Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[C:3]([O:5][CH:6]([O:8][C:9](SCC)=[O:10])[CH3:7])=[O:4].S(Cl)([Cl:18])(=O)=O>>[CH3:1][CH:2]([CH3:14])[C:3]([O:5][CH:6]([O:8][C:9]([Cl:18])=[O:10])[CH3:7])=[O:4]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCSC(=O)OC(C)OC(=O)C(C)C
Product: CC(OC(=O)Cl)OC(=O)C(C)C
Reaction time: 0.75 h

Procedure:
1-{[(Ethylthio)carbonyl]oxy}ethyl 2-methylpropionate (WO2005/66122) (412 mg) was cooled to −30° C. Sulfuryl chloride (157 μl) was added thereto, and the mixture was then stirred for 45 minutes. The solvent in the reaction solution was distilled off under reduced pressure to obtain a crude product of the title compound.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([CH:9]=[O:10])[CH2:5][CH2:4]1)#[N:2].[CH2:11]([CH:16]([CH2:19]O)[CH2:17][OH:18])[CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:11]([C@@H:16]1[CH2:17][O:18][C@@H:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([C:1]#[N:2])[CH2:4][CH2:5]2)[O:10][CH2:19]1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: N#C[C@H]1CC[C@H](C=O)CC1
Reactant: CCCCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCCCC[C@H]1CO[C@H]([C@H]2CC[C@H](C#N)CC2)OC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2.00 g of trans-4-cyanocyclohexanecarboxaldehyde, 2.13 g of 2-pentyl-1,3-propanediol and 65 mg of p-toluenesulphonic acid in 100 ml of benzene was heated to reflux for 3 hours while gassing with argon and with separation of water in a round flask provided with a water separator and a reflux condenser. The mixture was subsequently treated with 3.0 g of potassium carbonate, stirred at room temperature for 16 hours, then filtered and the filtrate was concentrated. Recrystallization of the crystalline residue (4.1 g) from hexane at 0° C. gave 1.47 g (38%) of trans-4-(trans-5-pentyl-m-dioxan-2-yl)cyclohexanecarbonitrile as colourless crystals in a purity of 99.1%. After a further recrystallization from hexane at 0° C., the purity increased to 99.9%; m.p. (C--N) 45.6° C., cl.p. (N--I) 46.7° C.
Reaction SMILES: [CH:1]1([CH2:6][O:7][C:8]2[N:13]=[C:12]([C:14]([O:16]C)=O)[CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][C:19]#[N:20]>>[CH:1]1([CH2:6][O:7][C:8]2[N:13]=[C:12]([C:14](=[O:16])[CH2:18][C:19]#[N:20])[CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1cccc(OCC2CCCC2)n1
Reactant: CC#N
Product: N#CCC(=O)c1cccc(OCC2CCCC2)n1

Procedure:
CH3CN addition to methyl 6-(cyclopentylmethoxy)picolinate following the method described in Example 6 gave 3-(6-(cyclopentylmethoxy)pyridin-2-yl)-3-oxopropanenitrile as a yellow oil which was used in the next step without further purification. Yield (1.22 g, quant.).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:9]1[C:14]([NH:15][CH:16]([CH3:18])[CH3:17])=[N:13][CH:12]=[CH:11][N:10]=1>>[CH3:17][CH:16]([NH:15][C:14]1[C:9]([N:1]2[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=[CH:2]2)=[N:10][CH:11]=[CH:12][N:13]=1)[CH3:18]
Reactant: CC(C)Nc1nccnc1Cl
Reactant: C1CNCCNC1
Product: CC(C)Nc1nccnc1N1C=CC=NC=C1

Procedure:
Following the general procedure of PREPARATION 7 and making non-critical variations but starting with homopiperazine (2.46 g) and 2-chloro-3-(1-methylethyl)aminopyrazine (PREPARATION 6), the title compound is obtained, NMR (300 MHz, CDCl3) 7.56, 7.34, 4.75, 4.04, 3.28-3.18, 3.00-2.94, 1.79, and 1.15 δ.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.F[C:16]1[CH:17]=[CH:18][C:19]([N+:26]([O-:28])=[O:27])=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[ClH:35]>CS(C)=O.ClCCl.C(OCC)C>[ClH:35].[N+:26]([C:19]1[CH:18]=[CH:17][C:16]([O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:21][C:20]=1[C:22]([F:23])([F:24])[F:25])([O-:28])=[O:27].[ClH:35]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(OC2CCNCC2)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
A solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (2.2 g; 11.0 mmol), 5-fluoro-2-nitrobenzotrifluoride (2.5 g; 11.9 mmol) and potassium carbonate (3.0 g; 22.0 mmol) in dimethylsulfoxide (25 mL) is heated over night at 100° C. The mixture is then diluted with dichloromethane (200 mL) and is washed with water (25 mL), aq. sat. ammonium chloride (25 mL) and twice with water (25 mL). The organic layer is then filtered and the filtrate is evaporated under reduced pressure. The product is dissolved in a 1 to 1 mixture of dichloromethane and trifluoroacetic acid (16 mL) and the resulting solution is stirred at room temperature until complete conversion is observed (about 30 minutes). After concentration under reduced pressure, the residue obtained is co-evaporated with dichloromethane (3×30 mL). The crude product is diluted in diethylether (25 mL) and a molar solution of hydrochloric acid in diethylether (15 mL) is added under stirring. The solid obtained is finally filtered and is dried under high vacuum to yield the desired product as hydrochloride (1.86 g; 5.7 mmol).
Reaction SMILES: [C:1]1([C:13](=[O:18])[CH2:14][C:15]([NH2:17])=[O:16])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.C[O:20][C:21](=O)[C:22]([C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=O.CC(C)([O-])C.[K+].Cl>O1CCCC1.C(OCC)(=O)C.O>[C:1]1([C:13]([C:14]2[C:15](=[O:16])[NH:17][C:21](=[O:20])[C:22]=2[C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][CH:25]=2)=[O:18])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: COC(=O)C(=O)c1c[nH]c2ccccc12
Reactant: NC(=O)CC(=O)c1cn2c3c(cccc13)CCC2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1NC(=O)C(c2c[nH]c3ccccc23)=C1C(=O)c1cn2c3c(cccc13)CCC2
Yield: 78.6 %

Procedure:
To a solution of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-oxo-propionamide (2.0 g, 8.3 mmol) and (1H-indol-3-yl)-oxo-acetic acid methyl ester (1.8 g, 8.8 mmol) in anhydrous tetrahydrofuran (40 ml) at room temperature was added potassium tert-butoxide (26 ml, 26.0 mmol; 1M solution in tetrahydrofuran). After 45 minutes concentrated hydrochloric acid (10 ml) was added. Water (500 ml) was added to the mixture which was then extracted with ethyl acetate (350 ml). The organic layer was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue obtained was sonicated with ethyl acetate (50 ml) to afford 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carbonyl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione as an orange solid (2.58 g). M.p.=>300° C.; 400 MHz 1H NMR (DMSO-d6) δ: 11.99 (s, 1H), 11.12 (s, 1H), 8.18 (s, 1H), 8.13 (s, 1H), 7.93 (m, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.18 (m, 1H), 7.06-7.01 (m, 2H), 6.85 (m, 1H), 4.11 (m, 2H), 2.90 (m, 2H), 2.08 (m, 2H); LCMS: 396 [M+H].
Reaction SMILES: CS(C)=O.[Cl:5][C:6]1[CH:7]=[C:8]([C:13]([C:27]([F:30])([F:29])[F:28])=[CH:14][C:15]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19]([CH3:26])[CH:18]=2)=O)[CH:9]=[C:10]([Cl:12])[CH:11]=1.C1(C)C=CC=CC=1.[OH2:38].S(O)(O)(=O)=O.[NH2:44]O>[OH-].[Na+]>[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2([C:27]([F:30])([F:29])[F:28])[O:38][N:44]=[C:15]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19]([CH3:26])[CH:18]=3)[CH2:14]2)[CH:9]=[C:10]([Cl:12])[CH:11]=1
Reactant: O
Reactant: NO
Reactant: Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6.27 g of dimethylsulfoxide was added to solution in which 1.61 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid was dissolved into 10.5 g of toluene, and the mixture was cooled to 0° C. A solution in which 0.64 g of sodium hydroxide was dissolved into 1.6 g of water was carefully added to the mixtures so that the temperature of the reaction solution did not exceed 5° C. Moreover, a solution in which 0.46 g of hydroxylamine sulfate was dissolved into 2.24 g of water was carefully added to the mixtures so that the temperature of the reaction solution did not exceed 5° C. The reaction was performed for 1 hour with stirring while keeping the reaction temperature at 0° C. The reaction solution was analyzed by high-performance liquid chromatography (detected by UV detector at a wavelength of 254 nm, and calculated with omitting the peak of toluene). The target product of 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid was produced in 85.0% of relative area.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][N:21]3[C:29]([C:32]([NH:34][CH2:35][C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)=[O:33])=[CH:30][CH:31]=[C:20]3[CH2:19]2)=[O:17])=[CH:12][CH:11]=1)#[N:2].Cl.[NH2:43][OH:44].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[NH2:2][C:1](=[N:43][OH:44])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[CH:12][C:13]([C:16]([N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][N:21]3[C:29]([C:32]([NH:34][CH2:35][C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)=[O:33])=[CH:30][CH:31]=[C:20]3[CH2:19]2)=[O:17])=[CH:14][CH:15]=1
Reactant: NO
Reactant: N#CCc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: NC(Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1)=NO
Yield: 22.3 %

Procedure:
A mixture of 0.806 g (0015 mol) of 10-{[2′-(cyanomethyl)-1,1′-biphenyl-4-yl]carbonyl}-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 17, 0.52 g (0.0075 mol) of hydroxylamine hydrochloride and 1.03 g (0.0075 mol) of potassium carbonate in 100 mL of ethanol and 25 mL of water was heated under reflux for 2 hours. An additional 1.04 g (0.015 mol) of hydroxylamine hydrochloride and 2.06 g (0.015 mol) of potassium carbonate was added to the and refluxing was allowed to continue until LC/MS indicated that all the starting nitrile was consumed. The solvents were removed in vacuo and the residue was washed with water and purified by chromatography to provide the title compound (0.191 g), m.p. 131-134° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][C:10]([S:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]([OH:22])=O)[CH:15]=2)=[CH:11][N:12]=1.[NH2:23][CH2:24][C:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[OH:26].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[OH:26][C:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:24][NH:23][C:20](=[O:22])[C:16]1[CH:15]=[C:14]([S:13][C:10]2[S:9][C:8]([NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:12][CH:11]=2)[CH:19]=[CH:18][N:17]=1
Reactant: O=C(O)c1cc(Sc2cnc(Nc3ccccn3)s2)ccn1
Reactant: NCC(O)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(O)(c1ccccc1)c1ccccc1)c1cc(Sc2cnc(Nc3ccccn3)s2)ccn1
Temperature: 23 °C
Reaction time: 3.5 h
Yield: 0 %

Procedure:
To a solution of 4-(2-(pyridine-2-ylamino)thiazol-5-ylthio)picolinic acid (0.063 g, 0.19 mmol) and 2-amino-1,1-diphenylethanol (0.060 g, 0.28 mmol, 1.5 eq, described in Example D) in NMP (3 mL), was added EDAC (0.055 g, 0.28 mmol, 1.5 eq), HOBt (0.026 g, 0.19 mmol, 1 eq) and diisopropylethylamine (0.100 mL, 0.57 mmol, 3 eq). The resulting mixture was stirred at 23° C. for 3.5 h. The mixture was purified on preparative HPLC (ammonium acetate/water/acetonitrile) and freeze dried to give the title compound as a solid (0.024 mg, 24%). The product was converted to the HCl salt by dissolving it in ethyl acetate (2 mL) and tetrahydrofuran (2 mL) and treating the mixture with a solution of HCl (4.0 M in dioxane, 0.011 mL, 0.045 mmol, 1 eq). The mixture was concentrated, then diluted with water and lyophilized to give the HCl salt of the title material (0.029 g) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.10 (2H, d, J=5.56 Hz), 6.30 (1H, s), 7.01 (1H, dd, J=6.69 and 5.43 Hz), 7.11-7.20 (3H, m), 7.28 (4H, t, J=7.71 Hz), 7.37 (1H, dd, J=5.31, 2.02 Hz), 7.42-7.48 (4H, m), 7.66 (1H, d, J=1.52 Hz), 7.79 (1H, ddd, J=9.22, 6.32 and 1.89 Hz), 8.31 (1H, dd, J=5.43 and 1.39 Hz), 8.40 (1H, t, J=4.80 Hz), 8.41 (1H, d, J=4.8 Hz), 11.86 (1H, s). LC/MS (M+H)+: 526. Ret. time: 2.00 (Condition D). HRMS: calcd: 526.1371; found: 526.1387.
Reaction SMILES: [P:1](Cl)([S:5][CH2:6][CH3:7])([O:3][CH3:4])=[O:2].[Br:9][C:10]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]2[C:11]=1[CH2:12][CH2:13][C:14]2=[O:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:1]([O:19][C:16]1[CH:17]=[CH:18][C:10]([Br:9])=[C:11]2[C:15]=1[C:14](=[O:20])[CH2:13][CH2:12]2)([S:5][CH2:6][CH3:7])([O:3][CH3:4])=[O:2]
Reactant: O=C1CCc2c(Br)ccc(O)c21
Reactant: CCSP(=O)(Cl)OC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCSP(=O)(OC)Oc1ccc(Br)c2c1C(=O)CC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
O-Methyl S-ethyl chlorothiophosphate (0.015 mole) dissolved in dry toluene (80) is charged into a glass reaction vessel equipped with a stirrer, thermometer and gas inlet tube. The solution is cooled to about 0° C. and a solution of 4-bromo-7-hydroxyindan-1-one (0.015 mole) and triethylamine (0.0175 mole) in toluene (20 ml) is slowly added with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 8 hours. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed solution is then dried and is stripped of solvent leaving a residue. This residue is chromatographed through a 200 ml clay column using ethyl acetate and hexane mixtures as the eluant. Ten separate fractions each containing increasing percentages of ethyl acetate are collected and analyzed by IR for the product. The appropriate fractions are then combined stripped of solvent and subjected to vacuum to yield the desired product O-methyl S-ethyl O-(4-bromoindan-1-on-7-yl) thiophosphate.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:7][C:6]=12.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:7][C:6]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccn2ncc(Br)c2n1
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1cnn2ccc(NC[C@@H]3CCCN3C(=O)OC(C)(C)C)nc12
Yield: 68 %

Procedure:
The Suzuki coupling of (5)-tert-butyl 2-(((3-bromopyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)pyrrolidine-1-carboxylate with (2-methoxyphenyl)boronic acid under the same conditions as described in example 5.6.5 to give 68% of the titled compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.50 (s, 9 H) 1.85-2.12 (m, 4 H) 3.40 (dd, J=7.58, 4.04 Hz, 2 H) 3.46-3.59 (m, 1 H) 3.59-3.67 (m, 1 H) 3.94 (s, 3 H) 4.19 (br. s., 1 H) 6.07 (d, J=7.07 Hz, 1 H) 6.99 (d, J=7.58 Hz, 1 H) 7.06 (td, J=7.45, 1.01 Hz, 1 H) 7.15-7.22 (m, 1 H) 8.14-8.28 (m, 1 H) 8.45 (d, J=6.82 Hz, 1 H) 8.51 (s, 1 H); LRMS (ESI) m/e 424.0 [(M+H)+, calcd for C23H29N5O3 423.0].
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[Na+].[Na+].C(=O)=O.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[O-:20].[Na+]>>[OH:20][C:11]1[C:12]([C:1]([OH:2])=[O:4])=[CH:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: [O-]c1ccc2ccccc2c1
Agent: O=C=O
Agent: [Na+]
Product: O=C(O)c1cc2ccccc2cc1O
Temperature: 240 °C
Yield: 65 %

Procedure:
A stainless steel pressure autoclave is charged with 150 parts of kerosene and 32 parts of sodium carbonate and heated to 240° C. It is then pressurized with 10 bar of carbon dioxide. Over the course of 6 hours, 50 parts of sodium β-naphtholate are metered in as a suspension in kerosene via a metering pump, part of the kerosene being distilled off, condensed and transferred out of the reaction vessel at reduced pressure. After the usual workup, the 2-hydroxynaphthalene-3-carboxylic acid is obtained in a yield of 65% based on sodium β-naphtholate used. In addition, 23% of unreacted β-naphthol and small amounts of 2-hydroxynaphthalene-6-carboxylic acid and 2-hydroxynaphthalene-3,6-dicarboxylic acid are obtained.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>CC(N(C)C)=O.C(OCC)(=O)C.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:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]2[C:11]3[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1cccc2c(Br)cccc12
Reactant: Nc1ccc(Cl)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1cccc2c(Nc3ccc(Cl)cc3)cccc12
Temperature: 140 °C
Reaction time: 3 h
Yield: 65.5 %

Procedure:
1-bromo-5-nitronaphthalene (131 mg, 0.52 mmol) was dissolved in DMA (5 mL), and added with 4-chloroaniline (60 mg, 0.47 mmol), Xantphos (27 mg, 0.047 mmol), Pd2(dba)3 (17.2 mg, 0.019 mmol) and CsCO3 (306 mg, 0.94 mmol) at room temperature. The reaction solution was sealed and stirred for about 3 hours under microwave conditions at 140° C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with a saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated compound purified using silica gel chromatography (ethyl acetate:hexane=1:5 (v/v)) to obtain the title compound (92 mg, 66%).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5][CH2:4]1.C(O)(C(F)(F)F)=O>>[NH3:2].[CH3:1][N:2]([CH3:17])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH2:9])[CH2:5][CH2:4]1
Reactant: CN(C)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)[C@H]1CC[C@H](N)CC1
Product: N
Temperature: 75 °C

Procedure:
To a solution of tert-butyl trans-4-(dimethylamino)cyclohexylcarbamate (800 mg, 3.3 mmol) was added TFA (5 mL) and the reaction mixture was stirred with heat at 75° C. for 18 h. The reaction mixture was concentrated, the residue was loaded onto an SCX® ion-exchange column, flushed with methanol and then 7 N ammonia in methanol to obtain the desired product. The fractions containing the product were concentrated to dryness to obtain the desired product as the free base (400 mg, 85%) as an orange oil: ESI MS m/z 143 [C8H18N2+H]+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.[C-:26]#[N:27].[Na+].[F:29][C:30]1[C:36]([F:37])=[C:35]([F:38])[CH:34]=[CH:33][C:31]=1[NH2:32]>>[F:29][C:30]1[C:36]([F:37])=[C:35]([F:38])[CH:34]=[CH:33][C:31]=1[NH:32][C:2]1([C:26]#[N:27])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1
Reactant: Nc1ccc(F)c(F)c1F
Reactant: [C-]#N
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Agent: [Na+]
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(C#N)(Nc4ccc(F)c(F)c4F)CC3)c(F)c2)C(=O)O1
Yield: 68 %

Procedure:
By using procedure as described in Example 45 and by reacting (S)—N-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide with sodium cyanide and 2,3,4-trifluoroaniline the compound was obtained in 68% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]2[CH:7]=[CH:8][C@H:9]([OH:10])[C@@H:4]2[O:3]1>CO.[Pd]>[CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]2[CH2:7][CH2:8][C:9](=[O:10])[C@@H:4]2[O:3]1.[CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]2[CH2:7][CH2:8][C@H:9]([OH:10])[C@@H:4]2[O:3]1
Reactant: CC1(C)O[C@H]2[C@@H](O)C=C[C@H]2O1
Agent: [Pd]
Solvent: CO
Product: CC1(C)O[C@@H]2CCC(=O)[C@@H]2O1
Product: CC1(C)O[C@H]2[C@@H](O)CC[C@H]2O1

Procedure:
(3aS,4S,6aR)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (1-1) (10 g, 64.0 mmol, 1 equiv) was dissolved in MeOH (200 mL), the system was placed under nitrogen and 10% Pd/C (681 mg, 6.4 mmol, 0.1 equiv) was carefully added. The resulting mixture was stirred under a H2 atmosphere (1 atm) until disappearance of the starting material as monitored by LC-MS analysis. Hydrogen was removed followed by filtration through a celite plug and washing of the solids with MeOH (4×75 mL). The filtrate was concentrated and the residue was purified via flash chromatography on a 120 g silica gel column (gradient elution 0 to 50% ethyl acetate in hexanes) to yield (3aR,6aR)-2,2-dimethyldihydro-3aH-cyclopenta[d][1,3]dioxol-4(5H)-one (1-2) as a white fluffy solid and (3aS,4S,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (1-3) as a colorless oil. 1H NMR (1-2) (500 MHz, CDCl3): δ 4.84 (t, J=4.8 Hz, 1H); 4.19 (d, J=5.2 Hz, 1H); 2.65-2.53 (m, 1H); 2.33-2.23 (m, 2H); 2.11-2.01 (m, 1H); 1.43 (s, 3H); 1.38-1.31 (m, 3 II). 1H NMR (1-3) (400 MHz, CDCl3): δ 4.61 (t, J=5.3 Hz, 1H); 4.40 (t, J=5.6 Hz, 1H); 3.88-3.77 (m, 1H); 2.43 (d, J=9.9 Hz, 1H); 1.93-1.75 (m, 2H); 1.70-1.55 (m, 1H); 1.49 (s, 3H); 1.47-1.35 (m, 1H); 1.34 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.Cl.[N:22]1([CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)[CH:26]=[N:25][CH:24]=[N:23]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[F:1][C:2]1[C:3]([N:29]2[CH2:30][CH2:31][CH:27]([N:22]3[CH:26]=[N:25][CH:24]=[N:23]3)[CH2:28]2)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23
Reactant: C[C@H]1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: c1ncn(C2CCNC2)n1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1COc2c(N3CCC(n4cncn4)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23

Procedure:
A suspension of 70.25 mg (0.25 mmol) of (-) -9,10-difluoro-3(S)-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de]-1,4-benzoxazine-6-carboxylic acid and 87 mg (0.5 mmol) of 3-(1,2,4-triazol-1-yl)pyrrolidine hydrochloride in 3 ml of acetonitrile in the presence of 76 mg (0.5 mmol) DBU was stirred under nitrogen at reflux condition overnight. The yellow solution was then evaporated to dryness and to the residue, water was added and solid collected. The off-white solid was dissolved in chloroform and the small amounts of the suspension were filtered off. The supernatant was evaporated and to the residue, water was added and solid collected (60 mg), m.p. 229°-231° C. 1H NMR (CDCl3) δ: 8.59 (s, 1H), 8.26 (s, 1H), 7.98 (s, 1H), 7.7 (d, 13.5Hz, 1H), 5.17-5.00 (m, 1H), 4.6-3.73 (m, 7H), 2.67-2.4 (m, 2H), 1.61 (d, 6.7Hz, 3H).