMILES: C1(O[C:8](=[O:32])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:12][C:11]=2[F:31])C=CC=CC=1.[NH2:33][C:34]1[S:35][CH:36]=[CH:37][N:38]=1.C(OCC)(=O)C.O>CS(C)=O.CO>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH3:30])[N:20]=[CH:19][CH:18]=[C:17]2[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:8]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)=[O:32])=[C:11]([F:31])[CH:12]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)c(F)c3)c2cc1OC
Reactant: Nc1nccs1
Solvent: O
Solvent: CO
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)c2cc1OC
Yield: 86.4 %

Procedure:
4-(6,7-Dimethoxyquinolin-4-yloxy)-2-fluorophenylcarbamic acid phenyl ester (109 mg, 0.250 mmol) and 2-aminothiazole (50.0 mg, 0.500 mmol) were heated and stirred in dimethylsulfoxide (1 ml) at 85° C. for 2 hours. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with 1N aqueous sodium hydroxide, water and saturated saline and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent-ethyl acetate:methanol=30:1), the fraction containing the target substance was concentrated and suspended in ethyl acetate, the suspension was diluted with hexane and the crystals were filtered out, washed with hexane and blow-dried to obtain the title compound (95.0 mg, 0.216 mmol, 86%) as colorless crystals.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:28])[O:13][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[CH:15]=2)=[CH:7][C:6]=1[CH3:29])C.C1COCC1.O.[OH-].[K+]>CO>[Cl:27][C:22]1[CH:21]=[C:20]([C:14]2([C:16]([F:18])([F:17])[F:19])[O:13][N:12]([CH3:28])[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:30])=[O:3])=[C:6]([CH3:29])[CH:7]=3)=[CH:15]2)[CH:25]=[C:24]([Cl:26])[CH:23]=1
Reactant: CCOC(=O)c1ccc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)cc1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 120 h
Yield: 94.7 %

Procedure:
0.27 g of 4-[5-(3,5-Dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid ethyl ester (VIIIa) was stirred in a mixture of 5 ml of methanol, 5 ml of THF and 1 ml of water. To this solution 0.2 g KOH was added and the mixture was stirred for 5 days at ambient temperature. The solvents were then evaporated, the residue was diluted with water and acidified with 1N HCl. The solid that precipitated was isolated by filtration and dried to give 0.240 g (95%,) of 4-[5-(3,5-Dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (IIa) as a pale solid. 1H-NMR (CDCl3, δ in ppm): 8.05 (d, 1H), 7.26-7.44 (m, 5H), 5.46 (s, 1H), 3.00 (s, 3H), 2.65 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]2[C:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:16]=1[CH2:17]Br)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:19][NH2:20]>CO>[CH3:19][N:20]1[CH2:17][C:16]2[C:3](=[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]3=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]3=2)[CH2:2]1
Reactant: CN
Reactant: BrCc1c(CBr)c2ccccc2c2ccccc12
Solvent: CO
Product: CN1Cc2c(c3ccccc3c3ccccc23)C1

Procedure:
13.4 g of 9,10-bis-bromomethyl-phenanthrene [see S. Hauptmann, Chem. Ber. 93, 2604 (1960)] is added within one hour, with stirring, to a solution of 37.5 g of methylamine in 225 ml of methanol, with the reaction temperature being maintained at 45°-50°. The reaction mixture is stirred for a further hour at 50°, and the solvent and excess methylamine are subsequently distilled off. 50 ml of water is added to the residue, and the formed suspension is extracted with ether. The ethereal solution is washed with water, dried over potassium carbonate and concentrated by evaporation. The residue is recrystallised from acetone to yield 2-methyl-2,3-dihydro-1H-dibenz[e,g]isoindole, m.p. 122°-123°.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[N:13]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:12]([CH3:20])=[N:11][CH:10]=2)=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.Br[C:22]1[CH:34]=[CH:33][C:25]([CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:24][C:23]=1[F:35].CCC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[C:3]([C:9]2[N:13]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:12]([CH3:20])=[N:11][CH:10]=2)=[N:4][C:5]([NH:8][C:22]2[CH:34]=[CH:33][C:25]([CH2:26][N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)=[CH:24][C:23]=2[F:35])=[N:6][CH:7]=1
Reactant: Fc1cc(CN2CCOCC2)ccc1Br
Reactant: Cc1ncc(-c2nc(N)ncc2F)n1C1CCOCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: Cc1ncc(-c2nc(Nc3ccc(CN4CCOCC4)cc3F)ncc2F)n1C1CCOCC1
Temperature: 110 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
5-Fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (5.12 g, 18.46 mmol), 4-(4-bromo-3-fluorobenzyl)morpholine (5.06 g, 18.46 mmol), (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.152 g, 0.18 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.107 g, 0.18 mmol) and sodium tert-pentoxide (4.07 g, 36.92 mmol) in toluene (70 mL) were mixed and degassed. The mixture was stirred at 110° C. under nitrogen atmosphere overnight. The mixture was concentrated. Dichloromethane and water were added and the phases were separated. The organic phase was concentrated and the crude was purified by preparative HPLC. The pooled fractions were concentrated to about half volume. The residue was extracted with EtOAc (×2). The combined organic phases were concentrated and the residue was dried in vacuo at 40° C. for 24 h to give the title compound (5.34 g, 61%) as a solid.
Reaction SMILES: [CH3:1][SH:2].C(=O)([O-])[O-].[K+].[K+].F[C:10]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].[Cl-].[NH4+]>>[F:20][C:19]1[C:10]([S:2][CH3:1])=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cccc(F)c1F
Reactant: CS
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Product: COC(=O)c1cccc(F)c1SC
Temperature: 25 °C
Reaction time: 27 h
Yield: 70.8 %

Procedure:
Approximately 12.6 g of methanethiol was dissolved in N,N-dimethylformide. Potassium carbonate (41.5 g) and methyl 2,3-difluorobenzoate (43.1 g) were added and the mixture stirred at 25° C. for 27 hours. Saturated ammonium chloride was added and the mixture partitioned between ether and water. The organic phase was washed with water, dried over magnesium sulphate, filtered and evaporated. The product was obtained by distillation to give 35.5 g of methyl 3-fluoro-2-methylsulphenylbenzoate, b.p. 140° C. (9mm Hg) as a clear oil. NMR (CDCl3) 2.5(3H, d), 3.9(3H,s), 7.2(1H,m), 7.3(1H,m), 7.5(1H, m).