Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].C(N(CC)CC)C>CC(C)=O>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:3]([S:4]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)(=[O:6])=[O:5])=[CH:2][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)C(=O)C(Br)C(c1ccc(Cl)cc1Cl)S(=O)(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)C=C(c1ccc(Cl)cc1Cl)S(=O)(=O)c1ccccc1
Temperature: 0 °C
Yield: 60.2 %

Procedure:
A solution of 9.6 g of 2-bromo-1-(2,4-dichlorophenyl)-4,4-dimethyl-1-phenylsulfonylpentan-3-one and 2.23 g of triethylamine in 100 ml of acetone was refluxed for 3 hours. The mixture was poured into ice water and extracted with 150 ml of ethyl acetate. The organic layer was washed twice with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of n-hexane (20 parts) and acetone (1 part) to give 4.8 g of 1-(2,4-dichlorophenyl)-4,4-dimethyl-1-phenylsulfonyl-1-penten-3-one. nD25 1.5723
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([C:12]2([Cl:15])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[H][H]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([C:12]2([Cl:15])[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(C=Cc1ccc(Cl)cc1)C1(Cl)CC1
Reactant: [H][H]
Solvent: Cc1ccccc1
Product: O=C(CCc1ccc(Cl)cc1)C1(Cl)CC1
Temperature: 50 °C
Yield: 90.5 %

Procedure:
460 mg (0.5 mmol) of tris-triphenylphosphine rhodium chloride (=1 mol %, with reference to the reaction components) is added to a 100 ml autoclave. After purging with nitrogen, an air-free solution of 12 g (0.05 mol) of 1-chlorocyclopropyl 4-chlorophenylethenyl ketone in 40 ml of toluene is added and heated at 50° C. under a hydrogen pressure of 30 bar. The hydrogen pressure is kept between 40 and 50 bar until the absorption of gas is complete (after about 1 hour). The mixture is subsequently allowed to react for 1 hour. For working up, the solvent is removed under reduced pressure and the residue which remains is purified on silica gel using dichloromethane as the eluant. 11 g (90% of theory) of 1-chlorocyclopropyl 4-chlorophenylethyl ketone are obtained in the form of an oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][NH2:8].[F:14][C:15]([F:28])([F:27])[C:16]1[CH:26]=[CH:25][C:19]([CH2:20][CH2:21][C:22](O)=[O:23])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][NH:8][C:22](=[O:23])[CH2:21][CH2:20][C:19]1[CH:18]=[CH:17][C:16]([C:15]([F:27])([F:28])[F:14])=[CH:26][CH:25]=1
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(CCN)cc1OC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(CCNC(=O)CCc2ccc(C(F)(F)F)cc2)cc1OC
Yield: 70.4 %

Procedure:
3,4-Dimethoxyphenethylamine 42a (3.62 g, 3.4 mL, 20 mmol, 1.0 eq) was added to a solution of 4-(trifluoromethyl)hydrocinnamic acid 43 (4.36 g, 20 mmol, 1.0 eq) in toluene (75 mL). After 5 min a thick suspension formed. The suspension was heated to reflux, giving a clear solution. The mixture was heated at reflux for 24 h using a Dean-Stark trap to remove water that was formed. The mixture was partially cooled, diluted with ethyl acetate (100 mL) and concentrated under reduced pressure to near dryness. The thick slurry was diluted with ethyl acetate (200 mL) and the solution washed sequentially with 1N hydrochloric acid (100 mL), aqueous sodium bicarbonate solution (200 mL), water (100 mL) and brine (100 mL). The organic solution was dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The solid was triturated with heptanes (50 mL), filtered and dried to give 5.37 g (70%) of 44a as a white, fluffy solid.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][CH2:6][C@@:7]([OH:12])([CH3:11])[C:8](O)=[O:9].[N+:13]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[C:23]([F:26])([F:25])[F:24])([O-:15])=[O:14]>CC(N(C)C)=O>[N+:13]([C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:8](=[O:9])[C@:7]([OH:12])([CH3:11])[CH2:6][Br:5])=[CH:18][C:17]=1[C:23]([F:24])([F:25])[F:26])([O-:15])=[O:14]
Reactant: C[C@](O)(CBr)C(=O)O
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: C[C@](O)(CBr)C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reaction time: 2 h
Yield: 80.8 %

Procedure:
Thionyl chloride (8.6 g, 72 mmol) was added dropwise under argon to a solution of bromoacid R-131 (11.0 g, 60 mmol) in 70 mL of DMA at −5 to −10 ?C. The resulting mixture was stirred for 2 h under the same conditions. A solution of 4-nitro-3-trifluoromethyl-aniline (12.4 g, 60 mmol) in 80 mL of DMA was added dropwise to the above solution, and the resulting mixture was stirred overnight at room temperature. The solvent was removed on Rotavapor using high vacuum oil pump; the residue was diluted with saturated NaHCO3 solution, and extracted with ethyl ether (100 mL×3). Combined extracts were dried over anhydrous Na2SO4, filtered through Celite, and purified by flash chromatography on silica gel, using methylene chloride as eluent to afford 18.0 g (80%) of the desired compound: mp 98-100 ?C (Rf=0.2, silica gel, CH2Cl2); 1H NMR (300 MHz, DMSO-d6) ? 10.54 (s, 1H, NH), 8.54 (d, J=2.1 Hz, 1H, ArH), 8.34 (dd, J=9.0 Hz, J=2.1 Hz, 1H, ArH), 8.18 (d, J=9.0 Hz, 1H, ArH), 6.37 (s, 1H, OH), 3.82 (d, J=10.4 Hz, 1H, CHHa), 3.58 (d, J=10.4 Hz, 1H, CHHb), 1.48 (s, 3H, Me); 13C NMR (75 MHz, DMSO-d6) ? 173.6 (C═O), 143.0, 127.2, 123.2, 122.6 (q, J=33.0 Hz), 122.0 (q, J=271.5 Hz), 118.3 (q, J=6.0 Hz), 74.4, 41.4, 24.9; IR (KBr) 3344 (OH), 1680 (C═O), 1599, 1548 (C═C, Ar), 1427, 1363, 1161 cm−1; MS (ESI): m/z 370.8 (M)+; Anal. Calcd. for C11H10BrN2O4: C, 35.60; H, 2.72; N, 7.55. Found: C, 35.68; H, 2.72; N, 7.49.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[Cl:16][C:17]1[C:22]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:21]=2[C:20]([F:34])=[C:19](Cl)[N:18]=1.CC(O)C.CCN(C(C)C)C(C)C>CS(C)=O>[C:11]([O:10][C:9]([NH:8][C@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]1[NH:1][C:19]1[N:18]=[C:17]([Cl:16])[C:22]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:25][C:21]=2[C:20]=1[F:34])=[O:15])([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1Cc2c(F)c(Cl)nc(Cl)c2C1=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 78 °C
Reaction time: 34 h
Yield: 72.38 %

Procedure:
To the 5-L RBF containing tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (STEP A) was added tert-butyl 4,6-dichloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (400.0 g, 1.246 mol, 1 eq). To this mixture was added IPA (400 mL), DMSO (400 mL) and DIPEA (282 mL, 1.3 eq). The resulting pink slurry was heated up to 78° C. and was stirred for 34 hours. The mixture was then cooled to room temperature and was stirred over the weekend. HPLC analysis indicated the presence of 1.6% of the starting material, 4.63% of the des-Boc side product, 72.38% of the desired product, and 11.23% of an isomer. 1H NMR analysis indicated a ratio of 5.49 of the IPA/DMSO. Isopropanol (200 mL) was added to the mixture to adjust the ratio to 6. The slurry was heated up to 78° C. Water (1.6 L) was added over a period of 1 hour at a rate which kept the temperature of the mixture above 64° C. The mixture was then cooled to room temperature and was stirred overnight. The slurry was filtered the next morning through a fritted glass funnel. The filter cake was washed with IPA/water/DMSO (800 mL, 6:4:1) and IPA/water (2×800 mL, 3:2) to give the title compound, which was dried under high vacuum at 40-45° C. until a constant weight was obtained (299.27 g, 48% yield with a 96.6% purity). 1H NMR (300 MHz, CDCl3) δ ppm 1.80-1.30 (m, 26H), 4.04 (m, 1H), 4.21 (m, 1H), 4.64 (d, J=0.9 Hz, 1H), 4.85 (br, 1H), 6.08 (br, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([O:14]C)=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=1.BrC1C=CC(CN)=CC=1.N.Cl>O>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH:25][C:12](=[O:14])[CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)[CH3:24])=[CH:19][CH:18]=1
Reactant: COC(=O)Cc1cccc2cnccc12
Reactant: CC(N)c1ccc(Br)cc1
Agent: Cl
Agent: N
Agent: NCc1ccc(Br)cc1
Solvent: O
Product: CC(NC(=O)Cc1cccc2cnccc12)c1ccc(Br)cc1

Procedure:
The title compound was prepared using the procedure described in Example 132C using the product from Example 133B and 1-(4-bromophenyl)ethanamine instead of the product from Example 132B and 4-bromobenzylamine. 1H NMR (300 MHz, d6-DMSO) 9.81 (s, 1H), 9.00 (d, 1H), 8.70 (d, 1H), 8.48 (d, 1H), 840 (d, 1H), 8.04 (d, 1H), 7.92 (m, 1H), 7.51 (d, 2H), 7.23 (d, 2H), 4.84 (m, 1H), 4.10 (s, 2H), 1.35 (d, 3H). MS (DCI/NH3) m/e 369 (M+H)+; Anal. Calcd. For C19H17N2OBr. 1.0 HCl. 1.0 H2O: C 53.86; H 4.76; N 6.61. Found: C 53.47; H 4.53; N 6.76.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:5][C:6]=1[CH:7]=[O:8].[CH3:19][Mg]Br.C(OCC)C>C1COCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=2)[S:5][C:6]=1[CH:7]([OH:8])[CH3:19]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbaldehyde (1.5 g, 5.53 mmole) in THF (50 mL) at 0° C., is added a solution of methyl magnesium bromide in diethyl ether (3.0M, 2.0 mL, 6.0 mmole) dropwise. The reaction is stirred for 5 minutes and then warmed up to room temperature for 2 hrs. The reaction is quenched with NH4Cl(aq) (10 mL), partitioned between ethyl ether (50 mL) and water (50 mL). Extracted the aqueous layer with ethyl ether (2×50 mL). The combined organic is washed with brine (3×100 mL), dried over Na2SO4, filtered and concentrated. Column chromatography on silica gel gave 1.35 gram of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=[O:12])[CH2:8][CH2:7]2.[BH4-].[Na+].O>CO>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]2
Reactant: Nc1cccc2c1CC(=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1cccc2c1CC(O)CC2
Reaction time: 1 h
Yield: 71.3 %

Procedure:
Next, to 8-amino-3,4-dihydro-1H-naphthalen-2-one (0.050 g, 0.318 mmol) in methanol (10 mL) was added sodium borohydride (0.030 g, 0.175 mmol) at 0° C., and the mixture was stirred for 1 hour. The mixture was poured into water, and the product was extracted with ethylacetate. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol (0.037 g, 71% yield).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]1[O:16][C@@H:15]2[C@H:17]([OH:20])[CH2:18][O:19][C@@H:14]2[C@@H:13]1[OH:21].O>N1C=CC=CC=1>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:21][C@@H:13]2[CH2:12][O:16][C@@H:15]3[C@H:17]([OH:20])[CH2:18][O:19][C@H:14]23)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
A solution of p-toluenesulfonyl chloride (24.8 g, 130 mmol) in pyridine (150 mL) was added to a stirred solution of isomannide (40) (19.0 g, 130 mmol) in pyridine (150 mL) over 1 hour at 0° C. then stirred at ambient temperature for 1 hour. The mixture was poured onto iced-water (1 L) then extracted with dichloromethane (3×300 mL). The organic phase washed with brine (300 mL), dried (MgSO4), filtered and reduced in vacuo to leave a residue. Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 0:100 to 50:50 gave monotosylate (50) (23.4 g, 60%) as a white solid.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH2:11][C:12](OC)=[O:13])#[N:4].C(OCC)(=O)C>C(O)C.CCCCCC>[OH:13][CH2:12][CH2:11][C:10]1[C:5]([C:3]#[N:4])=[CH:6][N:7]=[CH:8][CH:9]=1
Reactant: COC(=O)Cc1ccncc1C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: N#Cc1cnccc1CCO
Temperature: 0 °C
Reaction time: 4 h
Yield: 22.4 %

Procedure:
NaBH4 (228 mg, 6.023 mmol) was added portion wise over a period of 20 minutes to a solution of methyl 2-(3-cyanopyridin-4-yl)acetate (I-65a: 530 mg, 3.011 mmol) in ethanol (6 mL) at 0° C. and the resulting reaction mass was stirred at 0° C. for 4 hours. The reaction was monitored by TLC (50% ethyl acetate in hexane). The reaction mass was quenched with saturated NH4Cl solution and extracted using ethyl acetate. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (2% methanol in DCM) afforded 100 mg of the product (22.42% yield).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25](Br)[CH:24]=2)[CH2:15][CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([Mg]Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[NH4+].[Cl-].O(C1C=C(CC(NCC2C=CC=C(CC3C=CC=CC=3)C=2)(O)C(F)(F)F)C=CC=1)C1C=CC=CC=1>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.CCO.C1COCC1>[O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:24]=2)[CH2:15][CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(CN(Cc1cccc(Br)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Reactant: Br[Mg]Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OC(Cc1cccc(Oc2ccccc2)c1)(NCc1cccc(Cc2ccccc2)c1)C(F)(F)F
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Product: OC(CN(Cc1cccc(Cc2ccccc2)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F

Procedure:
To a THF (4 mL) solution of 3[(3-phenoxyphenyl)[[3-bromophenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (0.60 g, 1.3 mmol) from EX-595B was added benzyl-magnesium bromide in THF (2.0 mL, 2.0 M, 4.0 mmol) and Pd(PPh3)4. The resulting yellow solution was refluxed under N2 for 18 h. The cooled solution was poured into saturated aq. NH4Cl, extracted with ethyl acetate, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 15% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0.39 g (62%) of the desired 3[(3-phenoxyphenyl)[[(3(phenylmethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a colorless oil. Anal. calcd. for C29H26NO2F3.0.4 EtOH: C. 72.17: H, 5.77; N, 2.82. Found: C, 72.17; H, 5.42; N, 2.83. HRMS calcd. 478.1994 ([M+H]+, found: 478.1984. H NMR (C6D6) δ1.58 (d, 1H), 3.22 (dd, 1H), 3.46 (dd, 1H), 3.69 (s, 2H), 3.73 (m, 1H), 4.18 (s, 2H), 6.34 (dd, 1H), 6.47 (dd, 1H), 6.53 (t, 1H), 6.8-7.1 (m 15H).
Reaction SMILES: [C:1]1([CH2:10][C:11]#[N:12])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.N>[Ni].C(O)C>[NH2:9][CH2:8][CH2:7][C:3]1[CH:4]=[CH:5][CH:6]=[C:1]([CH2:10][CH2:11][NH2:12])[CH:2]=1
Reactant: N#CCc1cccc(CC#N)c1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCCc1cccc(CCN)c1

Procedure:
A mixture of 25.0 g (0.16 mmol) meta-xylylene dicyanide, 300 ml ethanol and50 ml conc. NH3 is hydrogenated in the presence of Raney nickel for 5 hrs. at 100° C. and 150 bar. One then filters off with suction and evaporates. The residue is dissolved in ether, the solution is clarified with active carbon and finally mixed with HCl-containing ether, whereby the dihydrochloride precipitates out. One filters off with suction, washeswith ether and dries. Yield 23.2 g (61% of theory) of dihydrochloride with the m.p. 282°-286° C.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13]C)=[C:9]2[C:4]=1[N:5]=[CH:6][CH:7]=[N:8]2.Br>C(O)(=O)C>[OH:13][C:10]1[CH:11]=[CH:12][C:3]([OH:2])=[C:4]2[C:9]=1[N:8]=[CH:7][CH:6]=[N:5]2
Reactant: COc1ccc(OC)c2nccnc12
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(O)c2nccnc12

Procedure:
Ten grams of 5,8-dimethoxyquinoxaline were dissolved in 100 ml. of glacial acetic acid. After 60 ml. of 48% hydrobromic acid were added to the solution, the reaction was allowed to reflux overnight. The solution was evaporated to dryness in vacuo and a solution of 5% sodium bicarbonate was added until the reaction was basic. The solution was extracted several times with methylene chloride. The combined methylene chloride extracts were dried with sodium sulfate and evaporated to give an amorphous powder which was used without purification for the subsequent reactions.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[N:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1)=[O:5].[CH3:17][Mg]Br.C([O-])(O)=O.[Na+]>C1COCC1>[F:13][C:12]([F:15])([F:14])[C:9]1[N:8]=[CH:7][C:6]([C:4](=[O:5])[CH3:17])=[CH:11][CH:10]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(F)(F)F)nc1
Reaction time: 16 h
Yield: 98.7 %

Procedure:
Dissolve N-methoxy-N-methyl-6-(trifluoromethyl)pyridine-3-carboxamide (0.685 g, 2.92 mmol) in THF (20 mL). Add methylmagnesium bromide (3.0 M in EtO2, 1.950 mL, 5.850 mmol). Stir the mixture for 16 hours. Pour the reaction mixture into a saturated NaHCO3 aqueous solution (20 mL). Extract with EtOAc (3×20 mL). Wash the combined organic extracts with water (30 mL) and saturated sodium chloride (2×30 mL). Dry the organic extracts over sodium sulfate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure to give the title compound (0.545 g, 98%) as a light yellow solid. 1H NMR (400.43 MHz, d6-DMSO) δ 9.21-9.21 (m, 1H), 8.51-8.49 (m, 1H), 8.03 (d, J=8.2 Hz, 1H), 2.64 (s, 3H).
Reaction SMILES: [OH-].[K+].F[C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([OH:9])=[O:8].Cl.[CH2:17]([OH:19])[CH3:18]>>[CH2:17]([O:19][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([OH:9])=[O:8])[CH3:18]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CCOc1cc(C(=O)O)ccc1[N+](=O)[O-]

Procedure:
Potassium hydroxide (0.278 g) was added to a solution of 3-fluoro-4-nitrobenzoic acid (0.4 g) in ethanol (7 ml) and the reaction treated with microwaves (300W, 100° C.) for 5 minutes. The reaction mixture was acidified using 2N HCl and extracted with ethyl acetate. The extracts were combined, washed with water, dried (MgSO4) and evaporated to give 3-ethoxy-4-nitro-benzoic acid (0.325 g).
Reaction SMILES: C1(C(C)C)C=CC=CC=1.[Na].[O-]O.C1(C(C)C)C=CC=CC=1.[CH2:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:30]1([CH2:36][CH2:37][C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([CH3:40])[CH3:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CO>[C:24]1([CH2:23][CH2:22][CH:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:37][C:38]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)([CH3:40])[CH3:39])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(CCc1ccccc1)c1ccccc1
Reactant: C=Cc1ccccc1
Agent: [Na]
Agent: [O-]O
Solvent: CC(C)c1ccccc1
Solvent: CO
Product: CC(C)(CC(CCc1ccccc1)c1ccccc1)c1ccccc1
Temperature: 135 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
A one-liter glass flask equipped with a stirrer, a dropping funnel with a gas introduction conduit, a reflux condenser with a calcium chloride tube, and a thermometer was charged with 240 grams (2.0 moles) of purified cumene, 4.0 grams (0.17 mole) of metallic sodium, and 3.6 grams (0.02 mole) of 80% cumene hydroperoxide while introducing argon gas through the gas introduction conduit, and the resulting mixture was heated to 135° C. A mixture of 69 grams (0.66 mole) of purified styrene and 60 grams (0.50 mole) of purified cumene was dropped thereto with stirring over 2 hours while maintaining the temperature of the reaction system at 135°-140° C. After dropwise addition was completed, the reaction mixture was further stirred while heating for 1 hour and then cooled to room temperature. An excess of metallic sodium was decomposed by dropping methanol in small portions while stirring. Introduction of argon gas was stopped, and the contents were transferred to a separating funnel and washed with water. The aqueous layer was removed, and the remaining oily layer was analyzed by gas chromatography. This gas chromatographic analysis showed that 67.6 grams (0.31 mole) of 1,3-diphenyl-3-methylbutane and 36.5 grams of (0.11 mole) of 1,3,5-triphenyl-5-methylhexane were formed. The total yield (per styrene) was 80 mole %.
Reaction SMILES: [OH-].[Na+:2].[SH:3][CH2:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=1)[C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[O:6]>O1CCCC1>[Na+:2].[SH:3][CH2:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=1)[C:11]([NH:13][CH2:14][C:15]([O-:17])=[O:16])=[O:12])=[O:6]
Reactant: O=C(O)CNC(=O)c1cccc(NC(=O)CS)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([O-])CNC(=O)c1cccc(NC(=O)CS)c1
Reaction time: 2 h
Yield: 88.3 %

Procedure:
An aqueous solution of 10% sodium hydroxide (65 ml., 0.1625 mole) is slowly added to a suspension of N-[3-(mercaptoacetylamino)benzoyl]glycine (43 g., 0.16 mole) in 230 ml. of tetrahydrofuran with cooling at 10°-20° C. The mixture is warmed to about 20°-25° C. and filtered from a trace of solid. Diluting the filtrate with 480 ml. of tetrahydrofuran promotes the formation of a suspension which is stirred for 2 hr. and collected. The collected material is washed with tetrahydrofuran and air dried to provide 50 g. (88.3% yield) of N-[3-(mercaptoacetylamino)benzoyl]glycine sodium salt hydrated with 3.5 moles water, m.p. 68°-120° C. (dec.).
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[CH:2]1.C([Mg]Cl)(C)C.[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH2:26][CH3:27])[CH:24]=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH2:26][CH3:27])[CH:24]([C:2]1[O:1][C:9]2[C:4]([N:3]=1)=[N:5][CH:6]=[CH:7][CH:8]=2)[OH:25])=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: c1cnc2ncoc2c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)OC(C)(C)C)C(O)c1nc2ncccc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
In a clean roundbottom flask equipped with stir bar was placed oxazolo[4,5-b]pyridine (600 mg, 5 mmol) in THF (30 mL) and the reaction mixture was cooled to 0° C. under N2 atomosphere. Isopropylmagnesium chloride (2 M in THF, 2.5 mL, 5 mmol) was added. After stirring for 1 h at 0° C., (S)-2-(tert-butoxycarbonyl)aminobutyraldehyde (573 mg, 3 mmol) in THF (20 mL) was added. The ice bath was removed and the reaction mixture was allowed to warm to room temperature. After 2 h, the reaction mixture was quenched with saturated ammonium chloride solution and concentrated to dryness. The residue was extracted with EtOAc, then washed with brine, dried with anhyd. MgSO4, filtered and concentrated. The crude product was purified by chromatograph to yield 383 mg of the desired compound.