Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21](C(OC)=O)[C:22](OC)=[O:23])=[C:17]([N+:30]([O-])=O)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Sn].Cl>C(O)C>[NH:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:16]=[C:17]3[C:18]([CH2:21][C:22](=[O:23])[NH:30]3)=[CH:19][CH:20]=2)[CH2:10][CH2:9]1
Reactant: COC(=O)C(C(=O)OC)c1ccc(C=C2CCN(C(=O)OC(C)(C)C)CC2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Sn]
Solvent: CCO
Product: O=C1Cc2ccc(C=C3CCNCC3)cc2N1
Reaction time: 18 h
Yield: 80.5 %

Procedure:
Dimethyl 2-[4-(1-tert-butoxycarbonylpiperidin-4-ylidenemethyl)-2-nitrophenyl]malonate (1.65 g; 3.7 mmol) was dissolved in ethanol (50 ml), tin powder (1.31 g; 11 g atom) was added followed by conc. hydrochloric acid (10 ml) and the mixture heated at reflux for 3 h before being left to stand at ambient temperature for 18 h. Evaporated to dryness under reduced pressure, water added to the residue and the insoluble material removed by filtration. The filtrate and washings were combined and evaporated to dryness under reduced pressure and this residue extracted with hot methanol. The insoluble materials were further extracted with hot ethanol, the extracts combined and evaporated to dryness under reduced pressure to give the title compound (680 mg; 81%) as a brown foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][CH:15]=[CH:14]4)=[CH:9][N:8]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.[CH:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:31].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:35]5[CH:36]=[CH:37][C:32]([CH:30]=[O:31])=[CH:33][CH:34]=5)[CH:3]=4)[N:8]([S:20]([C:23]4[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=4)(=[O:21])=[O:22])[CH:9]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(Br)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(-c4ccc(C=O)cc4)cnc32)cc1
Yield: 88.5 %

Procedure:
Intermediate B (4.04 g) and 4-formylphenylboronic acid (1.56 g) were suspended in 150 mL of acetonitrile and treated with 150 mL of 1 M sodium carbonate solution. To this was added dichloro-bis-(triphenylphosphine)-palladium(II) (608 mg) and the mixture was heated at reflux for 2.5 hours. The reaction mixture was filtered and the residue washed with EtOAc, the filtrates were combined and washed with water, and brine, dried over MgSO4, and concentrated. MPLC silica gel chromatography eluting with 0-30% EtOAc in hexane, produced 3.77 g of the title compound (M+H 492).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].Br[CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C1C=CC=CC=1>[CH2:1]([N:4]([CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCCNCCC
Reactant: CCOC(=O)C(Br)C(=O)OCC
Solvent: c1ccccc1
Product: CCCN(CCC)C(C(=O)OCC)C(=O)OCC
Yield: 87 %

Procedure:
Di-n-propylamine (15.2 g) and diethyl bromomalonate (17.9) were dissolved in dry benzene (90 ml), and the mixture was heated under reflux for 7 hours with stirring. The reaction mixture was worked up in the same way as in Example 2, (1). The resulting residue was chromatographed on a silica gel column using benzene/ethyl acetate (20:1) as an eluent to give 16.9 g (yield 87%) of diethyl di-n-propylaminomalonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]([NH:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[O:15])=[C:5]2[OH:25].C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:5]2[OH:25]
Reactant: Cn1c(=O)c(C(=O)NCC(=O)OC(C)(C)C)c(O)c2cc(Cl)ncc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)c(C(=O)NCC(=O)O)c(O)c2cc(Cl)ncc21

Procedure:
The title compound was prepared similarly to the procedure described for Example 1 (g), by treatment of tert-butyl 2-(6-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxamido)acetate (Example 105 (i)) with TFA. MS (ESI, pos. ion) m/z: 310 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.46 (s, 1 H), 8.91 (s, 1 H), 7.94 (s, 1 H), 4.15 (d, J=5.5 Hz, 2 H), 3.69 (s, 3 H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([O:24]C)=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)=[C:5]([CH3:26])[CH:4]=1)#[N:2].O[Li].O.C1COCC1>O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)=[C:5]([CH3:26])[CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccnc(-n2nccc2OCc2ccc(C#N)cc2C)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C#N)ccc1COc1ccnn1-c1cc(C(=O)O)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Charged methyl 2-[5-[(4-cyano-2-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate (112 mg, 0.32 mmol), LiOH.H2O (14 mg, 0.32 mmol), water (2 mL) and THF (2 mL) to a flask, then the mixture was stirred at room temperature for 30 min, added another 2 mL water, and the mixture was washed with ethyl acetate twice (6 mL×2). The aqueous phase was acidified with 1N HCl (pH=3), filtered and dried the solid to give the title compound. 1H NMR (300 MHz, DMSO-d6): δ 2.37 (3H, s), 5.37 (2H, s), 6.10 (1H, d, J=1.8 Hz), 7.62 (1H, d, J=1.5 Hz), 7.70-7.77 (4H, m), 8.08 (1H, s), 8.68 (1H, d, J=5.4 Hz). [M+H] Calc'd for C18H14N4O3, 335. Found, 335.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:13])[CH:9]=2)[N:4]=1)#[N:2].[Cl-].[N+:15]([C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][CH:19]=1)([O-:17])=[O:16].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.C(Cl)Cl>[C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][C:19]3[CH:20]=[CH:21][C:22]([C:24]([F:27])([F:25])[F:26])=[CH:23][C:18]=3[N+:15]([O-:17])=[O:16])[CH:9]=2)[N:4]=1)#[N:2]
Reactant: O=[N+]([O-])c1cccc(C(F)(F)F)c1
Reactant: N#Cc1ccc2cc(O)ccc2n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: N#Cc1ccc2cc(Oc3ccc(C(F)(F)F)cc3[N+](=O)[O-])ccc2n1
Temperature: 100 °C
Yield: 35 %

Procedure:
The mixture of 2-cyano-6-hydroxyquinoline (0.50 g, 2.94 mmol), 2-nitro-4-trifluoromethylbenzene chloride (0.67 g, 2.94 mmol) and potassium carbonate (0.41 g, 2.97 mmol) in 30 ml of DMSO was heated to 100° C. for 30 min. Upon cooling to room temperature, the mixture was poured into 30 ml of cold water and exacted three times with methylene chloride. The combined organic layer was washed with water and dried over magnesium sulfate. The product was purified by flash chromatography using heptane/methylene chloride (1:2) as eluent in a yield of 35%.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[O:8][C:7]([CH2:9][S:10][CH2:11][CH2:12][NH2:13])=[CH:6][CH:5]=1.[C:14]([NH:16][C:17](SC)=[N:18][CH3:19])#[N:15]>>[C:14]([NH:16][C:17]([NH:13][CH2:12][CH2:11][S:10][CH2:9][C:7]1[O:8][C:4]([CH2:3][NH:2][CH3:1])=[CH:5][CH:6]=1)=[N:18][CH3:19])#[N:15]
Reactant: CNCc1ccc(CSCCN)o1
Reactant: CN=C(NC#N)SC
Product: CN=C(NC#N)NCCSCc1ccc(CNC)o1
Yield: 38.6 %

Procedure:
A mixture of 2-[[[5-(methylamino)methyl-2-furanyl]methyl]thio]ethanamine (2.0 g) and N-cyano-N'-methylcarbamimidothioic acid, methyl ester (1.25 g) was heated on a steam bath for 6.5 hr. Vacuum was applied at regular intervals to remove methanethiol. The crude product was purified by column chromatography Rf 0.65 (silica/methanol:ammonia 79:1) to give N-cyano-N'-[2-[[[5-(methylamino)methyl-2-furanyl]methyl]thio]ethyl]-N"-methylguanidine (1.05 g) m.p. 81°-85°.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:17][CH:16]=2)=[CH:13][C:12]([CH2:29][N:30]([CH3:40])[C:31](=[O:39])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:11][CH:10]=1)C1C=CC=CC=1.I[Si](C)(C)C.Cl.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C.C(#N)C>[O:27]=[C:25]1[NH:24][C:23](=[O:28])[CH:22]([CH2:21][C:18]2[CH:17]=[CH:16][C:15]([C:14]3[C:9]([OH:8])=[CH:10][CH:11]=[C:12]([CH2:29][N:30]([CH3:40])[C:31](=[O:39])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:13]=3)=[CH:20][CH:19]=2)[S:26]1
Reactant: CCCCCCCC(=O)N(C)Cc1ccc(OCc2ccccc2)c(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCCCCC(=O)N(C)Cc1ccc(O)c(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Temperature: 50 °C
Yield: 71.1 %

Procedure:
250 mg (0.45 mmol) of N-[6-benzyloxy-4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyloctanamide, 4 ml of acetonitrile and 130 mg (0.65 mmol) of iodotrimethylsilane are introduced into a round-bottomed flask under a stream of nitrogen. The reaction medium is heated, at 50° C. for 3 hours. At room temperature, 450 μl of 1N hydrochloric acid and 450 μl of tetrabutylammonium fluoride are added. The medium is then diluted with ethyl acetate and washed with sodium thiosulfate solution. After separation of the phases once settling has taken place, the organic phase is dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with an ethyl acetate/heptane mixture (6/4). 150 mg (72%) of N-[4′-(2,4-dioxo-thiazolidin-5-ylmethyl)-6-hydroxybiphenyl-3-ylmethyl]-N-methyloctanamide are obtained in the form of a yellowish foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:12][C:11](=[O:21])[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cu][C:23]#[N:24]>CN(C)C=O>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:12][C:11](=[O:21])[N:10]=2)=[CH:3][C:2]=1[C:23]#[N:24]
Reactant: N#C[Cu]
Reactant: O=c1nc(-c2ccc(F)c(Br)c2)cc(-c2ccccc2)[nH]1
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2cc(-c3ccccc3)[nH]c(=O)n2)ccc1F
Yield: 114.4 %

Procedure:
A solution of 4-(3-bromo-4-fluorophenyl)-6-phenylpyrimidin-2(1H)-one (0.3 g, 0.9 mmol) and copper(I) cyanide (0.16 g, 1.7 mmol) in N,N-dimethylformamide (3 mL) was heated to 155° C. for 24 hours. The crude reaction mixture was concentrated in vacuo then partitioned between saturated sodium bicarbonate (aqueous) and ethyl acetate/methanol (10:1). The layers were separated and the aqueous layer was extracted once with 10:1 ethyl acetate/methanol. The combined organic layers were dried (sodium sulfate), filtered and concentrated in vacuo to give 0.30 g (quantitative yield) of crude 2-fluoro-5-(2-oxo-6-phenyl-1,2-dihydropyrimidin-4-yl)benzonitrile that was used without further purification for the next step. A solution of 2-fluoro-5-(2-oxo-6-phenyl-1,2-dihydropyrimidin-4-yl)benzonitrile (0.30 g, 1.0 mmol) and hydrazine monohydrate (1.7 mL, 36 mmol) in t-butanol (34 mL) was heated at 120° C. for 12 hours. The solution was concentrated in vacuo to give a solid, which was taken into hot methyl alcohol and treated with an excess of 4.0M hydrogen chloride in dioxane. After concentration in vacuo, the resultant solid was triturated in hot ethyl acetate, collected by vacuum filtration then lyophilized from aqueous solution to give 4-(3-amino-1H-indazol-5-yl)-6-phenylpyrimidin-2(1H)-one dihydrochloride (0.034 g, 11% yield). 1H NMR (400 MHz, DMSO): 8.93 (broad s, 1H), 8.20 (d, 1H), 8.11 (d, 1H), 7.70 (t, 1H), 7.65 (t, 2H), 7.57 (broad s, 1H), 7.47 (d, 1H). MS (EI) for C17H13N5O: 304 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1)([O-])=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:30].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:30].[ClH:30].[S:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[CH2:12][CH2:11][NH:10][C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(NCCc2cccs2)cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(NCCc2cccs2)cc1

Procedure:
The N-(4-nitrophenyl)-N-(2-thien-2-ylethyl)amine (1) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.[F:10][C:11]([F:17])([F:16])[CH2:12][CH2:13][CH2:14]I.C(=O)([O-])[O-].[K+].[K+]>>[F:10][C:11]([F:17])([F:16])[CH2:12][CH2:13][CH2:14][N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1
Reactant: NC(=O)C1CCNCC1
Reactant: FC(F)(F)CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)C1CCN(CCCC(F)(F)F)CC1
Yield: 106.8 %

Procedure:
Prepared from isonipecotamide (0.422 g, 3.3 mmol), 4,4,4-trifluorobutyliodide (0.82 g, 3.4 mmol) and potassium carbonate (0.47 g, 3.4 mmol) according to the procedure used for Example 8 (Step A) to give 0.84 g of the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([OH:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][C:5]=1[CH3:17].[CH3:18]I>C1COCC1>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([O:16][CH3:18])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][C:5]=1[CH3:17]
Reactant: CI
Reactant: Cc1cc([C@H](O)CCC(=O)O)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@H](CCC(=O)O)c1ccc(F)c(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the suspension of NaH (373 mg of a 60% dispersion in mineral oil, 9.3 mmol) in 20 mL THF was slowly added (R)-4-(4-Fluoro-3-methyl-phenyl)-4-hydroxy-butanoic acid as a solution in 10 mL THF at 25° C. Methyl iodide (974 mg, 6.9 mmol, 427 μL) was then added dropwise to the mixture. The resulting mixture was stirred for 3 h at room temperature and then the reaction was quenched by the addition of 20 mL of 1M HCl. The mixture was and extracted with ethyl acetate (3×30 mL) and the combined organic layers washed with brine (2×20 mL) and dried over sodium sulfate. Evaporation of solvent left the crude product as an oil which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][NH:15][C:14]3=[O:28])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:33]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=4)[CH2:16][N:15]([CH3:33])[C:14]3=[O:28])=[CH:11][CH:12]=2)=[CH:29][CH:30]=1
Reactant: CI
Reactant: O=C1NCC(c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[4-(4-chloro-phenoxy)-phenyl]-5-(3-trifluoromethyl-phenyl)-imidazolidin-2-one (20.0 mg, 0.046 mmol) in anhydrous DMF (0.5 mL) is added NaH (2.2 mg, 60% dispersion in mineral oil, 0.055 mmol) at 0° C. The reaction mixture is stirred at room temperature for 30 minutes before MeI (8.63 μL, 0.138 mmol) is added. The mixture is stirred at room temperature for 2 hours and then partitioned between water and ethyl acetate. The organic layer is concentrated and purified by preparative LC/MC to provide the title compound; HPLC-MS calculated for C23H18ClF3N2O2 (M+H+) 447.1, found 447.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([P:14]([OH:33])([O:16][C@@H:17]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25]C(OC(C)(C)C)=O)[C:18]([OH:20])=[O:19])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[NH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C@H:17]([O:16][P:14]([C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:13])([OH:33])=[O:15])[C:18]([OH:20])=[O:19]
Reactant: C[C@H](NC(=O)OCc1ccccc1)P(=O)(O)O[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: C[C@H](NC(=O)OCc1ccccc1)P(=O)(O)O[C@@H](CCCCN)C(=O)O
Reaction time: 2 h

Procedure:
A dichloromethane (0.5 ml) suspension of the (S)-2-(((R)-1-(benzyloxycarbonylamino)ethyl)(hydroxyphosphinoyl)oxy)-6-(tert-butoxycarbonylamino)hexanoic acid (3.1 mg) obtained in the above step (b) was added with anisol (0.05 ml) and trifluoroacetic acid (0.5 ml) at 0° C., and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated, and the residue was washed with isopropyl ether to obtain trifluoroacetic acid salt of the title compound: (S)-6-amino-2-(((R)-1-(benzyloxycarbonylamino)ethyl)(hydroxyphosphinoyl)oxy)hexanoic acid (3.0 mg, 94%).
Reaction SMILES: S(=O)(=O)(O)O.N[C:7]1[CH:8]=[CH:9][C:10]([CH3:15])=[C:11]([CH:14]=1)[C:12]#[N:13].N([O-])=[O:17].[Na+].NC(N)=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O>[OH:17][C:7]1[CH:8]=[CH:9][C:10]([CH3:15])=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: Cc1ccc(N)cc1C#N
Reactant: O=N[O-]
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: Cc1ccc(O)cc1C#N
Temperature: 15 °C
Reaction time: 0.08 h
Yield: 57.2 %

Procedure:
Concentrated sulfuric acid (5 mL, 94 mmol) was added to H2O (10 mL) (causing an exotherm). While the diluted acid was still hot, 5-amino-2-methylbenzonitrile (826 mg, 6.25 mmol) was added giving a clear solution. This was cooled to 15° C. (during which time a precipitate occurred) and 8 g of ice was added. As soon as the temperature was below 5° C., a solution of sodium nitrite (522 mg, 7.57 mmol) in H2O (5 mL) was added from a syringe (with the needle extended below the surface of the liquid) keeping the internal temperature below 5° C. The solution went clear after 5 min of stirring and then cold H2O (5 mL), urea (59 mg, 0.97 mmol) and ice (5 g) were added sequentially. In a separate flask H2O (5 mL) was added to sodium sulfate (4.75 g, 33.4 mmol) under an atmosphere of argon. Concentrated sulfuric acid (10 mL) was cautiously added and the reaction heated to reflux. The diazonium species was added to the refluxing mixture in portions and the heating continued for 2 h (NOTE: Blast shield used during heating). The mixture was cooled to rt and extracted with Et2O (2×). The combined organics were washed with H2O and 10% Na2CO3 solution before being extracted with 10% NaOH solution. The NaOH solution was acidified with concentrated HCl and then extracted with Et2O (2×). The combined organics from this second extraction were dried (Na2SO4) and concentrated by rotary evaporation to give a light brown solid which was purified via flash column chromatography (silica, DCM to 0.5% NH3/9.5% MeOH/90% DCM) to give 5-hydroxy-2-methylbenzonitrile (D36, 476 mg, 52%) as an orange solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:27][N:28]2[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]2)=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.ClCCl>>[CH2:1]([O:8][C:9]1[C:10]([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(OCc3ccccc3)ccc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1ccc2c(CN3CCNCC3)c(OCc3ccccc3)ccc21
Yield: 41.2 %

Procedure:
tert-Butyl 4-{[5-(benzyloxy)-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-1-carboxylate (30 mg, 0.05 mmol, Intermediate 63) was stirred with a 50/50 mixture of TFA/dichlorometane (3 mL) in room temperature for four hours. The solvent was removed at reduced pressure and the crude was purified on a preparative HPLC, method B, to give 9.5 mg (40%) of a colorless oil. MS (ESI+) for C26H27N3O3S m/z 462 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)=[CH:4][CH:3]=1.[CH2:14]1[CH2:20][S:17](=[O:19])(=[O:18])[O:16][CH2:15]1>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:14][CH2:20][S:17]([OH:19])(=[O:18])=[O:16])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2=CCNCC2)cc1
Reactant: O=S1(=O)CCCO1
Solvent: CC(C)=O
Product: O=S(=O)(O)CCCN1CC=C(c2ccc(Cl)cc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine (2.07 g, 10.7 mmol) in acetone (25 mL) was added 1,3-propane sultone (1.41 g, 11.8 mmol). The mixture was stirred at reflux for 2 h. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×20 mL) and dried in vacuo. The product was suspended in 50% MeOH/acetone (75 mL). The suspension was stirres at reflux for 5 minutes before 25 mL of cold acetone was added. The solid material was filtered and washed with acetone (2×25 mL). This allowed the isolation of compound J, 1.48 g (44%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]([CH3:12])([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:5].[ClH:14]>CO.O.[Pt](=O)=O>[ClH:14].[CH3:1][O:2][C:3](=[O:13])[C:4]([CH3:5])([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)[CH3:12]
Reactant: COC(=O)C(C)(C)c1cccnc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(=O)C(C)(C)C1CCCNC1
Reaction time: 5.5 h

Procedure:
A mixture of 0.823 g of 2-methyl-2-pyridin-3-yl-propionic acid methyl ester [476429-23-9] and 0.062 g of platinum(IV) oxide hydrate in 8 ml of methanol and 1.7 ml of 1.2M HCl in methanol at room temperature is hydrogenated for 5.5 hours. The catalyst is removed by filtration over Hyflo and the filtrate is concentrated by evaporation to provide the crude title compound as a brown oil which is used in the next step without further purification.
Reaction SMILES: C(OC([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:12][CH:11]=1)=O)(C)(C)C.C([N:42]1[CH2:46][CH2:45][C:44](=O)[CH2:43]1)(OC(C)(C)C)=O.COC(OC)OC.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][N:17]([CH:44]2[CH2:45][CH2:46][NH:42][CH2:43]2)[CH:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(CNC2CCCc3cccnc32)cc1)Cc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: COC(OC)OC
Product: c1ccc(CNCc2ccc(CN(C3CCNC3)C3CCCc4cccnc43)cc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
To the solution of N-(t-butyloxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (195 mg, 0.43 mmol) and N-Boc-3-pyrrolidone (91 mg, 0.49 mmol) in methanol (3 ml) was added trimethylorthoformate (2 ml) and three drops of acetic acid, at room temperature. This mixture was allowed to stir for 30 min. at room temperature and sodium cyanoborohydride (130 mg, 2.09 mmol) was added. Stirring was continued for a further 18 hours at room temperature and then the reaction mixture was concentrated. The residue was dissolved in ethylacetate (300 mL), and washed with saturated aqueous NaHCO3 and brine, then dried (Na2SO4) and evaporated. Purification of the residue by column chromatography on silica gel (1.5×20 cm, 50:50 EtOAc/CH2Cl2) gave the desired product (120 mg, 45%) as a mixture of diastereomers.