Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C.[F:28][C:29]1[C:34]([N+:35]([O-])=O)=[CH:33][C:32]([N:38]2[C:42](=[O:43])[N:41]([CH3:44])[N:40]=[N:39]2)=[C:31]([C@@H:45]2[CH2:47][C@H:46]2[C:48]([F:51])([F:50])[F:49])[CH:30]=1.CCO>[Pd].CC(O)=O>[NH2:35][C:34]1[C:29]([F:28])=[CH:30][C:31]([C@@H:45]2[CH2:47][C@H:46]2[C:48]([F:50])([F:49])[F:51])=[C:32]([N:38]2[C:42](=[O:43])[N:41]([CH3:44])[N:40]=[N:39]2)[CH:33]=1
Reactant: Cn1nnn(-c2cc([N+](=O)[O-])c(F)cc2[C@@H]2C[C@H]2C(F)(F)F)c1=O
Agent: [Pd]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1nnn(-c2cc(N)c(F)cc2[C@@H]2C[C@H]2C(F)(F)F)c1=O
Reaction time: 168 h
Yield: 80.2 %

Procedure:
Palladium on charcoal, wet (Degussa grade E101; 29 mg) was added to a mixture of trans-1-(4-fluoro-2-(2-(trifluoromethyl)cyclopropyl)-5-nitrophenyl)-4-methyl-1H-tetrazol-5(4H)-one (145 mg, 0.46 mmol), EtOH (10 mL) and AcOH (75 μL) under nitrogen. The mixture was evacuated and filled with hydrogen—this procedure was repeated another two times. The mixture was hydrogenated at 30 psi for 7 days (topping-off the hydrogen if necessary). More Pd on charcoal, wet (Degussa grade E101; 15 mg) was added and the mixture hydrogenated at 30 psi for another 10 days (LC/MS was used to monitor the progression of the reaction over the 2 week experiment). After complete reaction, the mixture was filtered through a small plug of Celite and the filter cake washed with EtOH (3×10 mL). The filtrate was concentrated under vacuum (dry-loaded on to silica) and purified by column chromatography on silica gel using EtOAc/hexane (1:4 to 2:3) as eluent to give the product (117 mg, 89%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[S:13])=[CH:7][CH:6]=1)=[O:4].[N:14]#[C:15][NH2:16].CC(C)([O-])C.[K+].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:26]>C(#N)C.C(O)(C)(C)C.O>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[S:13][C:24]([C:25](=[O:26])[C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[C:15]([NH2:16])[N:14]=2)=[CH:7][CH:6]=1
Reactant: N#CN
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: COC(=O)c1ccc(N=C=S)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(Nc2nc(N)c(C(=O)c3ccc(OC)cc3)s2)cc1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a mixture of 4-methoxycarbonylphenyl isothiocyanate (82 mg, 0.5 mmol) and cyanamide (23 mg, 0.55 mmol) in acetonitrile (5 mL), a solution of potassium tert-butoxide (61 mg, 0.55 mmol) in tert-butanol (5 mL) was added. After 30 minutes at ambient temperature, 2-bromo-4′-methoxy-acetophenone (115 mg, 0.5 mmol) was added. After 2 hours at ambient temperature, the reaction mixture was diluted with water (50 mL). The product was collected by filtration, rinsed with water and ethyl ether, and dried under vacuum to furnish a yellow solid, 172 mg (90% yield).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:22][OH:23])[C:8]([O:20][CH3:21])=[C:9]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][C@@H:25]1[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[F:34])[C@@H:26]1[OH:35].C(O)(=O)[C@@H]([C@H](C(O)=O)O)O>>[C:1]([C:5]1[CH:6]=[C:7]([CH2:22][OH:23])[C:8]([O:20][CH3:21])=[C:9]([NH:11][C:12]([NH:24][C@@H:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[F:34])[C@@H:26]2[OH:35])=[O:19])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1c(CO)cc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Reactant: N[C@@H]1Cc2c(F)cccc2[C@@H]1O
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Product: COc1c(CO)cc(C(C)(C)C)cc1NC(=O)N[C@@H]1Cc2c(F)cccc2[C@@H]1O
Yield: 32 %

Procedure:
Using 2,2,2-trichloroethyl 5-tert-butyl-3-(hydroxymethyl)-2-methoxyphenylcarbamate (0.100 g, 0.260 mmol) and (1S,2R)-2-amino-4-fluoro-2,3-dihydro-1H-indene-1-ol.L-tartaric acid salt (0.091 g, 0.286 mmol), the same reaction as in Example 1 (5th Step) was carried out to obtain 0.034 g of the captioned compound (32% yield).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)=[O:4].[N:13]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[C@@H:15]([O:21][C:22]([C:24]1([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23])[CH2:14]2.C(OCC)C>C(#N)C>[Cl-:1].[F:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3]([CH2:2][N+:13]23[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]2)[C@@H:15]([O:21][C:22]([C:24]2([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH2:14]3)=[O:4])=[N:7][CH:8]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Reactant: O=C(CCl)Nc1ccc(F)cn1
Solvent: CC#N
Solvent: CCOCC
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C1(c3ccccc3)CCCCCC1)C2)Nc1ccc(F)cn1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
2-Chloro-N-(5-fluoro-pyridin-2-yl)-acetamide (Example 17a) (31 mg) was added to a solution of 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 14e) (49 mg) in acetonitrile (1 mL). The reaction mixture was stirred at room temperature overnight. Diethyl ether (2 mL) was added to the reaction mixture and the white solid was filtered off, washed several times with diethyl ether and dried under vacuum at 40° C. to give the title compound (49 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1.[CH3:20][N:21]([CH3:31])[C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[CH3:20][N:21]([CH3:31])[C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:9][C:10]3([CH3:19])[CH3:18])=[CH:24][CH:23]=1
Reactant: CC1(C)CN(Cc2ccccn2)c2ccc(O)cc21
Reactant: CN(C)c1ccc(N=C=O)cc1
Product: CN(C)c1ccc(NC(=O)Oc2ccc3c(c2)C(C)(C)CN3Cc2ccccn2)cc1

Procedure:
The title compound was synthesized from 1-(2-pyridylmethyl)-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with 4-dimethylaminophenylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (5.2 mg, 16%) having the following characteristics.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:13])([CH3:3])[CH3:2].[CH2:14]=O.CNC.[CH2:19]=[CH:20][CH:21]=[CH2:22]>C(O)(C)C>[CH:1]([C:4]1[C:5](=[O:13])[C:6]([CH:10]([CH3:12])[CH3:11])=[CH:7][C:8]2([CH2:14][CH2:22][CH:21]=[CH:20][CH2:19]2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: C=CC=C
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: C=O
Agent: CNC
Solvent: CC(C)O
Product: CC(C)C1=CC2(C=C(C(C)C)C1=O)CC=CCC2

Procedure:
Following the same general procedure as in Example I, 50 mmols of 2,6-diisopropylphenol were reacted with 75 mmols of paraformaldehyde, 75 mmols of aqueous dimethylamine, and 210 mmols of 1,3-butadiene in 100 g of isopropyl alcohol at 190°-200° C. for five hours. The process resulted in the formation of 2,4-diisopropylspiro[5.5]undeca-1,4,8-trien-3-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9](C)([CH3:13])[CH2:10][CH:11]=[CH2:12].FC(F)(F)C1C=CC=CC=1C(Cl)=O.ClC1C=CC=CC=1C(Cl)=O.[Br:38][C:39]1[CH:47]=[CH:46][CH:45]=[CH:44][C:40]=1[C:41](Cl)=[O:42].IC1C=CC=CC=1C(Cl)=O>>[CH3:12][CH:11]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:41](=[O:42])[C:40]1[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=1[Br:38])[CH2:10][CH:9]([CH3:13])[CH3:8]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: Nc1ccccc1
Reactant: C=CCC(C)(C)C
Agent: O=C(Cl)c1ccccc1C(F)(F)F
Agent: O=C(Cl)c1ccccc1Cl
Agent: O=C(Cl)c1ccccc1I
Product: CC(C)CC(C)c1ccccc1NC(=O)c1ccccc1Br

Procedure:
Moreover, analogously to the examples mentioned above, the following compounds are obtained starting with aniline and 4,4-dimethyl-1-pentene and 2-(trifluoromethyl)benzoyl chloride, 2-chlorobenzoyl chloride, 2-bromobenzoyl chloride and 2-iodobenzoyl chloride, respectively:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCBr
Reactant: COC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)Cc1cccc(OCCCCl)c1
Reaction time: 24 h
Yield: 95.1 %

Procedure:
Methyl 3-hydroxyphenylacetate (87 g, 0.52 mol) was dissolved in acetone (500 mL). 1-Bromo-3-chloropropane (55 mL, 0.56 mol) was added, followed by potassium carbonate (73 g, 0.53 mol) and acetone (100 mL). The reaction was heated to reflux. After 24 hours, more 1-bromo-3-chloropropane (5 mL, 50 mmol) was added and the reaction refluxed for a further 24 hours. The mixture was cooled, filtered and rotary evaporated. The product was purified by passage over a short column of silica gel (650 g: 135 mm diameter column) eluted with hexane, and 30% ethyl acetate in hexane, to afford methyl 3-(3-chloro-propoxy)-phenylacetate (120 g, 95%) as an oil. 1H NMR (500 MHz, CDCl3) δ 7.25 (1H, dd), 6.93–6.85 (3H, m), 4.16 (2H, t), 3.79 (2H, t), 3.73 (3H, s), 3.62 (2H, s), 2.28 (2H, m).
Reaction SMILES: [H-].[Li+].[O:3]=[C:4]1[NH:9][CH:8]=[CH:7][N:6]=[C:5]1[C:10]([O:12][CH3:13])=[O:11].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.CCOC(C)=O>[CH2:14]([N:9]1[CH:8]=[CH:7][N:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]1=[O:3])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)c1ncc[nH]c1=O
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nccn(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
LiH was added to the solution of methyl 3-oxo-3,4-dihydropyrazine-2-carboxylate (0.10 g, 0.65 mmol) in DMF (3 mL) at 0° C. After stirring for 30 minutes, benzyl chloride (0.15 mL, 1.30 mmol) was added to the reaction mixture at the temperature, and the reaction was warmed to room temperature. After stirring for 3 days, the reaction mixture was diluted with EtOAc, quenched with ice water, extracted with EtOAc, dried over MgSO4, and concentrated to give the desired product, which was purified by silica gel flash column chromatography (2% MeOH in CH2Cl2, 0.102 g, 64%). 1H NMR (400 MHz, CDCl3) δ 7.35-7.40 (m, 6H), 7.29 (d, 1H), 5.14 (s, 2H), 3.99 (s, 3H).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[H-].[Na+].F[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17]>CN(C)C=O>[F:15][C:12]1[CH:13]=[CH:14][C:9]([O:4][CH2:3][CH2:2][CH2:1][OH:5])=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=1
Reactant: OCCCO
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)ccc1OCCCO
Reaction time: 2 h

Procedure:
To a stirred mixture of 30.4 parts of 1,3-propanediol and 90 parts of N,N-dimethylformamide were added 5.28 parts of a sodium hydride dispersion 50% at a temperature below 20° C. Stirring was continued for 2 hours at room temperature under nitrogen atmosphere. Then there were added dropwise 15.9 parts of 1,4-difluoro-2-nitrobenzene so that the temperature had been maintained below 30° C. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was poured onto water and the product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 21.5 parts 3-(4-fluoro-2-nitrophenoxy)propanol as a residue (intermediate 24).
Reaction SMILES: Cl.NC1C[C:10]2[C:5](=[CH:6][C:7]([Br:16])=[C:8]([NH2:15])[C:9]=2[N+:12]([O-:14])=[O:13])C1.[CH:17]([N:20]([CH:23]([CH3:25])[CH3:24])[CH2:21][CH3:22])([CH3:19])C.CCOC(C)=O.CO>CN(C=O)C>[NH2:15][C:8]1[C:9]([N+:12]([O-:14])=[O:13])=[C:10]2[C:5](=[CH:6][C:7]=1[Br:16])[CH2:24][CH:23]([N:20]1[CH2:17][CH2:19][CH2:22][CH2:21]1)[CH2:25]2
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1c(Br)cc2c(c1[N+](=O)[O-])CC(N)C2
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1c(Br)cc2c(c1[N+](=O)[O-])CC(N1CCCC1)C2
Temperature: 70 °C
Yield: 30.7 %

Procedure:
A mixture of 2,5-diamino-6-bromo-4-nitroindane hydrochloride (1.5 g, 5 mmol), 1-4-dibromobutane (1.3 g, 6 mmol) and diisopropylethylamine (1.9 g, 15 mmol) in DMF (100 mL) was heated at 70° C. for 24 h. The solvent was evaporated and the residue taken up in methylene chloride:water. The aqueous layer was basified with 1N NaOH and back extracted. The combined organic layers were dried over sodium sulfate, filtered and evaporated to give a dark syrup. The purified product (0.5 g) was obtained from column chromatography (4:1 EtOAc:methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH2:35]([N:37]([CH2:41]C)[CH2:38][CH2:39]O)[CH3:36].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][CH2:41][N:37]([CH2:38][CH3:39])[CH2:35][CH3:36])=[CH:18][CH:17]=1
Reactant: CCN(CC)CCO
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCN(CC)CCOC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Yield: 89.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-(diethylamino)-1-ethanol (31 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (66 mg, yield 71%).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]([CH:7]([CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([OH:10])=[O:9])=[CH:16][CH:15]=1
Reactant: O=C(O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(C(CC2CCCC2)C(=O)O)cc1
Yield: 135.4 %

Procedure:
A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid (100 mg, 0.38 mmol) in ethyl acetate (50 mL) was treated with 10% palladium on activated carbon. The reaction mixture was stirred under 60 psi of hydrogen gas at 25° C. for 16 h. The catalyst was then removed by filtration through a pad of celite and washed with ethyl acetate. The filtrate was concentrated in vacuo to afford 2-(4-amino-phenyl)-3-cyclopentyl-propionic acid (120 mg, 100%) as a white solid: mp 167-169° C.; EI-HRMS m/e calcd for C14H19NO2 (M+) 233.1415, found 233.1413.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][N:13]1[CH:22]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[S:31][CH3:32])[C:21]2[C:20](=[O:33])[CH2:19][CH2:18][CH2:17][C:16]=2[N:15]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:14]1=[O:44]>ClCCl>[CH3:32][S:31]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:23]=1[CH:22]1[C:21]2[C:20](=[O:33])[CH2:19][CH2:18][CH2:17][C:16]=2[N:15]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=2)[C:14](=[O:44])[N:13]1[CH3:12])[C:27]#[N:28])=[O:6]
Reactant: CSc1cc(C#N)ccc1C1C2=C(CCCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1S(C)=O
Reaction time: 0.67 h

Procedure:
3-chloroperoxybenzoic acid (77%, 15.3 mg, 0.068 mmol) is added at room temperature to a solution of 4-[3-methyl-2,5-dioxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4,5,6,7,8-octahydro-quinazolin-4-yl]-3-methylsulfanyl-benzonitrile (INTERMEDIATE 7, 41 mg, 0.076 mmol) in dichloromethane (1 mL), and the mixture is stirred for 40 min. The reaction mixture is concentrated under reduced pressure and purified by reversed phase HPLC (X-Bridge C18, gradient of acetonitrile in water, 0.1% NH4OH) yielding the two diasteromers of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:23][C:24]([NH:26][C:27](=[NH:30])SC)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([C:27](=[NH:30])[NH:26][C:24]([O:23][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:25])[CH2:14][CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSC(=N)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC1CCN(C(=N)NC(=O)OCc2ccccc2)CC1
Reaction time: 48 h
Yield: 33.4 %

Procedure:
7.8 g (36.4 mole) of 4-(N-tert-butyloxycarbonylaminomethyl) piperidine and 8.98 g (40 mmole) of N-benzyloxycarbonyl-S-methylisothiourea was mixed in 25 mL ethanol. The mixture was heated at 60°-70° C. for six hours and left at roomtemperature for two days. The solvent was evaporated and the residue was dissolved in CH2Cl2. The organic layer was washed twice with 0.3M KHSO4 and once with brine. The combined organic layer was dried (Na2SO4), filtered and evaporated. The crude product was purified by flash chromatography using a stepwise gradient of CH2Cl2 /MeOH (100/0, 97/3, 95/5, 90/10) as eluent to yield 5.22 g (37%) of the title product.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([S:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[C:5]([CH3:15])[N:6]2[CH2:11][C:12]([OH:14])=[O:13].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C1(C)C=CC=CC=1>CCOC(C)=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]>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([S:16][C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[N:34]3[CH2:33][CH2:32][N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:36][CH2:35]3)[N:6]([CH2:11][C:12]([OH:14])=[O:13])[C:5]=2[CH3:15])=[CH:18][CH:19]=1
Reactant: Cc1c(Sc2ccc(Cl)cc2)c2c(Br)cccc2n1CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1c(Sc2ccc(Cl)cc2)c2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc2n1CC(=O)O
Temperature: 110 °C

Procedure:
To a dry flask was charged the product from example 22 part (ii) (1 g), N-tert-Butoxycarbonylpiperazine (0.48 g), Pd2(dba)3 (3 mg), 2,2′-bis(diphenylphosphino)-1,1′-binapthyl Binap (10 mg) and toluene (5 ml). The reaction was heated to 110° C. for 1 hour then allowed to cool. The mixture was diluted with EtOAc, washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified using Flash column chromatography (eluent 25% EtOAc/Hexane then 50% EtOAc/Hexane/1% Acetic acid). Further purification using reverse phase preparative HPLC (eluent MeCN/NH3 (aq)) gave titled compound (0.021 g).
Reaction SMILES: [NH2:1][C:2]1[C:11](I)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[C:13]([C:15]1[CH:16]=[C:17]([NH:21][C:22]([C:24]2[N:28]([CH3:29])[N:27]=[C:26]([CH3:30])[CH:25]=2)=[O:23])[CH:18]=[CH:19][CH:20]=1)#[CH:14].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[C:11]([C:14]#[C:13][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]3[N:28]([CH3:29])[N:27]=[C:26]([CH3:30])[CH:25]=3)=[O:23])[CH:16]=2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(N)c(I)c1
Reactant: C#Cc1cccc(NC(=O)c2cc(C)nn2C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3cc(C)nn3C)c2)c1
Temperature: 60 °C
Yield: 78.3 %

Procedure:
A mixture of methyl 6-amino-5-iodonicotinate (111 mg, 0.40 mmol), N-(3-ethynylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (144 mg, 0.60 mmol), triethylamine (0.167 ml, 1.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (23 mg, 0.032 mmol) and triphenylphosphine (5.2 mg, 0.020 mmol) in 3.2 ml DMF at room temperature was degassed using vacuum and a balloon of H2, then copper(I)iodide (3.8 mg, 0.020 mmol) added. The reaction was heated at 60° C. for 1 hour 40 minutes, then partitioned between EtOAc and dilute brine. The EtOAc layer was dried with anhydrous Na2SO4 and rotary evaporated. The solid was recrystallized from EtOAc/hexane to give the title compound as a yellow-tan solid (122 mg, 78%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:19]=1[CH2:32][C:33](O)=[O:34])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C(OP(C#N)(OCC)=O)C>CN(C)C=O.O>[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:19]=1[CH2:32][C:33]([NH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:34])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NCCN1CCCCC1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1)NCCN1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
To a solution of 1-(2-aminoethyl)piperidine (368 mg) and 2,4-dibenzyloxyphenylacetic acid (1.0 g) in N,N-dimethylformamide are added triethylamine (1.2 ml) and diethylcyanophosphate (561 mg) in sequence. The mixture is stirred at room temperature for 30 minutes. To the reaction solution is added water and stirring carried out for 10 minutes. The product is extracted with dichloromethane. The dichloromethane layer is washed with water and dried over anhydrous sodium sulfate. The solvent is distilled off and the residue obtained is purified by silica gel column chromatography. The fractions eluted with dichloro-methane-methanol mixture (10 : 1) is recrystallized from dichloromethane-n-hexane mixture (1 : 5) to obtain 1-[2-(2,4-dibenzyloxyphenylacetyl)aminoethyl]piperidine (950 mg) in the colorless needle-like crystal form.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[S:20](Cl)(=[O:22])=[O:21]>>[C:1]([C:4]1[S:8][C:7]([NH:9][S:20]([C:13]2[C:14]([CH3:19])=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[Cl:11])(=[O:22])=[O:21])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)c1sc(N)nc1C
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Product: CC(=O)c1sc(NS(=O)(=O)c2c(C)cc(Cl)cc2Cl)nc1C

Procedure:
The title compound was prepared from 5-acetyl-2-amino-4-methylthiazole and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white-yellow solid (28.4 mg) with purity >90%. MS (pos) m/z 379.1, 381.1.