Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32])[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:6]([NH:8][C:9]1([C:18]([OH:20])=[O:19])[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)=[O:7].[H][H]>C(O)C.[Pd]>[CH3:25][O:24][C:23]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][C:9]2([C:18]([OH:20])=[O:19])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10]2)=[O:7])=[CH:4][C:3]=1[CH2:2][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32]
Reactant: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1C(O)c1ccccc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1Cc1ccccc1C
Yield: 81.3 %

Procedure:
The compound of example 241 (32 mg, 0.074 mmol) was dissolved in ethanol (10 ml), palladium (10%) on charcoal (10 mg) was added, and the mixture was hydrogenated at room temperature for 1 h at a hydrogen pressure of 5 bar. After completion of the reaction, the mixture was filtered over silica gel and evaporated to dryness. The residue was triturated with diethyl ether, filtered and dried in vacuo to yield 25 mg of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH2:10])=[O:9])[CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>CC(N(C)C)=O>[C:8]([C:4]1[CH:3]=[C:2]([O:18][C:15]2[CH:16]=[CH:17][C:12]([NH2:11])=[CH:13][CH:14]=2)[CH:7]=[CH:6][N:5]=1)(=[O:9])[NH2:10]
Reactant: Nc1ccc(O)cc1
Reactant: NC(=O)c1cc(Cl)ccn1
Solvent: CC(=O)N(C)C
Product: NC(=O)c1cc(Oc2ccc(N)cc2)ccn1

Procedure:
Entry 14: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2. Step 4 using DMAC in place of DMF to give 4-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C4,2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 4-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][S:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18]C1C=CC=CC=1.[ClH:25]>C(Cl)Cl>[ClH:25].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][S:16][CH3:17])[N:9]=[CH:8][NH:7][C:6]2=[O:18]
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCSC
Agent: Cl
Solvent: ClCCl
Product: COc1cc2c(=O)[nH]cnc2cc1OCCSC
Temperature: 100 °C
Yield: 83 %

Procedure:
A mixture of 6-methoxy-7-(2-methylthioethoxy)-4-phenoxyquinazoline (1.5 g, 4.4 mmol) and 2M hydrochloric acid (25 ml) was heated at 100° C. for 2 hours. The mixture was allowed to cool, and methylene chloride was added with stirring to give a white precipitate. The precipitate was collected by filtration, washed with water and methylene chloride and dried to give 6-methoxy-7-(2-methylthioethoxy)-3,4-dihydroquinazolin-4-one hydrochloride (1.1 g, 83%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].Cl.N1C=CC=CC=1>C(OCCO)C>[Br:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(Br)c1
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cccc2c(Nc3cccc(Br)c3)c(C#N)cnc12
Yield: 89.6 %

Procedure:
A solution of 328.0 mg (1.5 mmol) of 4-chloro-8-methoxy -3-quinolinecarbonitrile, 309.7 mg (1.8 mmol) of 3-bromoaniline and 173.3 mg (1.5 mmol) of pyridine hydrochloride in 15 ml of 2-ethoxyethanol was refluxed under nitrogen for 0.5 hours. The solvent was removed and the residue was diluted with water followed by neutralization to pH 7-8 with diluted sodium carbonate solution. The precipitate was collected and washed with ether and dried in vacuo to give 476.1 mg (89.6%) of the product as a yellow solid, m.p. 210-212° C.; mass spectrum (electrospray, m/e): M+H 353.8, 355.8.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7](=[O:30])[C@@H:8]1[CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10][N:9]1[C:18](=[O:29])[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH3:21].O>CN(C)C=O>[CH3:5][O:6][C:7](=[O:30])[C@@H:8]1[CH2:12][C@@H:11]([N:1]=[N+:2]=[N-:3])[CH2:10][N:9]1[C:18](=[O:29])[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH3:21]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)CN(C)C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)CN(C)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 3 h
Yield: 105.7 %

Procedure:
Sodium azide (675 mg) was added to a solution of 1-(N-tert-butoxycarbonyl-N-methylglycyl)-cis-4-methanesulfonyloxy-L-proline methyl ester (B, 0.82 g) in N,N-dimethylformamide (10 mL)-water (1 mL). After stirring at 70° C. for 3 hr, the solvents were removed in vacuo, and the residue was diluted with chloroform. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to afford the title compound (0.75 g) as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][C:15]#[N:16])[CH:6]=1)[CH3:3].C(Cl)(Cl)Cl.Cl.[S:22]([NH2:26])([NH2:25])(=[O:24])=[O:23]>CO>[S:22]([NH:26][C:15](=[NH:16])[CH2:14][CH2:13][S:12][CH2:11][C:7]1[CH:6]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[CH:10]=[CH:9][N:8]=1)(=[O:24])(=[O:23])[NH2:25]
Reactant: CN(C)Cc1ccnc(CSCCC#N)c1
Reactant: NS(N)(=O)=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN(C)Cc1ccnc(CSCCC(=N)NS(N)(=O)=O)c1

Procedure:
3-(4-Dimethylaminomethyl-2-pyridylmethylthio)propionitrile in a mixture of dry methanol and dry chloroform under nitrogen at 2° C. is treated with dried hydrogen chloride gas and allowed to stand at ca. 0° C. to give after basification with ice cold potassium carbonate solution methyl-3-(4-dimethylaminomethyl-2-pyridylmethylthio)propionimidate which is reacted in methanol with sulphamide under reflux. Evaporation of the solvent at reduced pressure and purification of the product by chromatography yields N-sulphamoyl-3-(4-dimethylaminomethyl-2-pyridylmethylthio)propionamidine.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:3]=1[CH2:4]OS(C1C=CC(C)=CC=1)(=O)=O.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>O1CCOCC1>[F:1][C:2]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:3]=1[CH2:4][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1ccc(S(=O)(=O)OCc2cc([N+](=O)[O-])ccc2F)cc1
Reactant: C1CCNC1
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(F)c(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of toluene-4-sulfonic acid 2-fluoro-5-nitro-benzyl ester (compound of step B of example 29) (0.696 g, 2.31 mmoles) in 1,4-dioxane (20 mL) was added TEA (0.32 mL, 2.31 mmoles) and pyrrolidine (0.19 mL, 2.31 mmoles). The reaction mixture was stirred for 24 h at room temperature, concentrated and purified by TLC (petroleum ether/AcOEt/NH4OH//8/2/0.2). The expected compound was obtained as a yellow oil (0.399 g, 77% yield). MALDI-TOF: m/z 225.1 [M+H]+. 1H NMR (300 MHz, CDCl3) δ8.38; (dd, J=6.2 Hz and 2.9 Hz, 1H), 8.15; (ddd, 4-CH, J=8.9 Hz, 2.9 Hz and 4.4 Hz, 1H), 7.17; (dd, J=8.9 Hz and 8.9 Hz, 1H), 3.76; (s, 2H), 2.5-2.6; (m, 4H), 1.8-1.9; (m, 4H). 13C NMR (75 MHz, CDCl3) δ127.0; (CH, d, J=6.4 Hz), 124.5; (CH, d, J=10.1 Hz), 116.2; (CH, d, J=24.9 Hz), 54.1; (CH2), 52.2; (CH2), 23.5; (CH2).
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][C:7]1[NH:12][C:11](=[S:13])[NH:10][C:9](=[O:14])[CH:8]=1.Cl[CH2:16][C:17]([NH2:19])=[O:18].C(O)C>O>[OH:14][C:9]1[CH:8]=[C:7]([CH3:6])[N:12]=[C:11]([S:13][CH2:16][C:17]([NH2:19])=[O:18])[N:10]=1
Reactant: NC(=O)CCl
Reactant: Cc1cc(=O)[nH]c(=S)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(O)nc(SCC(N)=O)n1

Procedure:
To a solution of 16.8 g. (0.2 mole) of sodium bicarbonate in 300 ml of water was added 22.8 g.(0.2 mole) of 6-methyl-2-thiouracil. The mixture was heated on a steam bath for 10 minutes. To this mixture was then added 18.6 g.(0.2 mole) of 2-chloroacetamide followed by 100 ml of absolute ethanol. The mixture was heated on a steam bath for 2 hours. The solution was cooled in an ice bath and the precipitate which formed was collected and recrystallized from a mixture of N,N-dimethylformamide and ethanol to afford 8 g. of product, m.p. 238°-240° d.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[CH:16]12[C:23](=[O:24])[O:22][C:20](=[O:21])[CH:17]1[CH2:18][CH2:19]2>>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([NH:6][C:23]([C@H:16]2[CH2:19][CH2:18][C@H:17]2[C:20]([OH:22])=[O:21])=[O:24])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1OC(=O)C2CCC12
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1CC[C@H]1C(=O)O

Procedure:
From 2.3 g of 3,5-bistrifluoromethyl aniline and 1.1 g of cyclobutane-1,2-dicarboxylic anhydride used as starting materials, the title compound was obtained in the same manner as in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:11])[CH2:9]O.C(N(CC)CC)C.F.F.F.C(N(CC)CC)C.[F:29]C(F)(C(F)(F)F)C(F)(F)C(F)(F)S(F)(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[F:29][CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:11]
Reactant: O=C(CO)c1ccccc1F
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CF)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
A solution of 1-(2-fluorophenyl)-2-hydroxyethanone [CAS 218771-68-7; WO9857925, ex. 16) (2.77 g, 18.0 mmol) in dichloromethane (42 ml) was treated consecutively at 0° C. with triethylamine (6.36 g, 62.8 mmol), triethylamine trihydrofluoride (3.05 g, 18.0 mmol) and nonafluoro-n-butanesulfonyl fluoride (8.48 g, 26.9 mmol). The tube was sealed and the reaction mixture stirred overnight at room temperature. For the workup, the dark red solution was poured on a saturated solution of sodium hydrogencarbonate and ice, then extracted with dichloromethane. The organic layer was separated, dried over sodium sulphate and evaporated. The crude material was purified by flash chromatography on silica gel (Telos Flash Silica) using dichloromethane as the eluent to give the 2-fluoro-1-(2-fluoro-phenyl)-ethanone (1.23 g, 61% yield) as a yellow semisolid.
Reaction SMILES: [CH2:1]([Si:7]([CH3:10])(Cl)Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:11]1[C:23]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:1]([Si:7]([CH3:10])([CH:22]1[C:23]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:16]2[C:21]1=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:23]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CCCCCC[Si](C)(Cl)Cl
Solvent: C1CCOC1
Product: CCCCCC[Si](C)(C1c2ccccc2-c2ccccc21)C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
n-Hexylmethyldichlorosilane (30.4 g, 0.152 mol) and 300 mL of dry THF were charged to a one liter Schlenk equipped with an addition funnel. Fluorene anion (52.4 g, 0.305 mol) was dissolved in approximately 200 mL of dry THF and charged to the addition funnel. The temperature of the stirring solution was lowered to −78° C. under positive nitrogen pressure. The fluorene anion was added dropwise over two hours. After the anion addition was complete, the reaction mixture was allowed to warm to room temperature. The solution was allowed to stir overnight. The solution was washed with three 200 mL aliquots of water, retaining the organic layer after each washing. The organic layer was dried with magnesium sulfate and filtered. The product was recrystallized from hexane. The yield of this reaction is 19.6%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)=[O:9].[NH2:15][C:16]1[C:17](Cl)=[N:18][CH:19]=[CH:20][CH:21]=1>>[NH2:15][C:16]1[C:17]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ccccc1C(=O)c1cccs1
Reactant: Nc1cccnc1Cl
Product: Nc1cccnc1Nc1ccccc1C(=O)c1cccs1

Procedure:
In accordance with the procedure of Intermediate 9, (2-aminophenyl)(2-thienyl)methanone, prepared by the method of Steinkopf & Gunther, Ann. 522, 28-34 (1936), is reacted with 3-amino-2-chloropyridine to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH:18]([OH:19])[CH2:17][N:16]([C:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)=[O:21])[CH2:15]3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:33]I>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH:14]3[CH:18]([O:19][CH3:33])[CH2:17][N:16]([C:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)=[O:21])[CH2:15]3)[CH2:12][CH2:13]2)=[O:7])=[CH:29][CH:30]=1
Reactant: CI
Reactant: O=C(c1ccc(Cl)cc1)N1CCN(C2CN(C(=O)c3ccc(Cl)cc3)CC2O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC1CN(C(=O)c2ccc(Cl)cc2)CC1N1CCN(C(=O)c2ccc(Cl)cc2)CC1
Temperature: 4 °C
Reaction time: 0.25 h

Procedure:
To a cold (3-5° C.) solution of starting material {3-[4-(4-Chloro-benzoyl)-piperazin-1-yl]-4-hydroxy-pyrrolidin-1-yl}-(4-chloro-phenyl)-methanone in 1 mL of NMP was added NaH (4 mg, 0.17 mmol). The mixture was then stirred at 3-5° C. for 15 mins. MeI (7.5 uL) was then added. After 2 hours, the reaction was quenched by adding 50 μL AcOH. The mixture was then partitioned in EtOAc and 1M K2CO3. The separated organic phase was washed with brine, dried over Na2SO4 and concentrated down to dryness. The resulting crude residue was purified by column chromatography on silica (Methanol 1 CH2Cl2: 0%-10%). The pure product was converted to it HCl salt by precipitation in a mixture of ethanol\ether and conc. HCl, to give 43 mg of salt of {3-[4-(4-Chloro-benzoyl)-piperazin-1-yl]-4-methoxy-pyrrolidin-1-yl}-(4-chloro-phenyl)-methanone as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][C:3]=1[Cl:9].[H-].[Na+].[CH2:12]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20]2[C:23]3[C:24](=[C:26]([O:42][CH3:43])[CH:27]=[CH:28][C:29]=3[C:30](OC3C=CC([N+]([O-])=O)=CC=3)=[O:31])[O:25][C:19]=2[CH2:18]1)=[O:16])[CH3:13].O>CN(C=O)C>[Cl:9][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Cl:8])[C:2]=1[NH:1][C:30]([C:29]1[CH:28]=[CH:27][C:26]([O:42][CH3:43])=[C:24]2[O:25][C:19]3[CH2:18][N:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])[CH2:22][CH2:21][C:20]=3[C:23]=12)=[O:31]
Reactant: Nc1c(Cl)cncc1Cl
Reactant: CCOC(=O)N1CCc2c(oc3c(OC)ccc(C(=O)Oc4ccc([N+](=O)[O-])cc4)c23)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCc2c(oc3c(OC)ccc(C(=O)Nc4c(Cl)cncc4Cl)c23)C1

Procedure:
To a solution of 4-amino-3,5-dichloro pyridine (0.125 g, 0.765 mmol) in dry DMF, sodium hydride (0.0162 g, 0.675 mmol) was added at 0° C. followed by 4-nitrophenyl 2-(ethoxycarbonyl)-8-methoxy-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine-5-carboxylate (0.197 g, 0.45 mmol). Water was added to RM. Solid filtered out and purified on Silica Gel column with CHCl3: EtOAc to yield N-(3,5-dichloropyridin-4-yl)-2-(ethoxycarbonyl)-8-methoxy-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine-5-carboxamide.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@:21]3([NH:25][C@@H:24]([C:26]([O:28]C)=O)[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH3:43]>>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C@@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@:21]3([NH:25][C@@H:24]([C:26]([NH2:43])=[O:28])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:41])[F:42])[CH:8]=1
Reactant: COC(=O)[C@H]1CC[C@@]2(CCN(C(=O)N(C)[C@@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Reactant: N
Product: Cc1cc(F)ccc1[C@H]1C[C@]2(CC[C@H](C(N)=O)N2)CCN1C(=O)N(C)[C@@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 72.5 %

Procedure:
In a sealed tube a solution of methyl (2R,5S,7R)-8-{[{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-1,8-diazaspiro[4.5]decane-2-carboxylate (Intermediate 28, 90 mg, 0.149 mmol) in 7M methanolic ammonia (5 ml, 35.0 mmol) was shaken overnight. The solvent was evaporated and the crude was purified by flash-chromatography (Si cartridge 5 g; from 1:0 to 95:5 DCM/MeOH) to give the title compound (63.3 mg, 0.108 mmol, 72.1% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.93 (s, 1H) 7.56 (s, 2H) 7.23-7.31 (m, 1H) 7.14-7.21 (m, 1H) 6.95-7.05 (m, 1H) 6.90 (d, 1H) 6.76 (t, 1H) 5.27-5.43 (m, 1H) 4.14 (d, 1H) 3.41-3.56 (m, 1H) 3.23-3.39 (m, 1H) 2.84 (s, 3H) 2.72 (t, 1H) 2.60-2.68 (m, 1H) 2.32 (s, 3H) 2.06-2.18 (m, 1H) 1.53-1.87 (m, 6H) 1.49 (d, 3H) 1.42 (t, 1H); HPLC: peak @ Rt=4.91 mins; MS: m/z=589 [M+H]+ and 611 [M+Na]+
Reaction SMILES: [C:1](C1C([N+]([O-])=O)=CC(C(O)=O)=CC=1O)(=O)[C:2]1C=CC=CC=1.[Cl:22][C:23]1[CH:43]=[CH:42][C:26]([C:27]([C:29]2[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][C:30]=2[OH:41])=[O:28])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:43]=[CH:42][C:26]([C:27]([C:29]2[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][C:32]([C:33]([O:35][CH2:1][CH3:2])=[O:34])=[CH:31][C:30]=2[OH:41])=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(O)c1cc(O)c(C(=O)c2ccc(Cl)cc2)c([N+](=O)[O-])c1
Reactant: O=C(O)c1cc(O)c(C(=O)c2ccccc2)c([N+](=O)[O-])c1
Product: CCOC(=O)c1cc(O)c(C(=O)c2ccc(Cl)cc2)c([N+](=O)[O-])c1

Procedure:
By replacing in Example 6, step A, 4-benzoyl-3-hydroxy5-nitrobenzoic acid with 4-(4'-chlorobenzoyl)-3-hydroxy-5-nitrobenzoic acid and following the procedure described, ethyl 4-(4'-chlorobenzoyl)-3-hydroxy-5-nitrobenzoate is obtained with a melting point of 188°-191.5° C.
Reaction SMILES: C([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([OH:24])[CH3:23])[C:13](=[O:25])[N:12]([CH3:26])[C:11]=2[N:10]=[C:9]1[CH3:27])C1C=CC=CC=1>C(O)(=O)C.C(OCC)(=O)C.[Pd]>[OH:24][C@H:22]([CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18][N:14]1[C:15](=[O:17])[C:16]2[NH:8][C:9]([CH3:27])=[N:10][C:11]=2[N:12]([CH3:26])[C:13]1=[O:25]
Reactant: Cc1nc2c(c(=O)n(CCCC[C@@H](C)O)c(=O)n2C)n1Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1nc2c([nH]1)c(=O)n(CCCC[C@@H](C)O)c(=O)n2C

Procedure:
A solution of (R)-7-benzyl-1-(5-hydroxyhexyl)-3,8-dimethylxanthine (250 mg) in a mixture of acetic acid (10 ml) and ethyl acetate (10 ml) was hydrogenated in presence of palladium on carbon (50 mg) for 12 hours. The mixture was filtered through celite (5 g) and concentrated. The residue was dissolved in ethyl acetate (100 ml), washed with saturated sodium bicarbonate solution (50 ml), dried over magnesium sulfate and concentrated. The product was purified by flash chromatography (silica gel) eluting with 10% methanol/ethyl acetate. Yield=180 mg.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:16][S:15][CH:14]3[N:11]([C:12](=[O:17])[CH2:13]3)[C:10]=2[C:18]([O:20]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:19])=[N:5][N:4]=[N:3]1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:16][S:15][CH:14]3[N:11]([C:12](=[O:17])[CH2:13]3)[C:10]=2[C:18]([OH:20])=[O:19])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)CC2SC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)CC2SC1

Procedure:
The 7β-[[DL-[[[2,4-dioxo-1-imidazolidinyl)amino]carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)-thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester obtained in Example 14 is treated with trifluoroacetic acid and anisole according to the procedure of Example 8, to obtain 7β-[[DL-[[[2,4-dioxo-1-imidazolidinyl)amino]carbonyl]amino]-2-thienylacetyl]-amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, m.p. 160°-180° (dec.). The sodium salt is obtained by treating this product with an equimolar amount of sodium bicarbonate in water, filtering and freeze drying the filtrate, m.p. 200°-220° (dec.).
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.Cl.[CH3:9][O:10][C:11](=[O:15])[C@H:12]([CH3:14])[NH2:13]>>[CH3:9][O:10][C:11](=[O:15])[C@H:12]([CH3:14])[NH:13][C:5](=[O:7])[CH2:4][CH:1]1[CH2:2][CH2:3]1
Reactant: COC(=O)[C@H](C)N
Reactant: O=C(O)CC1CC1
Agent: Cl
Product: COC(=O)[C@H](C)NC(=O)CC1CC1

Procedure:
Following General Procedure A above using cyclopropylacetic acid (Aldrich) and L-alanine methyl ester hydrochloride (Sigma), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.15 in 25% ethyl acetate/hexanes) and purification was by flash column chromatography using 25% ethyl acetate/hexanes as the eluant.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>O>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:10]([NH2:9])=[S:11])=[CH:24][CH:23]=1
Reactant: O=C(NC(=S)Nc1ccccc1-c1ccc(F)cc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=S)Nc1ccccc1-c1ccc(F)cc1

Procedure:
A mixture of N-benzoyl-N'-(4'-fluoro-2-biphenylyl)thiourea (2.8 g) and sodium hydroxide (0.4 g) and water (10 ml) was heated at 90°-95° C. for 8 hours to yield N-(4'-fluoro-2-biphenylyl)thiourea as a colourless solid (m.p. 140°-142° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:13][SH:14])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[CH2:16]([C:23]1[O:24][C:25]2[CH:45]=[CH:44][CH:43]=[CH:42][C:26]=2[C:27]=1[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=2)=[CH:30][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:15])[C@@H:4]([NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])[CH2:13][S:14][CH2:40][C:37]1[CH:36]=[CH:35][C:34]([C:31]2[CH:30]=[CH:29][C:28]([C:27]3[C:26]4[CH:42]=[CH:43][CH:44]=[CH:45][C:25]=4[O:24][C:23]=3[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:33][CH:32]=2)=[CH:39][CH:38]=1
Reactant: BrCc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Reactant: COC(=O)[C@H](CS)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](CSCc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
N-Boc-L-Cysteine methyl ester (260 mg, 0.23 mL, 1.1 mmol) was added dropwise to a stirred suspension of 2-Benzyl-3-(4′-bromomethylbiphen-4-yl)benzofuran (500 mg, 1.1 mmol) and cesium carbonate (720 mg, 2.21 mmol) in anhydrous dimethylformamide (20 mL). The reaction was stirred at room temperature for 2 hrs (TLC control) and then poured into water (100 mL) and extracted with diethyl ether (3×100 mL). The combined extract was washed with water, brine (3×), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification using 30% ethyl acetate in heptane as eluent afforded the title compound as a white solid (620 mg, 92%): 1H NMR (CDCl3, 300 MHz): δ 7.70 (2H, m, Ar—H), 7.64 (2H, m, Ar—H), 7.60 (3H, m, Ar—H), 7.48 (1H, m, Ar—H), 7.42 (2H, m, Ar—H), 7.26-7.36 (7H, m, Ar—H), 5.32 (1H, d, J=8 Hz, NH), 4.58 (1H, m, CHN), 4.26 (2H, PhCH2), 3.79 (2H, s, PhCH2S), 3.76 (3H, s, OMe), 2.95 (1H, dd, J=13, 5 Hz, CHHCHN), 2.84 (1H, dd, J=13, 7 Hz, CHHCHN), 1.46 (9H, s, CMe3); ESI-LCMS e/z calcd for C37H37NO5S 607.760, found 608 (M+H)+, 630 (M+Na)+.