Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:12]([O-])=O)[CH:9]=2)[C:4]1=[O:15])[CH3:2].C([O-])=O.[NH4+]>CN(C=O)C.[Pd]>[NH2:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4](=[O:15])[N:3]([CH2:1][CH3:2])[CH2:11]2
Reactant: CCN1Cc2cc([N+](=O)[O-])ccc2C1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCN1Cc2cc(N)ccc2C1=O
Yield: 98.3 %

Procedure:
Palladium/Carbon (10% wt) (63 mg, 0.30 mmol) was added to a stirred solution of 2-ethyl-5-nitro-2,3-dihydro-isoindol-1-one (634 mg, 3.06 mmol) and ammonium formate (949 mg, 15.31 mmol) in anhydrous DMF (12 ml) at room temperature. The resulting suspension was heated at reflux for 1 hr, then cooled and filtered through a pad of celite. The solvent was evaporated in vacuo and the crude residue purified by flash column chromatography (5% methanol in dichloromethane) to yield the title compound as a pale yellow oil (530 mg, 98%). HPLC retention time 0.95 min. Mass spectrum (ES+) m/z 177 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:19]([C:21]1[S:25][C:24]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:23][CH:22]=1)#[CH:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17]([C:20]#[C:19][C:21]4[S:25][C:24]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:23][CH:22]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(S(N)(=O)=O)s1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc2c(I)cnn12
Product: Cc1cc(-c2ccc(Cl)cc2)nc2c(C#Cc3ccc(S(N)(=O)=O)s3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-iodo-7-methyl-pyrazolo[1,5-a]pyrimidine (example 292) (185 mg, 0.5 mmol) and 5-ethynyl-thiophene-2-sulfonic acid amide (example D.3) (94 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (94 mg, 44%). MS (ISP) 429.5 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2F)[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[CH3:28])=[O:18].BrC1C=CC(C(C2C=C([N+]([O-])=O)C=CC=2C)=O)=C(Cl)C=1.FC1C=CC(N)=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[CH3:28])=[O:18]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Br)cc1Cl
Agent: Nc1ccc(F)cc1
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Nc2ccc(F)cc2)cc1Cl
Reaction time: 16 h

Procedure:
The reaction was carried out similarly as described in the preparation of compound 403, using compound 402 (22.6 mmol) and 4-fluoroaniline (24.8 mmol) except the time for the reaction was 16 h. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:5 as the eluent to afford the title compound as yellow solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH2:18])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[CH3:19][CH2:20][C:21](=O)[CH2:22][CH3:23].C(Cl)(Cl)Cl.CO>C1(C)C=CC=CC=1.C(O)(C)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([N:18]=[C:21]([CH2:22][CH3:23])[CH2:20][CH3:19])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1N
Reactant: CCC(=O)CC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2cnc3ccccc3c2n1N=C(CC)CC
Reaction time: 168 h
Yield: 92.6 %

Procedure:
A solution of 2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-amine (1.50 g, 6.19 mmol) in 20 mL of toluene and 5 mL of isopropanol was treated with 3-pentanone (5.00 mL, 47.2 mmol) and pyridinium p-toluenesulfonate (0.015 g, 0.062 mmol) and the reaction mixture was heated to reflux under an atmosphere of nitrogen. After 7 d, the reaction mixture was concentrated under reduced pressure, dissolved in CHCl3, washed with water (2×) and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield a light brown oil. Chromatography (SiO2, 95:5 CHCl3:MeOH) gave N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)(1-ethylpropylidene)amine (1.78 g) as a yellow/green syrup.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:15][CH2:14][C:13]2[C:12]3[NH:16][C:17](C(O)=O)=[CH:18][C:11]=3[S:10][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]>CN1C(=O)CCC1.O.[Cu]>[CH2:1]([O:3][C:4]([N:6]1[CH2:15][CH2:14][C:13]2[C:12]3[NH:16][CH:17]=[CH:18][C:11]=3[S:10][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2sc3cc(C(=O)O)[nH]c3c2CC1
Agent: [Cu]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)N1CCc2sc3cc[nH]c3c2CC1
Temperature: 250 °C
Yield: 93.4 %

Procedure:
To a stirred solution of the product from step (f) (0.50 g, 1.62 mmol) in NMP (10 ml) was added copper dust (0.10 g, 1.62 mmol). The reaction mixture was heated in a microwave reactor to 250° C. for 20 minutes. The cooled solution was diluted with water (100 ml) and extracted with Et2O (3×). The combined Et2O extracts were washed with brine, dried (MgSO4), filtered, and solvent evaporated in vacuo to give the crude product. Purification by silica-gel chromatography (gradient elution: 0 to 100% EtOAc in hexanes gave the sub-titled compound as a tan solid (0.40 g). MS: ESI (positive): 265 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[NH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][N:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[N:12]([CH:13]2[CH2:14][CH2:15]2)[C:11]1=[O:16])[CH3:23]
Reactant: CCOC(=O)CCl
Reactant: O=c1[nH]cc(-c2ccc(Br)cc2)n1C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Cn1cc(-c2ccc(Br)cc2)n(C2CC2)c1=O

Procedure:
392 mg (1.40 mmol) of 5-(4-bromophenyl)-1-cyclopropyl-1,3-dihydro-2H-imidazol-2-one from Example 120A are dissolved in 7.7 ml acetonitrile, treated with 172 mg (1.40 mmol) of ethyl chloroacetate and 388 mg (2.81 mmol) of potassium carbonate and heated under reflux for two hours. After cooling, this is filtered, the filtrate evaporated, and the residue partitioned between ethyl acetate and water, the organic phase is separated, dried over sodium sulphate and again concentrated. 502 mg (98% of theory) of the target compound, which is reacted without further purification, are thus obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([C:6](=[O:26])[C:7]([C:21]([O:23]CC)=[O:22])=[CH:8][N:9]2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:4][N:3]=1.O.S(=O)(=O)(O)O>C(O)(=O)C>[Cl:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([C:6](=[O:26])[C:7]([C:21]([OH:23])=[O:22])=[CH:8][N:9]2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2c(F)c(Cl)ncc2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(Cl)ncc2c1=O
Temperature: 0 °C

Procedure:
2.9 g (7.6 mmol) of ethyl 7-chloro-8-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,6-naphthyridine-3-carboxylate are heated at reflux in a mixture of 10 ml of acetic acid, 10 ml of water and 1 ml of concentrated sulphuric acid for two hours. The cooled mixture is put into ice-water, and the product is isolated and washed with water.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][O:24][CH3:25])=[CH:15][C:14]=3[F:26])=[O:9])=[CH:4][CH:3]=1.CO.C#C>C(Cl)Cl.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:15][C:14]=3[F:26])=[O:9])=[CH:27][CH:28]=1
Reactant: COCC#Cc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Agent: [Pd]
Agent: C#C
Solvent: CO
Solvent: ClCCl
Product: COCCCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 1 h
Yield: 28 %

Procedure:
A mixture of the title compound of Example 95 (0.113 g) and Pd/C (10%, 22.6 mg) is dissolved in 3:1 CH2Cl2 :MeOH. The reaction mixture is placed under the Parr hydrogenator at 25 psi H2 and monitored with the OAMS for complete reduction of the acetylene. The reaction is complete in 1 hr and is filtered over celite. The filtrate is condensed to obtain a white solid. The product is recrystallized with EtOAc/hexanes to yield 32.0 mg of the desired product.
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[NH2:29][C:30]1[N:31]=[N:32][C:33]([Br:37])=[CH:34][C:35]=1[Br:36].C(N(CC)C(C)C)(C)C>C(O)(C)C>[C:23]1([C:2]2[N:31]3[N:32]=[C:33]([Br:37])[CH:34]=[C:35]([Br:36])[C:30]3=[N:29][C:3]=2[C:5]2[CH:6]=[CH:7][C:8]([C:11]3([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:12][CH2:13][CH2:14]3)=[CH:9][CH:10]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1nnc(Br)cc1Br
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(Br)cc(Br)nn4c3-c3ccccc3)cc2)CCC1
Yield: 28 %

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-1-A (5.80 g, 13.1 mmol), 3-amino-4,6-dibromopyridazine (CAS Registry No. 1206487-35-5, 3.96 g, 15.7 mmol, 1.2 eq), N,N-diisopropylethylamine (2.3 mL, 13.0 mmol, 1.0 eq) and powdered activated 3 Å molecular sieves (10 g) in isopropanol (70 mL) was heated at the reflux temperature for 8 h. On cooling, the mixture was filtered through a pad of Celite. The Celite was washed with DCM, and the combined organics were washed with water, dried with sodium sulfate and concentrated under reduced pressure. The remaining material was purified using MPLC (Biotage Isolera; 100 g SNAP cartridge: 100% hexane 2.0 min., gradient to 75% hexane/25% EtOAc 2.5 min., 75% hexane/25% EtOAc 4.5 min., gradient to 50% hexane/50% EtOAc 2 min., 50% hexane/50% EtOAc 4.5 min., gradient to 100% EtOAc 2.5 min., 100% EtOAc 5.7 min.) to give partially purified tert-butyl (1-{4-[3-phenyl-6,8-dibromoimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate (2.65 g, ˜82% pure, 28% yield):
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][Si](C=[N+]=[N-])(C)C>>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Product: COC(=O)c1c(N)cccc1Cl

Procedure:
2Amino-6-chlorobenzoic acid is reacted with trimethylsilyldiazomethane to yield methyl 2-amino-6-chlorobenzoate (Chem. Pharm. Bull. Vol. 29, 1475 (1981)).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([O:9]CC)=O)=[N:4][N:3]=1.C(O)C.[CH3:15][NH2:16]>CO>[NH2:1][C:2]1[S:6][C:5]([C:7]([NH:16][CH3:15])=[O:9])=[N:4][N:3]=1
Reactant: CN
Reactant: CCOC(=O)c1nnc(N)s1
Solvent: CCO
Solvent: CO
Product: CNC(=O)c1nnc(N)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 102.3 %

Procedure:
To a suspension of ethyl 5-amino-1,3,4-thiadiazole-2-carboxylate (106 mg, 0.612 mmol) in methanol (1.5 mL) was added 33 wt % ethanol solution of methylamine (0.5 mL, 4.00 mmol). The mixture was stirred at room temperature for 6 h, heated to 70° C. and cooled. The mixture was concentrated, mixed with water and lyophilized to give 5-amino-N-methyl-1,3,4-thiadiazole-2-carboxamide as a white solid (99 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.69 (q, J=4.8 Hz, 1H), 7.70 (s, 2H) 2.73 (d, J=4.78 Hz, 3H); MS (ES+) m/z: 159 (M+H); LC retention time: 0.44 min (analytical HPLC Method A).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][Si](C(C)(C)C)(C)C)=[C:4]([F:17])[C:3]=1[I:18].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][OH:7])=[C:4]([F:17])[C:3]=1[I:18]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Cl)c(I)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCc1ccc(Cl)c(I)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (4-chloro-2-fluoro-3-iodobenzyloxy)(tert-butyl)dimethylsilane (6.64 g, 16.6 mmol) in THF (60 mL) was added tetrabutylammonium fluoride, 1.0 M in THF (19.9 mL, 19.9 mmol). The reaction solution was stirred at RT for 1 h. The volatile solvents were removed in vacuo. The residue was diluted with diethyl ether (150 mL), and then washed with saturated aqueous solution of sodium bicarbonate, and brine. The resulting organic solution was then dried over magnesium sulfate and concentrated under reduced pressure. Flash chromatography on silica gel (dichloromethane) gave (4-chloro-2-fluoro-3-iodophenyl)methanol as a colorless oil. 1H NMR (300 MHz, CDCl3) δ ppm 7.16-7.32 (2H, m), 4.66 (2H, d, J=5.7 Hz), 1.90 (1H, t, J=6.0 Hz)
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]([O:39][CH3:40])[C:16]3[N:17]([C:19]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([C:28]5([NH2:32])[CH2:31][CH2:30][CH2:29]5)=[CH:24][CH:23]=4)[N:21]=3)[CH:18]=2)[CH:10]=[N:9]1)=O)(C)(C)C.Cl.[OH-].[Na+]>C(Cl)Cl.CO>[CH3:40][O:39][C:15]1[C:16]2[N:17]([C:19]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:20]([C:22]3[CH:23]=[CH:24][C:25]([C:28]4([NH2:32])[CH2:29][CH2:30][CH2:31]4)=[CH:26][CH:27]=3)[N:21]=2)[CH:18]=[C:13]([C:11]2[CH:10]=[N:9][NH:8][CH:12]=2)[CH:14]=1
Reactant: COc1cc(-c2cnn(C(=O)OC(C)(C)C)c2)cn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(-c2cn[nH]c2)cn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude product from Step 1 was dissolved in DCM/MeOH (1.2 mL/0.74 mL) and treated with HCl (4M solution in dioxane, 0.9 mL). The reaction was stirred at rt overnight before it was poured onto ice, made alkaline with dilute aqueous sodium hydroxide solution (2M) and extracted with DCM. The organic phase was washed with brine, dried and concentrated in vacuo. Purification was achieved by chromatography on silica gel to give the title compound (18 mg).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1.N1([C:23](=[O:31])[CH2:24][CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][O:27]2)C=CN=C1.C(O)(=O)C>C1(C)C=CC=CC=1.O>[O:27]1[CH2:28][CH2:29][CH2:30][CH:26]1[CH2:25][CH2:24][C:23]([CH:13]1[C:14](=[O:17])[CH2:15][CH2:16][O:11][CH2:12]1)=[O:31]
Reactant: O=C1CCOCC1
Reactant: O=C(CCC1CCCO1)n1ccnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCOCC1C(=O)CCC1CCCO1
Reaction time: 0.03 h
Yield: 15.9 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.283 ml, 6.83 mmol) was added to a stirred solution of tetrahydro-4H-pyran-4-one (0.601 ml, 6.51 mmol) in toluene (3 mL) at 0° C. and the resulting mixture was stirred for 2 minutes. 1-(1H-imidazol-1-yl)-3-(tetrahydrofuran-2-yl)propan-1-one (0.632 g, 3.25 mmol) toluene (1 mL) was added and the reaction mixture was stirred for 5 minutes before it was quenched with acetic acid (0.559 ml, 9.76 mmol) in water (4 mL). The organic layer was separated and purified by flash column chromatography (ethyl acetate in heptane, 0 to 40%) yielding 3-(3-(tetrahydrofuran-2-yl)propanoyl)dihydro-2H-pyran-4(3H)-one (117 mg, 16%).
Reaction SMILES: C([O:8][CH2:9][C:10]1[NH:11][C:12]([C:19]2[C:20]([CH3:30])=[CH:21][C:22]([CH3:29])=[C:23]([CH:28]=2)[C:24]([O:26][CH3:27])=[O:25])=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1)C1C=CC=CC=1.Cl.[H][H]>CO.[Pd]>[OH:8][CH2:9][C:10]1[NH:11][C:12]([C:19]2[C:20]([CH3:30])=[CH:21][C:22]([CH3:29])=[C:23]([CH:28]=2)[C:24]([O:26][CH3:27])=[O:25])=[C:13]([C:15]([F:16])([F:18])[F:17])[N:14]=1
Reactant: COC(=O)c1cc(-c2[nH]c(COCc3ccccc3)nc2C(F)(F)F)c(C)cc1C
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(-c2[nH]c(CO)nc2C(F)(F)F)c(C)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
Into a 50-mL round-bottom flask, under a nitrogen atmosphere, was placed a solution of methyl 5-(2-((benzyloxy)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 219.3, 150 mg, 0.36 mmol) in methanol (8 mL). Palladium on carbon (150 mg, 1.00 equiv) and HCl (4 M, 2 mL) were added to the reaction under a nitrogen atmosphere. To the above hydrogen (1 atm) was introduced. The reaction mixture was stirred for 2 h at room temperature. The system was purged with nitrogen, then the solids were removed by filtration and the filtrate was concentrated under reduced pressure to give 100 mg (85%) of the title compound as a light yellow oil.
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:10]([O:12][CH3:13])=[O:11])[CH2:3][N+:4]([O-])=O>C(O)C.[Pt]=O>[NH2:4][CH2:3][CH:2]([C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:10]([O:12][CH3:13])=[O:11])[OH:1]
Reactant: COC(=O)c1ccc(NS(C)(=O)=O)c(C(O)C[N+](=O)[O-])c1
Agent: O=[Pt]
Solvent: CCO
Product: COC(=O)c1ccc(NS(C)(=O)=O)c(C(O)CN)c1
Temperature: 0 °C
Yield: 55.1 %

Procedure:
Methyl 3-[1-(R,S)-hydroxy-2-nitroethyl]-4-[(methylsulfonyl)amino]benzoate (200 mg, 0.63 mmol) was dissolved in ethanol (10 mL) and hydrogenated at 50 psi in the presence of platinum oxide (Aldrich, 20 mg) for 8 h. The catalyst was removed by filtration through Celite and the filtrate concentrated to 5 mL. To the concentrate, ethyl acetate (5 mL) and hexane (10 mL) were added and the mixture cooled to 0° C. A white precipitate formed which was collected by filtration. The cake was washed with ethyl acetate:hexane (1:1) and dried to give 100 mg (55%) of methyl 3-[2-amino-1-(R,S)-hydroxyethyl]-4-[(methylsulfonyl)amino]benzoate as a white powder, mp 172°-173° C. (dec).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1)([CH3:3])[CH3:2].Cl[C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH:14]=[CH:13][N:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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>[CH:1]([C:4]1[N:5]=[C:6]([NH:9][C:11]2[CH:16]=[C:15]([O:17][C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=3)[C:21]([O:23][CH3:24])=[O:22])[CH:14]=[CH:13][N:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cccc(Oc2ccnc(Cl)c2)c1
Reactant: CC(C)c1csc(N)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cccc(Oc2ccnc(Nc3nc(C(C)C)cs3)c2)c1
Yield: 83.2 %

Procedure:
Following the method of Example 1, Step B, 4-isopropylthiazol-2-amine (10.55 mL, 4.219 mmol), methyl 3-(2-chloropyridin-4-yloxy)benzoate (1.224 g, 4.641 mmol), potassium phosphate (0.9850 g, 4.641 mmol), tris(dibenzylideneacetone)dipalladium (0). (0.09658 g, 0.1055 mmol), and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.06713 g, 0.1160 mmol) were reacted in water (3 mL) and toluene (11 mL) to give the title compound (1.297 g, 81.55% yield) as yellow solid. 1H NMR (CDCl3) δ 8.19 (d, 1H), 7.93 (dt, 1H), 7.76 (m, 1H), 7.50 (t, 1H), 7.30 (m, 1H), 6.50 (m, 1H), 6.48 (dd, 1H), 6.33 (s, 1H), 3.92 (s, 3H), 2.87 (m, 1H), 1.22 (d, 6H).
Reaction SMILES: C([C:3](CC)(C([O-])=O)[C:4]([O-])=[O:5])C.[Na].[O:13]1[CH2:18][CH2:17][CH:16]([CH:19]=[CH:20][C:21](=[O:23])[CH3:22])[CH2:15][CH2:14]1>C(O)C>[O:13]1[CH2:18][CH2:17][CH:16]([CH:19]2[CH2:3][C:4](=[O:5])[CH2:22][C:21](=[O:23])[CH2:20]2)[CH2:15][CH2:14]1
Reactant: CC(=O)C=CC1CCOCC1
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Agent: [Na]
Solvent: CCO
Product: O=C1CC(=O)CC(C2CCOCC2)C1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Diethylmalonate (8.86 ml, 58 mmol) is added dropwise over 3 minutes to a chilled (ice-bath) solution of sodium (1.48 g, 64 mmol) in ethanol (80 ml). Once the addition is complete the cooling bath is removed and reaction is stirred for 25 minutes at room temperature, then the reaction mixture is cooled again in an ice-bath. A solution of 4-(tetrahydropyran-4-yl)-3-buten-2-one (7.50 g, 49 mmol) in ethanol (45 ml) is added to the reaction mixture via a dropping funnel over 15 minutes. Once the addition is complete, the cooling bath is removed and the yellow solution is stirred at room temperature for 19 hours. The reaction mixture is acidified to pH 3 by dropwise addition of 2M aqueous hydrochloric acid, water added to dissolve the precipitate and the reaction mixture is extracted into dichloromethane. The organic extracts are dried over anhydrous magnesium sulphate, filtered and the filtrate concentrated in vacuo. The residue is taken up in isopropanol (50 ml) and a 2M aqueous solution of sodium hydroxide (140 ml) added. The reaction mixture is stirred at room temperature for 20 hours. The reaction mixture is concentrated in vacuo to remove isopropanol, then heated to 70° C. A solution of 2M aqueous hydrochloric acid is added carefully until the reaction mixture reaches pH 2. The reaction mixture is heated for 2½ hours at 75° C., then cooled to room temperature and the product is extracted into ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and the filtrate concentrated in vacuo to give 5-(tetrahydropyran-4-yl)cyclohexane-1,3-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[NH:12][C:11]=3[C:10](=S)[NH:9][C:8]2=[O:20])=[CH:4][CH:3]=1.[CH2:23]([NH2:25])[CH3:24]>O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[NH:12][C:11]=3[C:10]([NH:25][CH2:23][CH3:24])=[N:9][C:8]2=[O:20])=[CH:4][CH:3]=1
Reactant: CC(C)c1nc2c([nH]1)c(=S)[nH]c(=O)n2Cc1ccc(Cl)cc1
Reactant: CCN
Solvent: O
Product: CCNc1nc(=O)n(Cc2ccc(Cl)cc2)c2nc(C(C)C)[nH]c12

Procedure:
5.02 g of 3-(4-chlorobenzyl)-8-isopropyl-6-thioxanthine and 60 ml of 70% ethylamine in water was heated in a 450 ml reactor to 150° C.: the pressure rose to 270 psi. After 20 hours the reaction mixture was cooled, filtered and evaporated to dryness. The residue was taken up in water, acidified with 2N HCl to pH 2, and neutralized with 2N NaOH to pH 7. The solid was collected, washed, redissolved in a mixture of 20 ml of methanol, 20 ml of THF and 100 ml of 2N NaOH, treated with 0.5 g of charcoal and filtered. Methanol and THF were removed in vacuo, and the solution neutralized to pH 7 with 5N HCl. The amorphous solid was collected, washed and dried to give the crude product (5.70 g). Recrystallization from methanol gave the title compound (4.42 g) as an off-white solid mp 187-196° C.;
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])[CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:23])[C:21]=1Cl.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:23])[C:21]=1[N:12]1[CH2:13][CH2:14][CH:9]([C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[O:8])[CH2:10][CH2:11]1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: O=C(C1CCNCC1)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=C(C1CCN(c2c(Cl)cncc2Cl)CC1)N1CCOCC1
Yield: 36.3 %

Procedure:
General procedure C was followed using morpholino(piperidin-4-yl)methanone (21 mg, 0.12 mmol), 3,4,5-trichloropyridine (23 mg, 0.12 mmol), triethylamine (32 μL, 0.23 mmol) and NMP (1 mL). The crude product was purified by flash column chromatography on silica gel (hexane/EtOAc, 1:1) to furnish the title compound as a white solid (15 mg, 35%), m.p. 172-174° C.; umax (CHCl3)/cm−1 3006, 2858, 1632, 1559, 1448, 1116, 1020; m/z (ESI) C15H20Cl2N3O2 requires 344.0927, found [M+H]+ 344.0929.