Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH:5]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[C:29]12([N:39]=[C:40]=[O:41])[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[CH2:30]1)[CH2:36]2>C(Cl)Cl>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH:5]([O:14][CH:15]1[CH2:18][N:17]([C:40]([NH:39][C:29]23[CH2:38][CH:33]4[CH2:32][CH:31]([CH2:37][CH:35]([CH2:34]4)[CH2:36]2)[CH2:30]3)=[O:41])[CH2:16]1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COc1ccc(C(OC2CN(C(=O)NC34CC5CC(CC(C5)C3)C4)C2)c2ccccc2C(F)(F)F)cc1
Yield: 90.7 %

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-methoxybenzhydryloxy]azetidine (157) (100 mg, 0.30 mmol) in anhydrous DCM (4 mL) was added MP-carbonate (3.01 mmol/g; 100 mg, 0.30 mmol) and 1-adamantyl isocyanate (55 mg, 0.30 mmol). The resultant mixture was shaken at ambient temperature for 5 h, after which time it was poured onto a DCM-wetted SCX-2 (1 g) cartridge. Elution with DCM (6 mL) followed by DCM-MeOH (6 mL), then removal of solvent in vacuo afforded the desired product as a white foam (140 mg, 92%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])[CH3:2].N1CCCCC1.[C:27]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)([OH:29])=[O:28]>C1C=CC=CC=1>[C:16]([O:15][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@H:8]1[C:6](=[O:7])/[C:5](/[C:4]([O:3][CH2:1][CH3:2])=[O:20])=[CH:34]/[C:33]1[CH:36]=[CH:37][C:30]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CCOC(=O)/C(=C\c1ccc(C(=O)O)cc1)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 75.8 %

Procedure:
To a solution of tert-butyl (2S)-2-(3-ethoxy-3-oxopropanoyl)-1-pyrrolidinecarboxylate (5.0 g, 17.5 mmol) in benzene (50 ml) and piperidine (0.3 ml, 3 mmol) was added 4-carboxybenzaldehyde (2.63 g, 17.5 mmol), and the mixture was refluxed for 3 h. The cooled solution was washed with 0.1 N HCl twice. The aqueous layer was extracted three times with ether. The combined organic phases were dried (Na2SO4) and concentrated to give C as a tan solid (5.54 g, 76% yield). LCMS m/z 416 (M−H), 833 (2M−H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:10][OH:11])[C:7]([OH:9])=[O:8].Br[C:13]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>O>[C:21]([O:20][C:18]([C:13]1([O:11][N:10]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[C:7]([OH:9])=[O:8])[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C(O)C(=NO)c1ccco1
Reactant: CC(C)(C)OC(=O)C1(Br)CCCC1
Solvent: O
Product: CC(C)(C)OC(=O)C1(ON=C(C(=O)O)c2ccco2)CCCC1

Procedure:
The dipotassium salt of 2-(fur-2-yl)-2-hydroxyiminoacetic acid (syn isomer) was generated under an atmosphere of dry nitrogen and alkylated with t-butyl 1-bromocyclopentanecarboxylate using the method of Preparation 2. The product was isolated by pouring into water, acidifying and extracting in the conventional manner, thereby yielding the title compound, m.p. 106.8°-107.3°; λmax (pH 6 buffer) 277.5 nm (ε 15,100); τ(d6 -DMSO) values include 8.03, 8.30 (m, cyclopentyl protons) and 8.63 (C(CH3)3).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Cl:13][S:14](O)(=[O:16])=[O:15]>C(Cl)Cl>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:14]([Cl:13])(=[O:16])=[O:15])[C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(C(C)(C)C)cc1
Solvent: ClCCl
Product: COc1ccc(C(C)(C)C)cc1S(=O)(=O)Cl
Reaction time: 0.67 h

Procedure:
12.3 g (0.075 mol) of 4-(1,1-dimethylethyl)anisole, dissolved in 30 ml of methylene chloride, are added dropwise, while cooling in ice, to 16.5 ml of chlorosulfonic acid dissolved in 20 ml of methylene chloride. The mixture is stirred for 40 minutes and then poured onto ice-water. The organic phase is separated off, washed with water, dried with MgSO4 and evaporated. Recrystallization from toluene/petroleum ether provides crystals of melting point: 75°-77° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1.[C:15]([CH:19]1[CH2:24][CH2:23][CH:22]([NH:25][CH2:26][C:27]2[CH:44]=[CH:43][C:30]([C:31]([CH:33]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])[CH:34]3[CH2:36][CH2:35]3)=[O:32])=[CH:29][CH:28]=2)[CH2:21][CH2:20]1)([CH3:18])([CH3:17])[CH3:16]>ClCCl>[C:15]([CH:19]1[CH2:20][CH2:21][CH:22]([N:25]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([CH:33]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])[CH:34]3[CH2:35][CH2:36]3)=[O:32])=[CH:43][CH:44]=2)[C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=2)=[O:12])[CH2:23][CH2:24]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)C1CCC(NCc2ccc(C(=O)C(NCCC(=O)O)C3CC3)cc2)CC1
Solvent: ClCCl
Product: CC(C)(C)C1CCC(N(Cc2ccc(C(=O)C(NCCC(=O)O)C3CC3)cc2)C(=O)Nc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
200 μmol 4-trifluoromethoxyphenylisocyanate dissolved in 500 μL dichloromethane was added to the above resin bound 3-({4-[(4-tert-butylcyclohexylamino)methyl]benzoyl}-cyclo-propylmethyl)aminopropionic acid (50 mg). Shaking the mixture 5 hours at 25° C. followed by filtration and washing of the resin with 2×1 mL dichloromethane, 4×1 mL DMF, 2×1 mL H2O, 3×1 mL THF and 3×1 mL dichloromethane afforded the resin bound title compound.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:15][CH:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:17]1[C:25]([F:26])=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][C:18]=1[F:27])[CH3:14].[CH2:33]([NH2:37])[CH:34]([CH3:36])[CH3:35].CCOC(C)=O>C1COCC1>[CH2:31]([O:30][C:28](=[O:29])[CH:16]([C:17]1[C:18]([F:27])=[CH:19][C:20]([C:21](=[O:23])[NH:37][CH2:33][CH:34]([CH3:36])[CH3:35])=[CH:24][C:25]=1[F:26])[O:15][CH2:13][CH3:14])[CH3:32]
Reactant: CCOC(=O)C(OCC)c1c(F)cc(C(=O)O)cc1F
Reactant: CC(C)CN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(OCC)c1c(F)cc(C(=O)NCC(C)C)cc1F
Reaction time: 3 h
Yield: 67.3 %

Procedure:
1,1′-Carbonyldiimidazole (88 mg) was dissolved in THF (1 ml) and a solution of (RS)-4-(ethoxy-ethoxycarbonyl-methyl)-3,5-difluoro-benzoic acid (156 mg) in THF (1 ml) was added. After 30 min stirring at rt isobutylamine (41 mg) was added and the mixture was stirred 3 h. AcOEt (20 ml) was added and the solution was washed with 1 N HCl (20 ml). The aqueous layer was extracted with two more portions AcOEt (20 ml), the the combined organic layers were dried (Na2SO4) and the solvent was evaporated. CC (Hept/AcOET 3:1) afforded 125 mg (67%) of (RS)-(2,6-difluoro-4-isobutylcarbamoyl-phenyl)-ethoxy-acetic acid ethyl ester. White solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH:11]([N:14](CC)[CH:15](C)C)(C)C.C(N(CC)CC)C.Cl.CNC>O1CCCC1>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([N:14]([CH3:15])[CH3:11])[CH:7]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1nc(Cl)cc(N(C)C)n1
Yield: 73.5 %

Procedure:
A mixture of 4,6-dichloro-2-(methylsulfanyl)pyrimidine (5.0 g, 26 mmol), N,N-diisopropylethylamine (3.1 g, 26 mmol), triethylamine (7.15 mL, 51 mmol), and N,N-dimethylamine hydrochloride (2.09 g, 26 mmol) in tetrahydrofuran (50 mL) was heated at reflux for 16 hours. The solvent was removed and the crude material was redissolved in EtOAc and washed with a solution of citric acid (2×100 mL), followed by water (2×100 mL) and brine (2×100 mL). The organic layers were combined, dried over anhydrous MgSO4, concentrated and purified by flash chromatography [eluent: EtOAc/hexane (1:19)], giving the desired product (3.89 g, 73%).
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8](=[O:26])[CH2:9][NH:10][C:11]([CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1)=[O:12])#[N:2].O.CC1C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8](=[O:26])[CH2:9][NH:10][C:11]([CH:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1)=[O:12])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)N2CCC[C@H]2C#N)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: N#C[C@@H]1CCCN1C(=O)CNC(=O)C1CCNCC1
Reaction time: 24 h

Procedure:
To a solution of (S)-tert-butyl 4-(2-(2-cyanopyrrolidine-1-yl)-2-oxoethylcarbamoyl)piperidine-1-carboxylate (0.100 g, 0.274 mmol) in 2 ml Acetonitrile was 4-methylbenzenesulfonic acid hydrate (0.073 g, 0.384 mmol) added and the mixture was stirred for 24 h. After evaporation of the volatiles, the sample was purified by preparative HPLC to yield an reddish oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](Cl)=[N:8][C:4]=2[CH:3]=1.[F:12][C:13]([F:27])([F:26])[C:14]1[C:15]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:16][CH:17]=[CH:18][CH:19]=1>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([N:23]3[CH2:24][CH2:25][N:20]([C:15]4[C:14]([C:13]([F:27])([F:12])[F:26])=[CH:19][CH:18]=[CH:17][N:16]=4)[CH2:21][CH2:22]3)[NH:8][C:4]=2[CH:3]=1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: Clc1nc2cc(Br)ccc2[nH]1
Product: FC(F)(F)c1cccnc1N1CCN(c2nc3ccc(Br)cc3[nH]2)CC1

Procedure:
The benzoimidazole from step (b) above (0.115 g, 0.5 mmol) and 1-(3-trifluoromethylpyridin-2-yl)piperazine (0.231 g, 1 mmol, Maybridge) reacted under the conditions of Example 3c to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 426 (M+1).
Reaction SMILES: [C:1]([S:4][CH:5]([CH2:9][C:10](=[O:25])[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[OH-].[Na+:27].C(OCC)C>C(O)C>[C:1]([S:4][CH:5]([CH2:9][C:10](=[O:25])[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)[C:6]([O-:8])=[O:7])(=[O:3])[CH3:2].[Na+:27]
Reactant: CC(=O)SC(CC(=O)c1ccc(Oc2ccc(C)cc2)cc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CC(=O)SC(CC(=O)c1ccc(Oc2ccc(C)cc2)cc1)C(=O)[O-]
Yield: 799.1 %

Procedure:
3.58 g of 2-acetylthio-3-[4-(4-methylphenoxy)benzoyl]-propionic acid were dissolved in 50 ml of ethanol, then a solution of 0.04 g of sodium hydroxide in 10 ml of ethanol was added dropwise, under ice-cooling and with stirring. The mixture was stirred at the same temperature for a further one hour. 20 ml of diethyl ether were added to the reaction mixture and the precipitate was collected by filtration, then washed with diethyl ether, to give 3.04 g of sodium 2-acetylthio-3-[4-(4-methylphenoxy)benzoyl]propionate.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4](Cl)[N:3]=1.[CH2:15]([NH2:19])[CH2:16][CH2:17][CH3:18]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:19][CH2:15][CH2:16][CH2:17][CH3:18])[N:3]=1
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Reactant: CCCCN
Solvent: CCN(CC)CC
Product: CCCCNc1nc(Cl)nc2c1ncn2C(C)C

Procedure:
2-Chloro-6-[(butyl)amino]-9-(2-propyl)purine is prepared from 2,6-dichloro-9-(2-propyl)purine (see Example 15 for preparation), butylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [Na].[C:2](#[N:4])[CH3:3].[C:5](OC)(=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7]>C(OCC)C.N>[CH3:7][C:6]([CH3:9])([CH3:8])[C:5](=[O:10])[CH2:3][C:2]#[N:4]
Reactant: CC#N
Reactant: COC(=O)C(C)(C)C
Agent: N
Agent: [Na]
Solvent: CCOCC
Product: CC(C)(C)C(=O)CC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
To 2.5 l of liquid ammonia containing 2.5 g of anhydrous ferric chloride was cautiously added 132 g of sodium metal portionwise while keeping the temperature of the reaction mixture at -50° C. To this portion was added rapidly a solution of 234 g of acetonitrile diluted with 300 ml of anhydrous diethyl ether followed by the controlled addition of a solution of 332 g methyl pivaloate diluted with 300 ml anhydrous ether at such a rate that the reaction temperature did not exceed -30° C. Allowed reaction to warm up to room temperature overnight. After all of the ammonia has evaporated off, 1 kg of crushed ice is added followed by enough cold water to make the final volume 4.5 l. The mixture is stirred for 30 min., then filtered through a celite bed. The celite was washed well with cold water and 1 l of 1:1 ether/hexane. The phases were separated, discarding the organic layer. The aqueous layer was cautiously acidified with conc. HCl, cooling as necessary to keep the temperature below 35° C. The acidified aqueous phase was extracted with dichloromethane (3×500 ml). The combined organic phases were dried over MgSO4, filtered, and the solvent removed to yield 316 g of the desired product, M.P. 68° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[CH2:10]([O:12][CH2:13][C:14](N)=[NH:15])[CH3:11]>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:14]([CH2:13][O:12][CH2:10][CH3:11])[N:15]=1
Reactant: N#Cc1nccnc1N
Reactant: CCOCC(=N)N
Solvent: CCO
Product: CCOCc1nc(N)c2nccnc2n1

Procedure:
A mixture of 36.0 g (0.30 mole) of 3-amino-2-pyrazinecarbonitrile [prepared according to A. Albert and K. Ohta, J. Chem. Soc. C, 1970, 1540] and 46.7 g of 2-ethoxyacetamidine in 700 ml of absolute ethanol is refluxed for 2 hours 30 minutes under a nitrogen atmosphere. After cooling, the precipitate obtained is isolated by filtration. It is purified by recrystallization from ethanol. Yld: 52.0 g (84%), m.p. 152°-154° C.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:15]([OH:17])=O)=[CH:5][N:4]=1.[CH3:19][NH:20][CH2:21][C@H:22]([OH:30])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=1.Cl.CN1CCOCC1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>O1CCCC1>[OH:30][CH:22]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=1)[CH2:21][N:20]([CH3:19])[C:15]([C:6]1[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:8][C:3]([N:2]([CH3:1])[CH3:18])=[N:4][CH:5]=1)=[O:17]
Reactant: CN(C)c1ncc(C(=O)O)c(-c2ccccc2)n1
Reactant: CNC[C@H](O)c1cccc(O)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CN(CC(O)c1cccc(O)c1)C(=O)c1cnc(N(C)C)nc1-c1ccccc1
Reaction time: 0.08 h
Yield: 18.3 %

Procedure:
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid (1.22 g, 5 mmol) is dissolved in tetrahydrofuran (60 ml). After 5 minutes of stirring to the solution are added: L-phenylephrine hydrochloride (1.22 g, 6 mmol) in tetrahydrofuran (50 ml), after another 5 minutes of stirring the N-methylmorpholine (1.21 g, 12 mmol) and after 2 minutes of stirring the 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (1.66 g, 6 mmol). The reaction mixture is stirred for 2 hours at room temperature, then heated at reflux temperature for 2 hours. The solvent is removed in vacuum. To the residue water (50 ml) is added, and the mixture is extracted with chloroform (75 ml), the extract is washed with 10% sodium carbonate solution (35 ml), with water (35 ml), dried over sodium sulphate and evaporated. The residue is chromatographed on silicagel using chloroform-methanol 100/1-100/5 mixture eluent. 0.36 g of the title compound is obtained, m.p.: 79-81° C.
Reaction SMILES: [ClH:1].Cl.[N+:3]([C:6]1[C:7]([NH2:23])=[N:8][CH:9]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][NH:18][CH2:17][C:16]=3[CH:22]=2)[CH:11]=1)([O-])=O>C(O)(=O)C.C(O)C.[Pd]>[ClH:1].[ClH:1].[O:21]1[C:15]2[CH:14]=[CH:13][C:12]([C:10]3[CH:11]=[C:6]([NH2:3])[C:7]([NH2:23])=[N:8][CH:9]=3)=[CH:22][C:16]=2[CH2:17][NH:18][CH2:19][CH2:20]1
Reactant: Nc1ncc(-c2ccc3c(c2)CNCCO3)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cc(-c2ccc3c(c2)CNCCO3)cnc1N
Reaction time: 1 h
Yield: 199.6 %

Procedure:
To a solution of 3-nitro-5-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)pyridin-2-amine dihydrochloride (1.0 g, 2.8 mmol) in acetic acid (20 mL) and ethanol (20 mL) was added Pd/C (10% wt/wt, 0.5 g) and the reaction mixture was stirred under H2 (45 PSI) for 1 hour. The resulting pale yellow solution was filtered through Celite and the filtrate was concentrated to give 5-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)pyridine-2,3-diamine dihydrochloride (0.92 g, 100%) as a yellow powder. MS (EI) for C14H16N4O: 257.3 (MH+).
Reaction SMILES: [SH:1][C:2]1[NH:6][CH:5]=[N:4][N:3]=1.Cl[C:8]1[CH:9]=[CH:10][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:18][C:19]3[S:23][N:22]=[C:21]([CH3:24])[N:20]=3)[C:16]=2[N:17]=1.C(O[K])(C)(C)C.O>CN(C)C(=O)C>[N:4]1[N:3]=[C:2]([S:1][C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH:18][C:19]4[S:23][N:22]=[C:21]([CH3:24])[N:20]=4)[C:16]=3[N:17]=2)[NH:6][CH:5]=1
Reactant: Cc1nsc(Nc2ncnc3ccc(Cl)nc23)n1
Reactant: Sc1nnc[nH]1
Agent: CC(C)(C)O[K]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1nsc(Nc2ncnc3ccc(Sc4nnc[nH]4)nc23)n1
Temperature: 130 °C
Reaction time: 16 h
Yield: 2.4 %

Procedure:
3-Mercapto-4H-[1,2,4]triazole (54 mg; 0.54 mmol) and 100 mg (0.36 mmol) of (6-chloro-pyrido[3,2-d]pyrimidin-4-yl)-3-methyl-[1,2,4]thiadiazol-5-yl-amine were added to a solution of 80 mg (0.72 mmol) of tert-butoxy potassium in 3 ml of N,N-dimethylacetamide and the mixture was stirred at 130° C. for 16 hours. Water was added to the reaction solution and the mixture was extracted with chloroform. The organic layer was dried and concentrated and the resulting residue was purified by a reversed phase preparative HPLC (0.1% TFA-containing water:acetonitrile=90:10→10:90) to give 3 mg (yield: 2%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12]Br.[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:12][CH:11]([O:14][CH3:15])[O:10][CH3:9])[CH:3]=1
Reactant: Sc1cccc(Cl)c1
Reactant: COC(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(CSc1cccc(Cl)c1)OC
Reaction time: 16 h
Yield: 95.8 %

Procedure:
To a solution of 3-chlorothiophenol (2.4 g, 16.6 mmol) in THF (200 mL) at 0° C. is added bromoacetaldehyde dimethyl acetal (2.8 g, 16.6 mmol). To the solution is added sodium hydride (60% mineral oil dispersion, 0.70 g, 17.4 mmol). The reaction is stirred for 16 hours, and then is quenched by the addition of saturated NH4Cl (aq.). The solution is diluted with EtOAc. The organic layer is washed with a saturated NaCl (aq.). The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with hexanes. The title compound (3.7 g, 15.9 mmol) is obtained as an oil. 1H NMR (CDCl3, 300 MHz) δ7.32 (m, 1H), 7.25 (m, 1H), 7.12 (m, 1H), 4.47 (m, 1H), 3.07 (s, 3H), 3.02 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([C:17]([CH:19]1[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].O.[Li+].[OH-].Cl>O1CCOCC1>[CH3:25][CH:22]1[CH2:21][CH2:20][CH:19]([C:17]([N:10]([CH:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[C:9]2[CH:8]=[C:7]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])=[O:18])[CH2:24][CH2:23]1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCNCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC1CCC(C(=O)N(c2cc(-c3ccccc3)sc2C(=O)O)C2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.4 %

Procedure:
3-[(4-Methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (20 mg, 0.045 mmol) was dissolved in a 4:1 mixture of dioxane:H2O (0.5 ml) and then LiOH 1N (135 ul, 0.135 mmol) was added. After 4 hours of stirring at room temperature, the reaction mixture was acidified to pH 3-4 with a 10% solution of hydrochloric acid and then the solvents were removed. It was further diluted in cold water (1 ml) and filtered out to give 16 mg (84%) of 3-[(4-Methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-5-phenyl-thiophene-2-carboxylic acid (Compound 41).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])=O>>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:25]1[N:12]=[C:11]([C:9]2[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=2)[S:13][CH:24]=1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: COc1ccccc1C(=O)CBr
Product: COc1ccccc1-c1csc(-c2ccc(-c3ccccc3[N+](=O)[O-])c(C(=O)O)c2)n1
Yield: 67 %

Procedure:
4-[4-(2-Methoxy-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (183 mg, 67%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-bromo-2′-methoxyacetophenone (available from ASDI Incorporated) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.57 (d, J=1.9 Hz, 1H), 8.13-8.31 (m, 4H), 7.63-7.81 (m, 2H), 7.35-7.47 (m, 3H), 7.18 (d, J=8.3 Hz, 1H), 7.10 (t, J=7.6 Hz, 1H).
Reaction SMILES: Cl[Mg][CH2:3][C:4]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH2:5].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[C@@H:22]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15].[Cl-].[NH4+]>C1COCC1>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][C@@:23]([OH:27])([CH2:3][C:4](=[CH2:5])[CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:22]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)[C@@H]1c1ccccc1
Reactant: C=C(COc1ccccc1)C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C(COc1ccccc1)C[C@]1(O)CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-(chloromagnesio)-2-(phenoxymethyl)-1-propene in THF (0.91M, 3 ml) (Louw et. al., Tetrahedron, 48, 6087-6104, 1992, prepared from 2.74 mmol of 3-chloro-2-(phenoxymethyl)-1-propene) was slowly added to a solution of (2S)-1-tert-butoxycarbonyl-2-phenylpiperidin-3-one (Preparation 1) in THF (3 ml). The mixture was stirred at room temperature for 1 hours, then saturated aqueous ammonium chloride (20 ml) was added and the mixture was extracted with ethyl acetate (20 ml). The organic phase was washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane/ethyl acetate (100:0 increasing to 80:20) to give the title compound. 1H NMR (360MHz, CDCl3) δ7.48 (2H, d, J=6.9 Hz), 7.35-7.2 (6H, m), 6.9-6.88 (3H, m), 5.4 (1H, s), 5.15 (2H, d, J=13.7 Hz), 4.61 (2H, s), 4.11 (2H, m), 3.17 (1H, m), 2.66 and 2.59 (2H, AB d, J=14.0 Hz), 1.95 (2H, m), 1.79 (2H, m), and 1.36 (9H, s). m/z (ES+) 424 (M+1).