Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:19][C:20]([NH2:22])=[S:21]>C(O)C>[NH2:22][C:20]1[S:21][C:2]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=2)=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:19]=1
Reactant: NC(N)=S
Reactant: CSc1nccc(C(Br)C(=O)c2ccccc2)n1
Solvent: CCO
Product: CSc1nccc(-c2sc(N)nc2-c2ccccc2)n1

Procedure:
A solution of 2-bromo-2-(2-methylthio-pyrimidin-4-yl)-1-phenyl-ethanone (45 g, 0.14 mol) and thiourea (21.2 g, 0.28 mol) in ethanol (300 ml) is heated at reflux for 4 hours. On cooling the product starts to crystallize as salt. It is filtered with suction and washed with ether. The free amine is obtained by partitioning of the product between an aqueous solution of sodium bicarbonate and a 1:1 mixture of ethyl acetate and tetrahydrofuran, followed by drying of the organic phase over magnesium sulfate, filtering and evaporation of the solvents. The 4-(2-amino-4-phenyl-thiazol-5-yl)-2-methylthio-pyrimidine is obtained in crystalline form, m.p. 208–209° C.
Reaction SMILES: C(OCC)(=O)C.[ClH:7].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:23][C:22]3[C:21](=[O:24])[N:20]([CH2:25][CH2:26][C:27]4[CH:47]=[CH:46][C:30]([CH2:31][N:32]5[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][C:33]5=[O:45])=[CH:29][CH:28]=4)[CH:19]=[N:18][C:17]=3[CH:16]=2)=[CH:11][CH:10]=1>>[ClH:8].[ClH:7].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[S:23][C:22]3[C:21](=[O:24])[N:20]([CH2:25][CH2:26][C:27]4[CH:28]=[CH:29][C:30]([CH2:31][N:32]5[CH2:37][CH2:36][NH:35][CH2:34][C:33]5=[O:45])=[CH:46][CH:47]=4)[CH:19]=[N:18][C:17]=3[CH:16]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(CCn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)cc2)C(=O)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1CNCCN1Cc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4N Hydrogen chloride-ethyl acetate solution (6 ml) was added to the compound (75 mg) obtained in Example 37, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate to give the title compound (72 mg) as a colorless powder.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17](=[O:26])[C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])=[CH:9]1.Cl[C:28]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[C:29]([C:32]#[N:33])[C:30]#[N:31]>CCO>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17](=[O:26])[C:18]([N:20]2[CH2:21][CH2:22][N:23]([C:28]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[C:29]([C:32]#[N:33])[C:30]#[N:31])[CH2:24][CH2:25]2)=[O:19])=[CH:9]1
Reactant: N#CC(C#N)=C(Cl)c1ccccc1
Reactant: O=C(C(=O)N1CCNCC1)c1c[nH]c2ccccc12
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#CC(C#N)=C(c1ccccc1)N1CCN(C(=O)C(=O)c2c[nH]c3ccccc23)CC1
Reaction time: 16 h

Procedure:
Triethyl amine (1 ml) was added into a solution of 1-(1H-indol-3-yl)-2-(piperazin-1-yl)ethane-1,2-dione (150 mg) and 2-(chloro(phenyl)methylene)malononitrile (110 mg) in EtOH (20 ml). After 16 hours at 115° C., the reaction mixture was cooled down. Then the solvents were removed to offer a residue which was purified using Shimadzu automated preparative HPLC System to afford 2-((4-(2-(1H-indol-3-yl)-2-oxoacetyl)piperazin-1-yl)(phenyl)methylene)malononitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[CH3:16][C:17](=O)[CH2:18][CH2:19][CH3:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:16][C:17]1([CH2:18][CH2:19][CH3:20])[NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[S:4][C:3]=2[C:13](=[O:14])[NH:15]1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Reactant: CCCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCC1(C)NC(=O)c2sc(-c3ccncc3)cc2N1
Temperature: 70 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.108 g, 0.500 mmol), 2-pentanone (3.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (3.0 mL) was stirred for 2 h at 70° C. then for 3 h at 80° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate-tetrahydrofuran (2:1, 150 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. The oil was triturated with dichloromethane, and the precipitate was collected by filtration to afford the title compound (0.0632 g, 44%) as a yellow solid:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[F:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:2]([O:15][C:12]1[CH:13]=[CH:14][C:9]([Br:8])=[C:10]([F:16])[CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCOc1ccc(Br)c(F)c1

Procedure:
A solution of 1-bromohexane (9.33 g) in acetone (20 ml) is added dropwise to a stirred mixture of 4-bromo-3-fluorophenol (9.00 g) and potassium carbonate (13.5 g) in acetone 75 ml) at room temperature. The stirred mixture is heated under reflux for 21 h (i.e. until glc analysis revealed a complete reaction). The product is extracted into ether twice, and the combined ether extracts are washed with water, 10% sodium hydroxide, water and dried (MgSO4). The solvent is removed under vacuo and the residue is distilled (bp 100°-105° C. at 0.1 mm Hg) to yield a colourless liquid.
Reaction SMILES: Cl.[CH3:2][C@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CC(=O)CC>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][N:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[CH3:2])[CH3:22]
Reactant: CCOC(=O)CCCBr
Reactant: C[C@H]1CCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCN1CCC[C@@H]1C
Temperature: 25 °C
Yield: 100.4 %

Procedure:
(S)-2-methyl-pyrrolidine hydrochloride (0.8 g, 6.6 mmol, 1.1 eq) was dissolved in 2-butanone (20 mL) and potassium carbonate (1.7 g, 12.6 mmol, 2.1 eq) was added. Ethyl 4-bromobutyrate (0.86 mL, 6.0 mmol, 1.0 eq) was added and the reaction mixture was refluxed for 2 days. The mixture was allowed to cool to room temperature and any solid present was filtered off and washed with ether. The filtrate was concentrated under reduced pressure to give 1.20 g of the title compound (yield 99%) which was used in the next step without further purification.
Reaction SMILES: [I:1][C:2]1[C:3]([NH:17]C(=O)OC)=[CH:4][C:5]([NH:8][C:9]([CH3:16])([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:10])=[N:6][CH:7]=1.[OH-].[K+].C(O)C>O>[I:1][C:2]1[C:3]([NH2:17])=[CH:4][C:5]([NH:8][C:9]([CH3:10])([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:16])=[N:6][CH:7]=1
Reactant: COC(=O)Nc1cc(NC(C)(C)CC(C)(C)C)ncc1I
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)CC(C)(C)Nc1cc(N)c(I)cn1
Temperature: 80 °C
Yield: 81 %

Procedure:
A mixture of methyl {5-iodo-2-[(2,4,4-trimethylpentan-2-yl)amino]pyridin-4-yl}carbamate (1.3 g, 3.2 mmol), potassium hydroxide (898 mg, 16 mmol), ethanol (10 mL) and water (10 mL) was heated at 80° C. for 2 hours. Ethanol was removed under vacuum, and the residue was stirred in water. The precipitated solid was filtered under vacuum and dried to yield 900 mg (81%) of 5-iodo-N2-(2,4,4-trimethylpentan-2-yl)pyridine-2,4-diamine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH2:12][CH2:13][C:14]1[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20]([OH:22])=O)=[CH:16][CH:15]=1)=[O:4].[Cl:25][C:26]1[CH:35]=[CH:34][C:29]([CH2:30][NH:31][CH2:32][CH3:33])=[CH:28][CH:27]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.O>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:31]([CH2:32][CH3:33])[C:20](=[O:22])[CH2:19][O:18][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][S:11][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:3]([O:2][CH3:1])=[O:4])=[CH:24][CH:23]=2)=[CH:34][CH:35]=1
Reactant: CCNCc1ccc(Cl)cc1
Reactant: COC(=O)c1ccccc1SCCc1ccc(OCC(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1ccc(Cl)cc1)C(=O)COc1ccc(CCSc2ccccc2C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 29.6 %

Procedure:
[4-(2-{[2-(Methoxycarbonyl)phenyl]thio}ethyl)phenoxy]acetic acid (0.200 g, 0.577 mmol) was dissolved in DMF (10 ml), N-(4-chlorobenzyl)-N-ethylamine (0.108 g, 0.635 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.204 g, 0.635 mmol) and N-ethyl-N,N-diisopropylamine (0.157 g, 1.212 mmol) were added. The solution was stirred overnight at room temperature. Water (100 ml) was added and the water phase was extracted with diethyl ether (3×20 ml). The organic phase was washed with Na2CO3 (3×20 ml, aq) and HCl (0.5 M, 2×, 10 ml). The organic layer was dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by flash chromatography (started with isocratic heptane/EtOAc 30/70 and then the EtOAc concentration was increased to 100%, (silica gel 60 0.004-0.063 mm). The product containing fractions were pooled and the solvent was removed by evaporation to give 0.085 g of methyl 2-{[2-(4-{2-[(4-chlorobenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)ethyl]thio}benzoate (yield 29.6%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH2:13][N:14]3C(OC(C)(C)C)=O)[CH2:11]2)=[N:7][CH:8]=1.Cl>CCOC(C)=O.O1CCOCC1>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH2:13][NH:14]3)[CH2:11]2)=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@@H](Nc3ccc(C(F)(F)F)cn3)[C@@H]1C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(N[C@@H]2C[C@@H]3CN[C@H]2C3)nc1
Reaction time: 1 h
Yield: 128.4 %

Procedure:
xHCl. To the title compound of step A (198 mg, 0.554 mmol) in EtOAc (3 mL) was added 4M HCl in dioxane (14 mL). After 1 h, the reaction was concentrated to give the title compound of step B (183 mg), which was used without further purification. MS (ESI) mass calcd. for C12H14F3N3, 257.1. m/z found 258.1 [M+H]+.
Reaction SMILES: [P:1]([OH:31])([OH:30])([O:3][C:4]1[CH:9]=[C:8]([CH2:10][S:11]([CH:14]=[CH:15][C:16]2[C:21]([O:22][CH3:23])=[CH:20][C:19]([O:24][CH3:25])=[CH:18][C:17]=2[O:26][CH3:27])(=[O:13])=[O:12])[CH:7]=[CH:6][C:5]=1[O:28][CH3:29])=[O:2].C(Br)(Br)(Br)Br.[CH2:37](N(CC)CC)[CH3:38].P([O-])(OCC)O[CH2:46][CH3:47]>C(#N)C>[P:1]([O:31][CH2:46][CH3:47])([O:30][CH2:37][CH3:38])([O:3][C:4]1[CH:9]=[C:8]([CH2:10][S:11](/[CH:14]=[CH:15]/[C:16]2[C:17]([O:26][CH3:27])=[CH:18][C:19]([O:24][CH3:25])=[CH:20][C:21]=2[O:22][CH3:23])(=[O:13])=[O:12])[CH:7]=[CH:6][C:5]=1[O:28][CH3:29])=[O:2]
Reactant: CCN(CC)CC
Reactant: COc1cc(OC)c(C=CS(=O)(=O)Cc2ccc(OC)c(OP(=O)(O)O)c2)c(OC)c1
Reactant: CCOP([O-])OCC
Agent: BrC(Br)(Br)Br
Solvent: CC#N
Product: CCOP(=O)(OCC)Oc1cc(CS(=O)(=O)/C=C/c2c(OC)cc(OC)cc2OC)ccc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenyl dihydrogen phosphate (1.9 g, 4.8 mmol) in acetonitrile (24 mL) at room temperature, was added carbon tetrabromide (1.94 g, 1.22 eq) and triethylamine (0.728 g, 1.5 eq). The resulting mixture was stirred for 10 minutes and than cooled to 0° C. in an ice-water bath. Diethyl phosphite (1.51 g, 1.2 eq) dissolved in acetonitrile (16 mL) was added dropwise to the cooled reaction mixture. The reaction mixture was stirred for 2 h and monitored by TLC. The reaction was terminated by dropwise addition of aqueous potassium dihydrogen phosphate (10 mL, 0.5 M). The resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic extract was dried (Na2SO4) and concentrated in vacuo to yield the desired product.
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[N+:6]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1)([O-:8])=[O:7].N1C=CC=CC=1>O1CCCC1>[Br:1][CH2:2][C:3]([O:14][CH2:13][C:12]1[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:16][CH:15]=1)=[O:4]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: O=C(Cl)CBr
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(CBr)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
Bromoacetyl chloride (113 g) was dropwise added to a stirred solution of 4-nitrobenzyl alcohol (9.2 g) and pyridine (10 ml) in dry tetrahydrofuran (100 ml) at 0° C. over 50 minutes. The mixture was stirred at 0° to 5° C. for 30 minutes, and evaporated in vacuo. The residue was dissolved in a mixture of chloroform (70 ml) and water (20 ml), and then the organic layer was separated. The organic layer was washed with a diluted aqueous hydrochloric acid and water in turn, and then dried over anhydrous magnesium sulfate. The solution was evaporated in vacuo, and the residue was recrystallized from methanol to give crystals (6.74 g) of 4-nitrobenzyl bromoacetate.
Reaction SMILES: [OH-].[Na+].CO.[C:5]([C:7]([CH3:19])([CH3:18])[CH:8]([OH:17])[CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])#[N:6]>C1(C)C=CC=CC=1>[C:5]([C:7]([CH3:19])([CH3:18])[CH:8]([OH:17])[CH2:9][C:10]([OH:12])=[O:11])#[N:6]
Reactant: CC(C)(C)OC(=O)CC(O)C(C)(C)C#N
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C#N)C(O)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To the reaction mixture obtained by the method of Example 2 were added 10% aqueous sodium hydroxide solution (113.8 g) and methanol (20 mL), and the mixture was stirred overnight at room temperature. The disappearance of tert-butyl 4-cyano-3-hydroxy-4-methylpentanoate was confirmed by GC. Toluene (50 mL) was added, and the mixture was stirred and then partitioned to remove the toluene layer. 20% Aqueous hydrochloric acid solution (67.5 g) was added to the aqueous layer to adjust its pH to an acidic one (ca. 1-2), and the mixture was extracted twice with a mixed solution (150 mL) of ethyl acetate-n-butanol (1:1). The layer of the mixed solution was concentrated under reduced pressure to give 4-cyano-3-hydroxy-4-methylpentanoic acid (18.75 g) as an oil. The yield was 84% relative to tert-butyl 4-cyano-3-hydroxy-4-methylpentanoate, but crystallization did not occur.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][C:24](=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH2:31][CH2:30][N:29]4[C:38]([CH:41]=[O:42])=[CH:39][N:40]=[C:28]34)[CH2:23][CH2:22]2)=[CH:15][CH:14]=1.[O-:43][C:44]#N.[Na+].C(O)(=O)C>CO.[O-2].[O-2].[Mn+4]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][C:24](=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH2:31][CH2:30][N:29]4[C:38]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][N:40]=[C:28]34)[CH2:25][CH2:26]2)=[CH:15][CH:14]=1
Reactant: O=Cc1cnc2n1CCc1ccccc1C2=C1CCN(CCc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Reactant: N#C[O-]
Agent: [Mn+4]
Agent: [Na+]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cnc2n1CCc1ccccc1C2=C1CCN(CCc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Temperature: 25 °C
Yield: 87.9 %

Procedure:
A mixture of compound 4 (164 g), sodium cyanate (80 g) and manganese dioxide (500 g) in methanol (5.5 l) was stirred at room temperature. Ethanoic acid (122 g) was added dropwise and the resulting reaction mixture was stirred and refluxed overnight. The reaction mixture was filtered over dicalite, and the filter residue was rinsed with CH3OH/CH2Cl2. The filtrate was evaporated. The residue was partitioned between DCM and aqueous K2CO3 solution. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from ACN. The precipitate was filtered off and dried, yielding 152 g (87%) of methyl 6,11-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]-benzazepine-3-carboxylate (compound 6, mp. 179.3° C.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]([F:35])([F:34])[C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:29][C@@H:28]3[C@@H:30]([NH2:33])[CH2:31][CH2:32][C@@H:27]3[CH2:26]2)=[N:23][CH:24]=1.[CH2:36](N1C[C@@H]2[C@@H](N)CC[C@@H]2C1)C1C=CC=CC=1>>[CH3:36][C:11]([CH3:12])([CH3:13])[CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:14](=[O:16])[NH:33][C@@H:30]1[C@@H:28]2[C@@H:27]([CH2:26][N:25]([C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:34])[F:35])=[CH:24][N:23]=3)[CH2:29]2)[CH2:32][CH2:31]1
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cn3)C[C@@H]21
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Product: CC(C)(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cn3)C[C@@H]21

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-L-neopentylglycine for N-(tert-butoxycarbonyl)-L-leucine and (3aR,4S,6aS)-2-(5-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine from Step B for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 221: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.52 (s, 1H), 7.81 (d, J=5.8, 1H), 7.60 (dd, J=8.9, 2.5, 1H), 7.07 (d, J=7.0, 1H), 6.35 (d, J=8.9, 1H), 4.53 (td, J=8.3, 4.7, 1H), 4.30-4.18 (m, 1H), 3.72 (dd, J=11.3, 3.5, 1H), 3.65 (dd, J=11.3, 7.6, 1H), 3.57 (dd, J=11.1, 7.8, 1H), 3.31 (dd, J=11.2, 3.9, 1H), 2.80-2.67 (m, 2H), 2.10 (ddd, J=19.9, 13.5, 5.8, 2H), 1.93 (td, J=13.1, 7.7, 1H), 1.74 (dd, J=14.3, 8.0, 1H), 1.64 (dq, J=12.9, 7.8, 1H), 1.50 (s, 9H), 1.44-1.33 (m, 1H), 1.00 (s, 9H); MS (ESI+) m/z 499 (M+H)+.
Reaction SMILES: C1(C2NN=C(N[C:10]3[N:15]=[C:14]([NH:16][C@H:17](C4C=CC(F)=CC=4)C)[C:13]([CH2:26]O)=C[C:11]=3[F:28])C=2)CC1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:41]=[N+:42]=[N-:43].[Na+]>C(Cl)Cl>[N:41]([CH:13]([C:14]1[N:15]=[CH:10][C:11]([F:28])=[CH:17][N:16]=1)[CH3:26])=[N+:42]=[N-:43]
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CO)c1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(N=[N+]=[N-])c1ncc(F)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
A round-bottom flask containing 1-(5-fluoropyrimidin-2-yl)ethanol (Method 74, 0.79 g, 5.55 mmol) was charged with triethylamine (0.67 g, 6.66 mmol) and anhydrous DCM (10 ml). The solution was cooled to 0° C., and methanesulfonyl chloride (0.70 g, 4.1 mmol) was added dropwise. The resulting mixture was allowed to stir at room temperature for 2 hours, at which point the volatile components were removed using a rotary evaporator. The residue was dissolved in DMF (15 ml) and treated with sodium azide (0.72 g, 11.1 mmol). The resulting mixture was stirred at room temperature for 60 hours. It was then partitioned between EtOAc and brine. The organic layer was obtained, dried (Na2SO4), and evaporated to dryness. The crude material was purified by silica gel chromatography (by ISCO Combiflash with gradient EtOAc and hexanes) to afford the title compound as a colourless oil (0.60 g, 65% yield over two steps). GC-MS, 167 (M), 138 (M-N2), 125 (M-N3); 1H NMR (CDCl3) δ 8.60 (s, 2H), 4.60 (m, 1H), 1.65 (d, 3H).
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18](=[O:27])[NH:19][O:20][CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:7]=[CH:6][C:5]=1[F:28].[OH-].[Li+]>C1COCC1.O>[CH:22]1([CH2:21][O:20][NH:19][C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][CH2:10][C:8]2[CH:7]=[CH:6][C:5]([F:28])=[C:4]([CH:9]=2)[C:3]([OH:29])=[O:2])=[O:27])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COC(=O)c1cc(CNc2ccccc2C(=O)NOCC2CCCC2)ccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(CNc2ccccc2C(=O)NOCC2CCCC2)ccc1F
Temperature: 60 °C
Reaction time: 15 h
Yield: 77.1 %

Procedure:
5-[(2-Cyclopentylmethoxycarbamoyl-phenylamino)-methyl]-2-fluoro-benzoic acid methyl ester (Example 493, 511 mg) was dissolved in THF (15 ml) and water (5 ml). Lithium hydroxide (122 mg) was added and the mixture was heated to 60° C. The reaction mixture was stirred at this temperature for 15 hours, cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water and 1M hydrochloric acid was added until a precipitate formed. The solid material was isolated by filtration and washed with water and dried under high vacuum and gave the title compound (380 mg) as a white powder. 13C-NMR (DMSO-d6) δ 166.9, 165.0, 160.0, 148.4, 135.9, 133.0, 132.4, 130.1, 128.0, 119.1, 116.9, 114.6, 113.4, 111.5, 79.4, 44.8, 37.6, 28.9, 24.9.
Reaction SMILES: [CH3:1][C:2]([C:4]#[CH:5])=[CH2:3].[Li]CCCC.[CH:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:3][C:2](=[CH2:1])[C:4]#[C:5][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:18]
Reactant: O=Cc1ccccc1
Reactant: C#CC(=C)C
Agent: [Li]CCCC
Product: C=C(C)C#CC(O)c1ccccc1
Yield: 93.9 %

Procedure:
2-Methylbut-1-en-3-yne (3.45 g, 52.19 mmol), nBuLi (36.0 mL, 57.6 mmol) and benzaldehyde (6.642 g, 62.63 mmol) were used according to the general method mentioned above. Purification of the resulting clear yellow-brown crude product yielded the pure product as a clear yellow-brown oil (8.442 g, 49.02 mmol, 93.9%): Rf 0.72 (hexanes/Et2O, 4:1); 1H NMR (300 MHz, CDCl3) δ 7.49-7.69 (m, 2H, H-8), 7.30-7.49 (m, 3H, H-9, 10), 5.58 (d, J=6.2 Hz, 1H, H-1), 5.37 (bs, 1H, H-5), 5.28 (p, J=1.5 Hz, 1H, H-5), 2.43 (d; J=6.2 Hz, 1H, —OH), 1.93 (bs, 3H, H-10); 13C NMR (300 MHz, CDCl3) δ 140.6 (C-7), 128.6 (C-9), 128.3 (C-10), 126.6 (C-8), 126.1 (C-4), 126.6 (C-5), 87.8 (C-2/3), 87.7 (C-2/3), 64.9 (C-1), 23.3 (C-6); HRMS calcd for C12H12O (M+) 172.0888. found 172.0885.
Reaction SMILES: [CH:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[N+:20]([CH3:23])([O-:22])=[O:21]>CCOCC>[N+:20]([CH2:23][CH:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([O-:22])=[O:21]
Reactant: CCCCCCCCCCCCCCCCCC=O
Reactant: C[N+](=O)[O-]
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCC(O)C[N+](=O)[O-]
Yield: 88.3 %

Procedure:
To a solution of octadecanal (9a) (2.22 g, 8.28 mmol) and nitromethane (1.52 g, 24.90 mmol) in anhyd Et2O (10 mL), Amberlyst A-21 (1.2 g) was added at r.t. The mixture was stirred and heated at reflux for 48 h. After removal of the Amberlyst A-21 by filtration, the filtrate was concentrated under reduced pressure. Flash column chromatography of the residue (EtOAc/petroleum spirit, 5/95) gave 1-nitrononadecan-2-ol (10a) (2.41 g, 89%) as a white solid; mp 55-56° C.