Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]4)[C:15]([C:17]([CH3:19])=[CH2:18])=[N:16][C:12]=3[CH:11]=[C:10]([C:28]3[NH:32][C:31](=[O:33])[O:30][N:29]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:34][S-:35].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:20][C@H:21]4[CH2:22][CH2:23][C@H:24]([CH3:27])[CH2:25][CH2:26]4)[C:15]([CH:17]([CH3:19])[CH2:18][S:35][CH3:34])=[N:16][C:12]=3[CH:11]=[C:10]([C:28]3[NH:32][C:31](=[O:33])[O:30][N:29]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C[S-]
Reactant: C=C(C)c1nc2cc(-c3noc(=O)[nH]3)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Agent: [Na+]
Solvent: CO
Product: CSCC(C)c1nc2cc(-c3noc(=O)[nH]3)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 65 °C

Procedure:
3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(1-methylethenyl)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one (synthesized in a manner similar to Example 9.1; 100 mg, 0.22 mmol) was taken up in MeOH (1.5 mL) at room temperature, and sodium thiomethoxide (376 mg, 5.4 mmol) was added. The reaction was sealed and heated at 65° C. for 2 hours. The reaction was then quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 100% EtOAc/hexanes) to afford 3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[1-methyl-2-(methylsulfanyl)ethyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (racemate). 1H NMR (300 MHz, CDCl3) δ 8.69-8.74 (m, 1H), 8.57-8.62 (m, 1H), 8.43 (s, 1H), 7.89-7.94 (m, 1H), 3.71-3.93 (m, 2H), 3.22-3.38 (m, 1H), 3.06-3.19 (m, 1H), 2.88-2.99 (m, 1H), 2.07 (s, 3H), 1.48-1.59 (m, 1H), 1.53 (d, J=6.7 Hz, 3H), 1.22-1.38 (m, 2H), 1.08-1.21 (m, 1H), 0.85-1.07 (m, 3H), 0.78 (d, J=6.4 Hz, 3H), 0.66-0.75 (m, 1H), 0.47-0.66 (m, 2H); MS ES calc'd. for C25H29ClN6O2S [M+H]+ 513. found 513.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:20]O>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:3]=1[C:4]([O:6][CH3:20])=[O:5]
Reactant: CO
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C(F)(F)F)ccc1N
Temperature: 125 °C
Yield: 51 %

Procedure:
A solution of 2-amino-5-(trifluoromethyl)benzoic acid (1.07 g, 5.2 mmoles) in methanol (20 ml) was treated with concentrated sulphuric acid (0.5 ml) and heated under microwave conditions at 125° C. for 2 h. The mixture was evaporated to dryness and treated with water (100 ml) then basified to saturation with potassium carbonate and extracted with ethyl acetate (2×40 ml). The combined extracts were dried over sodium sulphate, filtered and evaporated to dryness. The residue was chromatographed on silica gel eluting with an ethyl acetate/isohexane gradient. This gave the title compound 1 as a colorless oil (0.59 g, 51%).
Reaction SMILES: C([O:5][C:6](=[O:49])[CH2:7][C@H:8]([NH:31][C:32]([O:34][CH2:35][CH:36]1[C:48]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:33])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:47]1[C:48]2[CH:36]([CH2:35][O:34][C:32]([NH:31][C@H:8]([CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)[CH2:7][C:6]([OH:49])=[O:5])=[O:33])[C:37]3[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:43]=2[CH:44]=[CH:45][CH:46]=1
Reactant: CCCCCCCOc1ccc(-c2ccc(CC[C@H](CC(=O)OC(C)(C)C)NC(=O)OCC3c4ccccc4-c4ccccc43)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCOc1ccc(-c2ccc(CC[C@H](CC(=O)O)NC(=O)OCC3c4ccccc4-c4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To a stirred solution of (R)-3-(9-fluorenylmethoxycarbonyl-amino)-5-(4′-heptyloxybiphenyl-4-yl)pentanoic acid tert-butyl ester (crude, 3.34 g) in CH2Cl2 (20 ml) was added TFA (20 ml) dropwise. After being stirred for 1 h at room temperature, the mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (MeOH/CH2Cl2, 1:20) to give (R)-3-(9-fluorenylmethoxycarbonylamino)-5-(4′-heptyloxybiphenyl-4-yl)pentanoic acid (2.07 g, 77% in 3 steps) as a white amorphous powder.
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)[CH2:3][CH:4]([CH3:6])[CH3:5].N1CCCCC1.N1CCCCC1.N(C(O)=O)=NC(O)=O.C(P(CCCC)CCCC)CCC.[CH3:50][C:51]1[CH:56]=[C:55](O)[CH:54]=[C:53]([CH3:58])[C:52]=1[C:59]1[CH:64]=[CH:63][C:62]([C:65]([F:68])([F:67])[F:66])=[CH:61][CH:60]=1>C1(C)C=CC=CC=1.CO.CCOC(C)=O>[CH3:14][O:13][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:7]([CH:2]([O:1][C:55]2[CH:56]=[C:51]([CH3:50])[C:52]([C:59]3[CH:64]=[CH:63][C:62]([C:65]([F:66])([F:68])[F:67])=[CH:61][CH:60]=3)=[C:53]([CH3:58])[CH:54]=2)[CH2:3][CH:4]([CH3:6])[CH3:5])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(C(O)CC(C)C)cc1
Reactant: Cc1cc(O)cc(C)c1-c1ccc(C(F)(F)F)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(O)N=NC(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(C(CC(C)C)Oc2cc(C)c(-c3ccc(C(F)(F)F)cc3)c(C)c2)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Methyl 4-(1-hydroxy-3-methylbutyl)benzoate (44.00 g, 197.94 mmol) is dissolved in toluene (1.12 L) and the batch temperature is adjusted to 0° C. Solid azodicarboxylic acid dipiperidine (74.92 g, 296.92 mmol) is added to the reaction solution. Tri-n-butylphosphine (78.0 mL, 296.92 mmol) is added to the reaction solution drop-wise maintaining a batch temperature at 0° C. 2,6-Dimethyl-4′-(trifluoromethyl)biphenyl-4-ol (65.92 g, 237.53 mmol), dissolved in toluene (1 L), is added to the reaction drop-wise maintaining the batch temperature of 0° C. The reaction mixture is warmed to 25° C. and stirred approximately 16 h. The reaction is analyzed by TLC 30% EtOAc in hexanes. Product rf=0.63, carbinol rf=0.34, and the biaryl rf=0.39. The reaction is continued until no methyl 4-(1-hydroxy-3-methylbutyl)benzoate is observed by TLC. Upon reaction completion, the solvent is removed by vacuum distillation and replaced with hexane. The mixture is chromatographed using silica and is eluted with hexanes. The fractions, containing the product, are concentrated to 85.89 g (92.2%) of a viscous oil under reduced pressure at 45° C. 1H NMR (400 MHz, DMSO-d6): δ 7.92 (d, 2H), 7.72 (d, 2H), 7.55 (d, 2H), 7.29 (d, 2H), 6.68 (s, 2H), 5.44 (dd, 1H), 3.81 (s, 3H), 1.83 (m, 1H), 1.82 (s, 6H), 1.75 (m, 1H), 1.52 (m, 1H), 0.94 (dd, 6H).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[S:11][C:10]=2[CH2:20][CH3:21])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:24])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:24][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:13]=[C:12]([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[S:11][C:10]=1[CH2:20][CH3:21]
Reactant: O=S(Cl)Cl
Reactant: CCc1sc(C2CCOCC2)cc1C(O)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCc1sc(C2CCOCC2)cc1C(Cl)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of cyclohexyl[2-ethyl-5-(tetrahydro-2H-pyran-4-yl)thiophen-3-yl]methanol (737 mg) synthesized above in toluene (10 mL) was added thionyl chloride (209 μL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (725 mg, 93%) as a pale-yellow oil.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl[C:11]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]=[C:13]([S:22][CH3:23])[N:12]=1.Cl.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][NH2:33]>O1CCCC1>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][NH:33][C:11]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]=[C:13]([S:22][CH3:23])[N:12]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(SC)nc1NNc1ccccc1Cl

Procedure:
At room temperature, 16.2 mL of N,N-diisopropylethylamine was added to tetrahydrofuran (300 mL) solution of 9.4 g of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate and 8.3 g of 2-chlorophenylhydrazine hydrochloride, and heated under reflux for 18 hours. The solvent was concentrated under reduced pressure, water was added to this, and extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain crude ethyl 4-[2-(2-chlorophenyl)hydrazino]-2-(methylthio)pyrimidine-5-carboxylate as a yellow oily substance.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[S:15][CH2:14][CH2:13][O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([O:9][CH2:10][CH:11]1[S:15][CH2:14][CH2:13][O:12]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC[C@H]1OCCS1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(OCC1OCCS1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.3 %

Procedure:
2(S)-(Benzoyloxymethyl)-1,3-oxathiolane (0.045 mmol, 10 mg, 1.0 equiv.), para-toluenesulfonic acid monohydrate (0.015 mmol, 3 mg, 0.3 equiv.) and toluene (1 mL) were heated to reflux and stirred while monitoring the racemization reaction by chiral HLPC. After 24 h, the reaction was allowed to cool to ambient temperature and washed with saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and concentrated by rotary evaporation to give 8 mg (80% yield) of (+/−)-2-(benzoyloxymethyl)-1,3-oxathiolane.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.[S:13]([O-:16])([O-:15])=[O:14].[Na+:17].[Na+]>O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][S:13]([O-:16])(=[O:15])=[O:14].[Na+:17]
Reactant: O=S([O-])[O-]
Reactant: FC(F)(F)c1cccc(CCl)c1
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])Cc1cccc(C(F)(F)F)c1
Yield: 90.5 %

Procedure:
A mixture containing 50 g of 3-trifluoromethylbenzyl chloride and 32.4 g of sodium sulfite in 200 ml of water was refluxed for five hours and then concentrated by evaporation. The concentrate was then filtered to collect the precipitate (product). The precipitate was then washed with ethyl ether and then dried in a vacuum oven affording 61 g of sodium 3-trifluoromethylbenzylsulfonate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[O:43][N:42]=[C:41]([CH3:44])[CH:40]=2)[CH:34]=1)=[O:32])(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH:22][C:29](=[O:28])[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[O:43][N:42]=[C:41]([CH3:44])[CH:40]=2)[CH:34]=1)=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C#N)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C#N)c(N4CCOCC4)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-4-cyano-5-morpholin-4-yl-phenyl)-carbamic acid tert-butyl ester (Example J12) (318 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (400 mg, 73%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)O)=[O:5])[CH3:2].[NH2:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([Cl:31])[CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[NH:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([Cl:31])[CH:30]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Reactant: Nc1cncc(Cl)c1
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1C(Nc1cncc(Cl)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for step E2 using 2-bromo-5-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylic acid ethyl ester (intermediate B) and 3-amino-5-chloro-pyridine as starting materials. tR: 1.31 min (LC-MS 2); ESI-MS: 511.1/513.1 [M+H]+ (LC-MS 2).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:9][C:10]([O:12]CC)=[O:11].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[O:7]([CH2:9][C:10]([OH:12])=[O:11])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)COc1ccccc1
Yield: 60.5 %

Procedure:
Phenol (d5) 4.6 g, ethyl chloroacetate (6.25 g), sodium iodide (7.5 g) and anhydrous potassium carbonate (7 g) were refluxed for 12 hours in dry acetone (50 ml). The mixture was then stirred into a large volume of water and the solution extracted with ether. Unreacted phenol was removed with cold 1N NaOH solution. The ether extract was dried over anhydrous sodium sulphate, filtered and concentrated under vacuum. The residual oil (8.0 g) without further purification, was hydrolyzed by 10% NaOH in D2O affording phenoxyacetic acid (4.5 g)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:11].[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13]>CCN(CC)CC.[Cu]I>[CH3:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:13]#[C:12][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=2)[NH:7][N:6]=1
Reactant: Cc1n[nH]c2ccc(Br)cc12
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Cc1n[nH]c2ccc(C#C[Si](C)(C)C)cc12
Temperature: 25 °C

Procedure:
5-Bromo-3-methyl-1H-indazole (1.72 g, 8.2 mmol), PdCl2(PPh)2 (1.14 g, 1.64 mmol), CuI (155 mg, 0.82 mmol) and ethynyltrimethylsilane (3.5 mL, 24.6 mmol) were dissolved in 180 mL Et3N and refluxed over night. The mixture was cooled to room temperature, filtered and evaporated. The residue was taken up in MeOH (100 mL), filtered again and evaporated. The product thus obtained was purified on glass column chromatography (20% EtOAc in hexane). The title compound was obtained as a dark solid. LCMS (API-ES) m/z (%): 229.0 (100%, M++H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:8].Br.Br[CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>CN(C)C=O>[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([CH:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:10]1)=[O:8]
Reactant: BrCc1cccnc1
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)C2CN(Cc3cccnc3)c3ccccc3C2=O)cc1C
Yield: 25.3 %

Procedure:
Compound 4o was prepared following the procedure outlined in Step 3 of Example 1 using 32 mg (0.8 mmol) of sodium hydride (60%), 86 mg (0.31 mmol) of 3-(3,4-dimethyl-benzoyl)-2,3-dihydro-1H-quinolin-4-one 3a, 3 mL of anhydrous dimethylformamide, and 101.2 mg (0.40 mmol) of 3-bromomethylpyridine hydrobromide. The crude product was purified by flash chromatography to yield 29 mg of pale yellow solid 4o: LC-MSD, m/z for C24H20N2O2, [M+H]+=369.4, [M+2H]+=370.4; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=1.436 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.30 (d, 6H), 5.4 (s, 2H), 7.17 (d, 1H), 7.26-7.32 (m, 2H), 7.40 (t, 1H), 7.52-7.64 (m, 3H), 8.27 (s, 1H), 8.46 (d, 1H), 8.58-8.64 (m, 2H).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[C:7]2[CH:18]=[C:19](Br)[S:20][C:6]=2[C:5]1=[O:22])[CH:2]=[CH2:3].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.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]>[CH2:1]([N:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[C:7]2[CH:18]=[C:19]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[S:20][C:6]=2[C:5]1=[O:22])[CH:2]=[CH2:3]
Reactant: C1COCCN1
Reactant: C=CCN1CC(c2ccc(Cl)c(Cl)c2)c2cc(Br)sc2C1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C=CCN1CC(c2ccc(Cl)c(Cl)c2)c2cc(N3CCOCC3)sc2C1=O
Temperature: 140 °C
Yield: 108.2 %

Procedure:
A solution of 6-allyl-2-bromo-4-(3,4-dichlorophenyl)-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (0.02 g, 0.05 mmol) and morpholine (0.01 mL, 0.14 mmol) in anhydrous 1,4-dioxane (2.00 mL) was degassed under nitrogen for 10 min. Cesium carbonate (72.7 mg, 0.22 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8.32 mg, 0.01 mmol) was added followed by tris(dibenzylideneacetone)dipalladium(0) (4.4 mg, 0.0048 mmol). The reaction mixture was heated to 140° C. for 1 hour by microwave irradiation. The reaction was cooled to ambient temperature and quenched by the addition of a solution of saturated aqueous solution of sodium bicarbonate (10.0 mL) and extracted with EtOAc (10.0 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (4 g cartridge, gradient hexanes to 100% EtOAc) to afford the product (22.9 mg, 68%) as a yellow oil. LCMS (AA): ES+ 423, 425, 427. 1H NMR (DMSO-d6, 400 MHz): δ 7.59 (d, J=8.4 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.16 (dd, J=8.4, 2.0 Hz, 1H), 5.83 (s, 1H), 5.66-5.59 (m, 1H), 5.09-5.05 (m, 2H), 4.30 (t, J=6.0 Hz, 1H), 3.99-3.84 (m, 2H), 3.75-3.68 (m, 5H), 3.70-3.45 (m, 1H), 3.13-3.10 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([CH:11]3[NH:15]C(=O)N[C:12]3=[O:17])=[CH:7][C:5]=2[N:6]=1.[OH2:18]>>[NH2:15][CH:11]([C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([NH2:1])=[N:6][C:5]=2[CH:7]=1)[C:12]([OH:17])=[O:18]
Reactant: O
Reactant: Nc1nc2cc(C3NC(=O)NC3=O)ccc2s1
Product: Nc1nc2cc(C(N)C(=O)O)ccc2s1

Procedure:
23.6 g (0.095 mol) of 5-(2-aminobenzothiazol-5-yl)-2,4-imidazolidinedione are cleaved with 22.7 g (0.95 mol) of LiOH--dissolved in 1,000 m of water--in analogy to Example 1d.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=2)[NH2:10])=[CH:4][C:3]=1[CH2:16][CH3:17].[F:18][C:19]([F:24])([F:23])[CH:20]1[O:22][CH2:21]1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[C:9]([N:10]([CH2:16][CH:3]3[CH2:4][CH2:5][CH2:14][CH2:15][CH2:2]3)[CH2:21][CH:20]([OH:22])[C:19]([F:24])([F:23])[F:18])[CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[CH2:16][CH3:17]
Reactant: CCc1cc(Oc2cccc(N)c2)ccc1Cl
Reactant: FC(F)(F)C1CO1
Product: CCc1cc(Oc2cccc(N(CC3CCCCC3)CC(O)C(F)(F)F)c2)ccc1Cl
Temperature: 90 °C
Yield: 55.7 %

Procedure:
EX-18C) The 3-(4-chloro-3-ethylphenoxy)aniline (0.545 g, 0.002 mol) product from EX-18B was mixed with neat 3,3,3-trifluoro-1,2-epoxypropane (0.220 g, 0.002 mol) in a pressurized vial. The resulting mixture was heated at 90° C. for 18 h, cooled, and the excess 3,3,3-trifluoro-1,2-epoxypropane was removed in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with 1:4 ethyl acetate in hexane to give 0.254 g (35%) of the desired 3-[[3-(4-chloro-3-ethyl-phenoxy)phenyl]amino]-1,1,1-trifluoro-2-propanol product as a pure orange oil. Anal calcd. for C17H17NOF3Cl: C, 56.75; H, 4.76; N, 3.89. Found: C, 56.72; H, 4.70; N, 3.85. HRMS calcd.: 360.0978 [M+H]+, found: 360.0969. 1H NMR (CDCl3) δ 1.50 (t, 3H), 2.72 (m, 2H), 3.36 (m, 1H), 3.54 (m, 1H), 4.20 (m, 1H), 6.42 (m, 2H), 6.81 (dd, 1H), 6.94 (d, 1H), 7.18 (d, 1H), 7.25 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]2[C:20](OCC)=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].C1(C)C=CC=CC=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1.C(OCC)(=O)C.CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]2[CH2:20][OH:21])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2ccccc2n1S(=O)(=O)c1ccc(Br)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(Br)cc1)n1c(CO)cc2ccccc21
Temperature: -70 °C
Yield: 77.2 %

Procedure:
To a solution of 1.4 g of ethyl 1-[(4-bromophenyl)sulfonyl]-1H-indole-2-carboxylate in 10 mL of THF, 7.6 mL of diisobutylalminum hydride-toluene solution was added at a temperature of −60° C. or lower, and the resulting mixture was stirred under cooling in a dry ice-acetone bath for 5 hours and under ice cooling for 2 hours. After the solution was cooled to −70° C., 5 g of sodium sulfate decahydrate and 5 mL of methanol were added, the resulting mixture was warmed to room temperature, 50 mL of ethyl acetate and anhydrous sodium sulfate were added, insoluble matter was removed by filtration, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to obtain 0.97 g of {1-[(4-bromophenyl)sulfonyl]-1H-indol-2-yl}methanol as a pale violet solid. EI: 365, 367
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]2[CH3:30])[N:20]=[C:19]([Cl:31])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C.[ClH:39].[CH3:40]COCC>C(Cl)Cl>[ClH:31].[ClH:39].[F:23][C:22]1[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]2[CH3:30])=[N:20][C:19]([CH3:40])=[N:18][C:17]=1[NH:9][NH2:8]
Reactant: CCOCC
Reactant: C[C@H]1COCCN1c1nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F
Agent: Cl
Solvent: ClCCl
Product: Cc1nc(NN)c(F)c(N2CCOC[C@@H]2C)n1
Reaction time: 48 h
Yield: 65 %

Procedure:
To a solution of tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[(3S)-3-methyl-4-morpholinyl]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (0.6552 g, 1.166 mmol) in DCM (12 mL) was added 2 N HCl in Et2O (12 mL, 24 mmol). The solution was stirred for 2 days, and the resulting mixture was concentrated in vacuo. The solid was triturated with Et2O and collected by vacuum filtration to afford (3S)-4-(5-fluoro-6-hydrazino-2-methyl-4-pyrimidinyl)-3-methylmorpholine dihydrochloride (0.2543 g, 65%) as a yellow solid. LCMS: (M+H)+: 262.0.