Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[N:17][N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:19]=3[CH3:20])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[C:27]([CH2:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)#[N:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[ClH:1].[CH3:20][C:19]1[N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:17]=[CH:16][C:15]=1[CH2:14][N:11]1[CH2:12][CH2:13][N:8]([C:3]2[C:2]([C:33]3[CH:34]=[CH:35][C:30]([CH2:29][C:27]#[N:28])=[CH:31][CH:32]=3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:9][CH2:10]1
Reactant: Cc1c(CN2CCN(c3nccnc3Cl)CC2)cnn1-c1ccccc1
Reactant: N#CCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1c(CN2CCN(c3nccnc3-c3ccc(CC#N)cc3)CC2)cnn1-c1ccccc1
Product: Cl
Temperature: 25 °C
Yield: 72 %

Procedure:
Stir together 3′-chloro-4-(5-methyl-1-phenyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (177 mg, 0.480 mmol), 4-(cyanomethyl)benzene boronic acid (93 mg, 0.576 mmol), potassium carbonate (159 mg, 1.15 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.003 g, 0.003 mmol) and water (1 mL), in N,N-dimethylacetamide (2 mL) at room temperature under nitrogen, then heat at 120° C. for 4 hr. Cool to room temperature, dilute with water (5 mL) and extract with DCM (3×20 mL). Pass the combined DCM extracts through an IST Phase Separator Frit®, concentrate and purify (silica gel chromatography, eluting with 0:100 to 5:95 methanol:DCM). Dry in a vacuum oven over night, then dissolve the yellow oil in acetonitrile. Add 2 M aq. HCl and water then lyophilize to give the title compound as a dark yellow powder (168 mg, 72%). MS (ES): m/z=450.2 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](Cl)=[O:13])[CH:6]=[CH:5]2.[NH2:15][C:16]1[C:21]2[N:22]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:24][C:20]=2[CH:19]=[CH:18][CH:17]=1>>[C:26]([NH:25][C:23]1[S:24][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:15][C:12]([C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=4)[CH:8]=3)=[O:13])[C:21]=2[N:22]=1)(=[O:28])[CH3:27]
Reactant: O=C(Cl)c1ccc2cc(Br)ccc2c1
Reactant: CC(=O)Nc1nc2c(N)cccc2s1
Product: CC(=O)Nc1nc2c(NC(=O)c3ccc4cc(Br)ccc4c3)cccc2s1

Procedure:
This material was prepared analogous to the procedure described for Example 1(b). 6-Bromo-naphthalene-2-carbonyl chloride, Example 1(a), (98 mg, 0.36 mmol) reacted with N-(4-amino-benzothiazol-2-yl)-acetamide (50 mg, 0.24 mmol, prepared according to the procedure described in WO03099284) to give the title compound as a solid. Mp 241.6° C. MS (ESI, pos. ion.) m/z: 441 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([CH2:25]O)=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].C([N:33](CC)CC)C.CS(Cl)(=O)=O.O.N>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([CH2:25][NH2:33])=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: OCc1ccc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: N
Solvent: CC#N
Solvent: O
Product: NCc1ccc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
{6-[3-(3,4,5-Trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-(trifluoromethyl)pyridin-3-yl}methanol (Reference document: WO2010/043315) (1.8 g) and triethylamine (0.5 g) were dissolved in acetonitrile (30 mL), and an acetonitrile (10 mL) solution of methanesulfonyl chloride (0.5 g) was added dropwise thereto under ice cooling. Upon the completion of the dropwise addition, the reaction solution was stirred at room temperature for 1 hour, and then the resulting solution was added dropwise to a mixture solution containing 28% ammonia water (50 mL) and acetonitrile (200 mL), which had been prepared separately, under ice cooling. After stirring at room temperature for 12 hours, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The solvent was distilled off and the purification was carried out by silica gel chromatography to obtain the title compound (1.25 g).
Reaction SMILES: [C:1]([O:16]C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O-:14])=[O:13].C(SCCCCCCCCCC([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40][CH2:41][CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])=O)(C)C>>[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40][CH2:41][CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[O:16])([OH:14])=[O:13]
Reactant: COC(=O)CCCCCCCCCCC(=O)[O-]
Reactant: CCOC(=O)CCCSc1ccccc1NC(=O)CCCCCCCCCSC(C)C
Product: O=C(O)CCCCCCCCCCC(=O)Nc1ccccc1SCCCC(=O)O

Procedure:
When amine (11) is acylated with acid chloride (7) as per procedure Step (E), and the resultant diester (ethyl 4-(2-(11-carbomethoxy-undecanoylamino)phenylthio)butyrate 12 is hydrolyzed in Step I as per procedure (F), the title compound, 13 m.p. 113.5-115° C. is obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1([C:18]([F:21])([F:20])[F:19])[CH2:10][NH:9][C:8]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:7]=2[O:6]1)[CH3:4].Cl.Cl[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N+:25]=1[O-:30]>CS(C)=O>[CH2:3]([C:5]1([C:18]([F:21])([F:20])[F:19])[CH2:10][N:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N+:25]=2[O-:30])[C:8]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:7]=2[O:6]1)[CH3:4]
Reactant: CCC1(C(F)(F)F)CNc2cc([N+](=O)[O-])ccc2O1
Reactant: [O-][n+]1ccccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCC1(C(F)(F)F)CN(c2cccc[n+]2[O-])c2cc([N+](=O)[O-])ccc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
Sodium hydride (0.68 g, 60% in mineral oil) was added to a solution of 2-ethyl-2-trifluoromethyl-6-nitro-3,4-dihydro-2H-1,4-benzoxazine (0.235 g), 2-chloropyridine-N-oxide hydrochloride (0.142 g), and dimethylsulfoxide (10 mL) and stirred at room temperature overnight. The mixture was quenched with saturated ammonium chloride/water and extracted into ethyl acetate. The organic extract was washed (water, brine) dried, decolorized (charcoal), filtered (celite) and evaporated. Chromatography, eluting successively with dichloromethane, ethyl acetate, and then methanol, gave the title compound as a yellow solid (0.11 g); mp 59°-62 ° C.; NMR: 0.95 (t,3), 2.04 (q), 4.05 (d,d), 7.01 (s,1), 7.25 (d) 7.45 (m, 2), 7.63 (d), 7.76 (d), 8.41 (d,1); MS: m/z=370(M+1). Analysis for C16H14F3N3O4 : Calculated: C, 52.04; H, 3.82; N, 11.38; Found: C, 51.95; 3.98; N, 11.10.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:11]=[C:12]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[O:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([N:21]2[C:26](=[O:27])[NH:25][C:24](=[O:28])[C:23]([C:29](O)=[O:30])=[N:22]2)=[CH:16][C:15]=1[CH3:32].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.ClCCCl.CN(C=O)C>[CH2:1]([NH:8][C:29]([C:23]1[C:24](=[O:28])[NH:25][C:26](=[O:27])[N:21]([C:17]2[CH:18]=[C:19]([CH3:20])[C:14]([O:13][C:12]3[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:10]([Br:9])[CH:11]=3)=[C:15]([CH3:32])[CH:16]=2)[N:22]=1)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Oc2c(C)cc(-n3nc(C(=O)O)c(=O)[nH]c3=O)cc2C)cc1Br
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: COc1ccc(Oc2c(C)cc(-n3nc(C(=O)NCc4ccccc4)c(=O)[nH]c3=O)cc2C)cc1Br

Procedure:
To a solution of benzylamine (6 μmol) in 10% DMF/DCE were added sequentially 10% DMF/DCE solutions of 2-[4-(3-bromo-4-methoxy-phenoxy)-3,5-dimethyl-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid (5 μmol) and N-methylmorpholine (6 μmol). A DMF solution of O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (7.5 μmol) and the resulting solution was shaken for 4 h at room temperature. The reaction was concentrated at 60° C. in a vacuum oven overnight. HPLC and LCMS shows complete conversion to the title compound of Step A. MS Calc.: 550.1; Found: 549.0 (M−1).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([O-:19])=[O:18].C1N2CCN(CC2)C1.C(N(CC)CC)C>ClCCCl.C(Cl)Cl>[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: C1CN2CCN1CC2
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Oc2ncnc3c2ncn3C2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 117.2 %

Procedure:
To a stirred slurry of 6-chloro-9-(tetrahydro-pyran-2-yl)-9H-purine (2.3 g, 10 mmol, 3 equiv) in anhydrous 1,2-dichloroethane (60 mL) was added a solution of 4-nitrophenol (2.3 g, 10 mmol, 3 equiv), DABCO (1.12 g, 1 mmol, 1 equiv) and triethylamine (3.03 g, 4.18 mL, 3 mmol, 3 equiv) in anhydrous 1,2-dichloroethane (5 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM (25 mL), washed with saturated solution of NaHCO3. The aqueous layer was re-extracted with DCM. The combined organic extracts were dried over MgSO4, filtered followed by solvent evaporation, giving 6-(4-nitro-phenoxy)-9-(tetrahydro-pyran-2-yl)-9H-purine (4 g, >99% yield). 1H NMR (400 MHz, CDCl3): δ 8.6 (s, 1H), 8.3 (m, 2H), 8.25 (s, 1H), 7.60 (m, 2H), 5.8 (m, 1H), 4.20 (m, 1H), 3.8 (m, 1H), 2.20 (m, 3H), 1.80 (m, 3H). MS (ESI) for C16H15N5O4: 342 (MH+).
Reaction SMILES: [O:1]=[C:2]1[O:6][C@@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3]1.[CH:10]1[C:11]2[C:26](=[O:27])[C:25]([C:28]([OH:30])=[O:29])=[CH:24][N:23]([CH:31]3[CH2:33][CH2:32]3)[C:12]=2[CH:13]=[C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[C:15]=1[F:16].O>CC(C)=O>[CH:10]1[C:11]2[C:26](=[O:27])[C:25]([C:28]([OH:30])=[O:29])=[CH:24][N:23]([CH:31]3[CH2:32][CH2:33]3)[C:12]=2[CH:13]=[C:14]([N:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)[C:15]=1[F:16].[O:1]=[C:2]1[O:6][C@@H:5]([C:7]([O-:9])=[O:8])[CH2:4][CH2:3]1
Reactant: O=C1CC[C@H](C(=O)O)O1
Agent: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Solvent: CC(C)=O
Solvent: O
Product: O=C1CC[C@H](C(=O)[O-])O1
Reaction time: 0.5 h

Procedure:
0.781 G (0.006 mole) of (R)-5-oxotetrahydrofuran-2-carboxylic acid and 1.99 g (0.006 mole) of Ciprofloxacin were added to 10 mL of distilled water. The resulting mixture was stirred for 30 minutes to dissolve it completely. After adding 20 mL of anhydrous acetone, the resulting solution was further stirred for 30 minutes under ice-cooling and allowed to stand to precipitate solids. The precipitated solids were filtered under reduced pressure through a filter paper (Whatman Filter Paper No. 1), washed three times with each 30 mL of anhydrous acetone, and dried under vacuum to give 2.33 g of the titled compound as white solids. M.P. 211-212° C. (decomposition) [α]D25 =+4.72 (H2O)
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:7]([CH2:8][OH:9])[O:6][CH2:5][O:4]1.[C:10](OC(=O)C)(=[O:12])[CH3:11].[CH2:17]([OH:19])[CH3:18]>N1C=CC=CC=1>[C:10]([O:1][CH2:2][CH:3]1[CH:7]([CH2:8][O:9][C:17](=[O:19])[CH3:18])[O:6][CH2:5][O:4]1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: OCC1OCOC1CO
Reactant: CCO
Solvent: c1ccncc1
Product: CC(=O)OCC1OCOC1COC(C)=O
Reaction time: 4 h
Yield: 85 %

Procedure:
(4RS,5SR)-4,5-bis(hydroxymethyl)-1,3-dioxolane obtained in Example 19 was dissolved in 100 ml of pyridine. An excessive amount of acetic anhydride (30.6 g) was added under cooling with ice. After reacting for about four hours at room temperature, 10 ml of ethyl alcohol was added dropwise under cooling with ice to decompose the excessive acetic anhydride. The reaction mixture was concentrated by evaporator. The concentrate was extracted with the addition of 300 ml of ethyl acetate, the extract was washed with water, and the solvent was removed by evaporator. Although it was possible to use this product in the next step as it was, the residue was purified by silica gel column chromatography (eluent, benzene:ethylacetate=95:5) to obtain 18.5 g (yield: 85.0%) of the title compound as a light yellow oil.
Reaction SMILES: C([NH:4][C@:5]1([C:22](NC(C)(C)C)=[O:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH2:8][NH:7][CH2:6]1)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH:36](=O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:46])C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl.C(O)(=O)C>[NH2:4][C@:5]1([C:22]([OH:23])=[O:46])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][N:7]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:6]1
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: N[C@@]1(C(=O)O)CN(Cc2ccccc2)C[C@@H]1CCCB(O)O
Reaction time: 2.5 h
Yield: 54.4 %

Procedure:
A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (166 mg, 0.42 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (2 g) and benzaldehyde (69 mg, 0.65 mmol), stirred for 2.5 h, then treated with sodium triacetoxyborohydride (212 mg, 1.0 mmol) and glacial acetic acid (2 drops) and stirred for 18 h. Aqueous sodium carbonate (10%, 5 mL) was added and the mixture stirred for a few minutes and extracted with ethyl acetate (30 mL, then 2×10 mL). The combined organic solution was washed with water and saturated aqueous sodium chloride (20 mL each), dried (MgSO4), and concentrated. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-1-benzyl-4-(3-boronopropyl)pyrrolidine-3-carboxylic acid (70 mg, 44%) as a white semisolid. NMR (d6-DMSO) δ 7.62 (br s, 2 H), 7.44 (br s, 3 H), 4.30-4.60 (m, 2 H), 3.60-3.90 (m, 2 H), 3.35-3.50 (m, 2 H), 2.85 (m, 1 H), 2.50 (m, 1 H), 1.20-1.80 (m, 3 H), 0.60-0.80 (m, 2 H). MS (m+1): 307.3; MS (m−H2O+1): 289.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.OO.COC1C=C2C(=CC=1)[N+:23]([O-])=[CH:22]C=C2.C(Cl)(=O)C1C=CC=CC=1>[Ag]C#N.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:22]#[N:23])[CH:7]=[CH:6]2
Reactant: COc1ccc2c(ccc[n+]2[O-])c1
Reactant: COc1ccc2ncccc2c1
Agent: N#C[Ag]
Agent: OO
Solvent: CC(=O)O
Solvent: O=C(Cl)c1ccccc1
Product: COc1ccc2nc(C#N)ccc2c1

Procedure:
Compounds of formula II can be manufactured starting from commercially available 6-methoxy-quinoline (1) that can converted to the N-oxide 2 by reaction with hydrogen peroxide and a solvent like acetic acid under refluxing conditions. The 6-methoxy-quinoline-1-oxide is reacted with silver cyanide and benzoyl chloride to obtain the 6-methoxy-quinoline-2-carbonitrile 3 via a modification of the Reisset'sche reaction (Ber., 38, 1610 (1905). Hydrolysis of the cyano group can be affected by employing an acidic or basic medium. We find it convenient to use a base like sodium hydroxide and after acidic treatment of the mixture we obtained the corresponding 6-methoxy-quinoline-2-carboxylic acid 4. Removal of the methyl group with an acid like hydrobromic acid 48% in water gives 6-hydroxy-quinoline-2-carboxylic acid (5). The acid can be esterified with an alcohol like ethanol and an acid like sulfuric acid to yield the 6-hydroxy-quinoline-2-carboxylic acid ester II, for example 6-hydroxy-quinoline-2-carboxylic acid ethyl ester (IIa).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([OH:18])C.[CH3:19][C:20]([OH:23])([CH3:22])[CH3:21]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:18])[O:23][C:20]([CH3:22])([CH3:21])[CH3:19])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: Nc1cc(OCc2ccccc2)ccn1
Reactant: CC(C)(C)O
Product: CC(C)(C)OC(=O)Nc1cc(OCc2ccccc2)ccn1
Temperature: 50 °C
Yield: 85 %

Procedure:
To a solution of 4-(benzyloxy)pyridin-2-amine (4.6 g, 22.97 mmol) in tBuOH (50 mL) was added boc-anhydride (5.57 g, 25.5 mmol). After heating to 50° C. for 1 hour, ethanol (200 mL) was added to the reaction mixture. The room temperature mixture was filtered to provide the solid product (5.89 g, 85%).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:50])[C@H:17]([N:25]([C:27](=[O:49])[C@H:28]([N:40](C(OC(C)(C)C)=O)[CH3:41])[CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[CH3:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:10])[CH3:9]>ClCCl>[C:8]([O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:50])[C@H:17]([N:25]([C:27](=[O:49])[C@H:28]([NH:40][CH3:41])[CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[CH3:26])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)OCCCNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCCCOC(C)=O
Reaction time: 0.08 h
Yield: 67.7 %

Procedure:
At 0° C., trifluoroacetic acid (3 mL) was added to a solution of 3-((2R)-2-(N-((2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)propyl acetate (885 mg, 1.50 mmol) in dichloromethane (3 mL). The reaction mixture was stirred for 5 min. The solvents were removed in vacuo at 20° C. The residue was dissolved in dichloromethane (40 mL). The S procedure was repeated twice. The crude product was purified by flash chromatography on silica (45 g) with dichloromethanelmethanol/25% solution of ammonia in water (100:10:1) to give 497 mg of 3-((2R)-2-(N-((2R)-2-methylamino-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)propyl acetate.
Reaction SMILES: ClC1C=C(F)C=CC=1CN[C:11](=[O:27])[C@@H:12]1[CH2:16][CH:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14](=[O:24])[N:13]1[CH2:25][CH3:26].[Cl:28][C:29]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:39][NH2:40].C(N1C(=O)C(CC2C=CC=CC=2)C[C@H]1C(O)=O)C>>[Cl:28][C:29]1[C:34]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:39][NH:40][C:11](=[O:27])[C@@H:12]1[CH2:16][CH:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14](=[O:24])[N:13]1[CH2:25][CH3:26]
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Reactant: CCN1C(=O)C(Cc2ccccc2)C[C@H]1C(=O)NCc1ccc(F)cc1Cl
Agent: CCN1C(=O)C(Cc2ccccc2)C[C@H]1C(=O)O
Product: CCN1C(=O)C(Cc2ccccc2)C[C@H]1C(=O)NCc1cccc(C(F)(F)F)c1Cl

Procedure:
N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-1-ethyl-5-oxo-4-(phenylmethyl)prolinamide was prepared in a manner analogous to that described above for the synthesis of N-[(2-chloro-4-fluorophenyl)methyl]-1-ethyl-5-oxo-4-(phenylmethyl)-prolinamide (E37), but using {[2-chloro-3-(trifluoromethyl)phenyl]methyl}amine in the place of [(2-chloro-4-fluorophenyl)methyl]amine. Method B, as described in Example 37, was used to prepare the 1-ethyl-5-oxo-4-(phenylmethyl)-proline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[C-:15]#[N:16].[K+].[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19]>C(#N)C.[I-].[Zn+2].[I-]>[CH3:14][O:13][C:9]1[CH:8]=[C:5]([CH:6]([O:7][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23])[C:15]#[N:16])[CH:4]=[C:3]([O:2][CH3:1])[C:10]=1[O:11][CH3:12]
Reactant: [C-]#N
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Agent: [Zn+2]
Solvent: CC#N
Product: COc1cc(C(C#N)O[Si](C)(C)C(C)(C)C)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
3,4,5-Trimethoxybenzaldehyde (50 g) is dissolved in acetonitrile (prepared by distillation with phosphorus pentoxide) (250 ml). To this solution are added potassium cyanide (24.9 g), zinc (II) iodide (8.1 g) and tert.-butyldimethylsilyl chloride (46.1 g) and the mixture is stirred at room temperature overnight. Acetonitrile is distilled off from the reaction mixture and to the residue is added diethyl ether and the insoluble materials are filtered off. The filtrate is washed with water, dried and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography [solvent: n-hexane/ethyl acetate (3:1)] and crystallized from a mixture of n-hexane and isopropyl ether to give (3,4,5-trimethoxyphenyl)(tert.-butyldimethylsilyloxy)acetonitrile (67 g) as colorless crystal.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]2[C:4]([C:8]#N)([CH2:5]2)[CH2:3]1.[OH-:10].[K+].[OH2:12]>>[CH3:1][N:2]1[CH2:7][CH:6]2[C:4]([C:8]([OH:12])=[O:10])([CH2:5]2)[CH2:3]1
Reactant: [OH-]
Reactant: CN1CC2CC2(C#N)C1
Reactant: O
Agent: [K+]
Product: CN1CC2CC2(C(=O)O)C1

Procedure:
A solution of 10 g of 3-methyl-3-azabicyclo[3.1.0]-hexane-1-carbonitrile is 60 ml of saturated ethanolic KOH and 20 ml of water is boiled under reflux for 15 hours. After neutralization with hydrochloric acid the mixture is evaporated and the title compound is extracted from the resultant dried residue with hot absolute ethanol (M.P. 193°-195°).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:7]=1.[CH3:22][S:23]([O:26]C)(=[O:25])=[O:24]>CO>[S:23]([OH:26])(=[O:25])(=[O:24])[CH3:22].[NH2:1][C:2]1[N:3]([CH3:22])[NH:4][C:5]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[N:7]=1
Reactant: Cc1ccc(-c2nnc(N)nc2-c2ccc(C)cc2)cc1
Reactant: COS(C)(=O)=O
Solvent: CO
Product: CS(=O)(=O)O
Product: Cc1ccc(C2=C(c3ccc(C)cc3)NN(C)C(N)=N2)cc1
Reaction time: 24 h

Procedure:
A mixture of 3-amino-5,6-bis(4-methylphenyl)-1,2,4-triazine (500 mg), methyl methanesulphonate (0.5 cm3) and methanol (10 cm3) was stirred at 40° for 24 hours and then evaporated to dryness. The resulting yellow solid was recrystallised from acetone giving the title compound as pale yellow needles,
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[C:10]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:9]=2)=[CH:4][CH:3]=1.CO>C1COCC1>[CH3:21][O:20][C:18](=[O:19])[CH2:17][C:10]1[CH:9]=[C:8]([O:7][CH2:6][C:5]2[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=2)[CH:16]=[CH:15][C:11]=1[CH2:12][OH:13]
Reactant: COC(=O)Cc1cc(OCc2ccc(F)cc2)ccc1C(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)Cc1cc(OCc2ccc(F)cc2)ccc1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The 4-(4-fluoro-benzyloxy)-2-methoxycarbonylmethyl-benzoic acid (1.15 g, 3.6 mmol) is solved in THF (28 mL) and borane-dimethylsulfide complex is added (0.69 mL, 7.26 mmol) at 0° C. The reaction is stirred for 2 hours at room temperature and more borane-dimethylsulfide complex (0.69 mL, 7.26 mmol) is added at 0° C. The reaction mixture was stirred at room temperature for 7 h. Methanol was added very slowly and the mixture stirred 20 min. Filtration and concentration in a rotatory evaporator left a solid that was purified through a Silica-gel column using hexane/ethyl acetate 3/1 to 1/2 as eluents (0.927 g, 71.4%). MS: m/e=304 (M+).