Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[CH2:18][CH2:17][CH2:16]2.CN(P(N(C)C)(N(C)C)=O)C.[CH2:35](Br)[CH:36]=[CH2:37]>C1COCC1>[CH2:37]([CH:18]1[CH2:17][CH2:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([O:12][CH3:11])[CH:14]=2)[C:19]1=[O:23])[CH:36]=[CH2:35]
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCC1CCc2cc(OC)ccc2C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
To a solution of LiHMDS (1.04 g, 6.24 mmol), in THF (40 mL) cooled at −78° C. is added slowly a solution of 6-methoxy-1-tetralone (1.0 g, 5.67 mmol) in anhydrous THF (40 mL). After the addition is complete, the solution is stirred at −78° C. for 30 minutes, then HMPA (1.97 mL, 11.3 mmol) is slowly added and the mixture is stirred for other 5 minutes followed by the addition of a solution of allyl bromide (0.74 mL, 8.5 mmol) in anhydrous THF (5 mL). The mixture is left to warm slowly to room temperature (2-3 h) and quenched at 0° C. with aqueous 1N HCl (20 mL), then extracted with diethylether. The organic phase is dried over MgSO4 and concentrated to dryness. The residue is purified by column chromatography on SiO2 (Petroleum Ether/EtOAc=95:5) to afford the title compound 53 as a colorless oil (Yield 0.56 g, 45%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][C:24]([CH3:26])=[CH:23][N:19]3[C:20](=[O:22])[CH:21]=2)[CH2:3][CH2:2]1.[I:27]N1C(=O)CCC1=O>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][C:24]([CH3:26])=[CH:23][N:19]3[C:20](=[O:22])[C:21]=2[I:27])[CH2:3][CH2:2]1
Reactant: COc1cccc(/C=C/c2cc(=O)n3cc(C)sc3n2)c1OCC1CC1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: COc1cccc(/C=C/c2nc3sc(C)cn3c(=O)c2I)c1OCC1CC1

Procedure:
To a solution of Step 3 intermediate (700 mg, 1.810 mmol) in acetonitrile (10 ml) was added N-iodosuccinimide (641 mg, 2.841 mmol) and reacted according to the procedure described in Step 4, Intermediate 2 to afford 600 mg of the desired compound; 1H NMR (300 MHz, CDCl3) δ 0.31-0.33 (m, 2H), 0.53-0.56 (m, 2H), 1.22 (br s, 1H), 2.43 (s, 3H), 3.76-3.81 (m, 2H), 3.81 (s, 3H), 7.05-7.11 (m, 2H), 7.25-7.28 (m, 1H), 7.51 (d, J=15.6 Hz, 1H), 7.80 (s, 1H), 8.14 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 495.10 (M+H)+.
Reaction SMILES: O.C[Si]([Cl:6])(C)C.[CH3:7][N:8]([CH2:10][CH:11]1[CH2:19][CH2:18][CH:17]2[CH:13]([CH2:14][CH2:15][CH2:16]2)[C:12]1([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=1)[OH:20])[CH3:9]>CC(=O)CC>[ClH:6].[CH3:9][N:8]([CH2:10][CH:11]1[CH2:19][CH2:18][CH:17]2[CH:13]([CH2:14][CH2:15][CH2:16]2)[C:12]1([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=1)[OH:20])[CH3:7]
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CC1CCC2CCCC2C1(O)c1cccc(O)c1
Solvent: CCC(C)=O
Solvent: O
Product: Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Add H2O (10 mg, 0.54 mmol) and TMSCl (35 mg, 0.33 mmol) to a solution of 5-((dimethylamino)methyl)-4-(3-hydroxyphenyl)octahydro-1H-inden-4-ol (78 mg, 0.27 mmol) in 2-butanone (10 mL). Then stir the mixture at room temperature for 12 hours. Evaporate the mixture under vacuum to give 5-((dimethylamino)methyl)-4-(3-hydroxyphenyl)octahydro-1H-inden-4-ol hydrochloride as a mixture of 4 diastereoisomers (91 mg, Yield: 100%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][CH:13]2[CH2:18][CH2:17][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)([N:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[CH:2]1.[Cl:28][Si](C)(C)C>CC(=O)CC>[ClH:28].[ClH:28].[ClH:28].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][CH:13]2[CH2:18][CH2:17][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)([N:19]([CH3:20])[CH3:21])[CH2:15][CH2:14]2)=[CH:2]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccn2)CCC(NCCc2c[nH]c3ccccc23)CC1
Solvent: CCC(C)=O
Product: Cl

Procedure:
The N′-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-yl cyclohexane-1,4-diamine obtained according to example 1 (342 mg) was dissolved in 2-butanone (20 ml) and converted to the corresponding trihydrochloride with chlorotrimethyl silane (0.59 ml) (beige-coloured solid; 408 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C[Si]([Cl:31])(C)C>CC(CC)=O>[ClH:31].[CH2:1]([N:8]1[C:12]2([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)[NH:11][C@@H:10]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Agent: O=C1[C@H](Cc2ccccc2)NC2(CCNCC2)N1Cc1ccccc1
Solvent: CCC(C)=O
Solvent: O
Product: Cl
Reaction time: 8 h

Procedure:
1,3-(S)-Dibenzyl-1,4,8-triazaspiro[4,5]decan-2-one (400 mg, 1.2 mmol) was dissolved in ethyl methyl ketone (3 ml), treated with water (12 μL) and with TMSCl (166 μL) and stirred overnight. The solid was filtered off, washed with ether and dried in vacuo. The product 1,3-(S)-dibenzyl-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 315 mg (71%).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].C1CCCCC1.[OH-].[Na+:39]>CO>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:39]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCCCC1
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Yield: 90 %

Procedure:
Fluvastatin methyl ester (3.0 g) was added to cyclohexane (60 ml) and the slurry was heated to reflux. A solution of NaOH (1 eq.) in MeOH (3 ml) was added to the slurry solution which became clear. After 15 min. a precipitate formed. After another hour, the mixture was cooled to room temperature and cyclohexane (40 ml) was added. The mixture was stirred over night. The product was isolated by filtration under nitrogen, washed with cyclohexane (90 ml) and dried at 50EC in a vacuum oven for 24 h to yield 2.73 g (90%) of amorphous fluvastatin sodium.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33]>C(#N)C.O>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
Fluvastatin methyl ester (3.01 g) was dissolved in acetonitrile (60 ml) by heating and a solution of NaOH (0.28 g) in water (0.75 ml) was added at about 50EC. The mixture was stirred at about 40EC for 2 h, cooled to room temperature and stirred for another h. The product was isolated by filtration under nitrogen, washed with acetonitrile (40 ml) and dried at 50EC in a vacuum oven for 24 h to obtain 2.52 g (82.2%) of fluvastatin sodium crystal Form I.
Reaction SMILES: CC(O)(C(C)=C)C.Cl[C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14]O)=[O:13].S([O-])([O-])=O.[Na+].[Na+].O>C(Cl)(Cl)Cl>[C:12]([OH:14])(=[O:13])[C:11]1[CH:16]=[CH:17][CH:18]=[CH:9][CH:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: C=C(C)C(C)(C)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 46.7 g of 2,3-dimethyl-3-buten-2-ol in 602 ml of chloroform was cooled to 0°-5° in a dry ice-acetone bath. To this was added dropwise, during 4 hours, a solution of 96.5 g of m-chloroperoxybenzoic acid (113.5 g of 85%) in 966 ml of chloroform. The reaction mixture temperature was maintained at 0°-5° throughout the addition. Upon complete addition, the reaction mixture was allowed to warm to ambient temperature where it was stirred for 18 hours. To the reaction mixture was slowly added a solution of 11.8 g of sodium sulfite in a minimum amount of water. The reaction mixture was tested for peroxides using wet acidic sodium iodide-starch paper; there were no peroxides present. Concentration of the reaction mixture to below one-half the original volume resulted in precipitation of benzoic acid from the reaction mixture. The benzoic acid was removed by filtration. The concentration, precipitation, and filtration was repeated several times until at the last concentration only a small amount of precipitated benzoic acid was collected. There remained 16.6 g of residual yellow liquid, from which on standing a white solid crystallized. The liquid portion was decanted off and the solid was washed with diethyl ether. The ether wash was added to the liquid portion. The white solid had a melting point of 116°-118° and decomposed explosively at 170°-180°. The liquid portion was distilled using a Vigreux column, to give 9.32 g of 2-[(1-hydroxy-1-methyl)ethyl]-2-methyloxirane bp 35°-65°/15-20 mm. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:19][S:20]([O:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCC2(CC1)OCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
A solution of 1,4-dioxaspiro[4.5]decan-8-ol (1.10 g, 6.81 mmol), triethylamine (1.21 mL, 8.67 mmol) in DCM (25.2 mL) was cooled in an ice/water bath and treated with methanesulfonyl chloride (675 μL, 8.67 mmol) added dropwise under an atmosphere of nitrogen. The mixture was stirred at 25° C. overnight. The mixture was treated with saturated aqueous NaHCO3 (20 mL) and extracted with DCM (2×50 mL). The extracts were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo leaving a beige oil which was recrystallized from hexanes (22 mL) to give 1.59 g (98%) of the title compound as a white crystalline solid. 1H NMR (400 MHz, CDCl3) δ 1.61-1.68 (m, 2H), 1.82-1.90 (m, 2H), 1.94-2.08 (m, 4H), 3.02 (s, 3H), 3.91-4.00 (m, 4H), 4.82-4.88 (m, 1H); MS (ESI): 237.10 [M+H]+; HPLC tR=2.54 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](I)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:29][CH2:28][C:23]2([O:27][CH2:26][CH2:25][O:24]2)[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].C(N(CC)CC)C.[CH3:38][C:39]([CH3:43])([CH3:42])[C:40]#[CH:41]>[Cu](I)I.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:41]#[C:40][C:39]([CH3:43])([CH3:42])[CH3:38])=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:29][CH2:28][C:23]2([O:27][CH2:26][CH2:25][O:24]2)[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: C#CC(C)(C)C
Reactant: COC(=O)c1sc(I)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC2(CC1)OCCO2
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC2(CC1)OCCO2
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a 25 mL RBF under nitrogen, 3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-iodo-thiophene-2-carboxylic acid methyl ester (1 eq.), copper iodide (0.025 eq.) and tris(dibenzylideneacetone) dipalladium (0) (0.01 eq.) are taken. DMF, triethylamine (2.5 eq.) and 3,3-dimethyl-but-1-yne (2 eq.) are added and the reaction mixture is stirred at 40° C. for 2 h under a N2 atmosphere. The reaction mixture is filtered on celite and washed with ethyl acetate. The solution is diluted with water and extracted 2 times with ethyl acetate. The organic phases are combined and washed 3 times with water. The organic layer is separated, dried (Na2SO4), evaporated to about 2 mL and then 8 mL of heptane is added. It is evaporated to 2-4 mL and cooled in an ice bath. The formed white solid is filtered, washed with heptane and dried in oven to obtain 5-(3,3-dimethyl-but-1-ynyl)-3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](O)=[O:6].Cl.[CH3:13][NH:14][O:15][CH3:16].C(N(CC)C(C)C)(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([N:14]([O:15][CH3:16])[CH3:13])=[O:6]
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(Cl)c(Br)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.7 %

Procedure:
3-Bromo-4-chlorobenzoic acid (1.0 g, 4.24 mmol, 1.0 eq) was dissolved in dry DMF and stirred for 10 minutes. The solution was cooled to 0° C. and treated with N,O-dimethyl hydroxylamine hydrochloride (0.828 mg, 8.48 mmol, 2.0 eq), 1-hydroxybenzotrizole (860 mg, 6.36 mmol, 1.5 eq), N,N-diisopropyl ethylamine (820 mg, 6.37 mmol, 1.5 eq), and EDC HCl (1.2 g, 6.37 mmol, 1.5 eq). The reaction mixture was stirred for 12 h, evaporated under reduced pressure and diluted with water (25 mL). The aqueous layer was extracted with ethyl acetate. The organic layer was dried under anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (60-120) eluting with 5-10% ethyl acetate/hexane to afford the desired product (1 g, 85%). 1H NMR (400 MHz, CD3OD) δ 3.34 (s, 3H), 3.57 (s, 3H), 7.47-7.49 (d, 1H), 7.71-7.74 (d, 1H), 7.85-7.88 (d, 1H). MS (ESI): 278.2 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:17][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10](=[O:18])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:19][C:20](OC(C)=O)=[O:21].N1C=CC=CC=1>O>[C:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:17][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10](=[O:18])[CH:9]=2)=[CH:6][CH:7]=1)(=[O:21])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1cc(-c2ccc(O)cc2)oc2ncccc12
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1ccc(-c2cc(=O)c3cccnc3o2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.9 %

Procedure:
In a 50 mL round-bottomed flask fitted with condenser and magnetic stirrer were placed 2-(4-hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one (212 mg, 0.89 mmol), Ac2O (99 mg, 0.97 mmol), and pyridine (5 mL). The reaction mixture was stirred for 24 h at room temperature. The reaction mixture was poured into water and extracted with EtOAc. The organic layer washed with water, dried and concentrated to afford 4-(4-oxo-4H-pyrano[2,3-b]pyridine-2-yl)phenyl acetate (240 mg, 96%). MS (ES) m/z: 282.89 (M+1), 281.92 (M); Mp. 167-169° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[H][H]>C(O)C.[Pd]>[NH2:1][CH:2]1[CH2:10][CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3]1
Reactant: [H][H]
Reactant: Nc1cccc(C(=O)O)c1
Agent: [Pd]
Solvent: CCO
Product: NC1CCCC(C(=O)O)C1
Reaction time: 192 h
Yield: 57.2 %

Procedure:
A mixture of 3-aminobenzoic acid (66.12 g, 0.48 mol) and 10% palladium-on-carbon (13.2 g) in 30% aqueous ethanol (1200 mL) was placed in a 4 L stainless steel high-pressure reactor and reduced at 50° C. and 500 psi of hydrogen for 30 h. The mixture was filtered through Celite and the filter cake was washed with ethanol. The solvent was evaporated, boiling ethanol (1 L) was added and the mixture was allowed to stand for 8 days at room temperature. The mixture was filtered and the product was washed with ethanol and then dried in a vacuum oven at 50° C., to give 3-aminocyclohexanecarboxylic acid (39.30 g, 57%) as a white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][C:16]([OH:18])=O)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]>C(Cl)Cl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][C:16]([Cl:3])=[O:18])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CC(=O)Cl)cc1OC

Procedure:
First, thionyl chloride (600 ml) is added dropwise with stirring over a period of 2 hours to a suspension of 3,4-dimethoxy-phenylacetic acid (549.4 g) in methylene chloride (600 ml). After the evolution of gas has ended (16 hours) the mixture is refluxed for a further hour. After the volatile components have been eluminated the residue is distilled in vacuo.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>ClCCl>[C:1]([NH:5][S:14]([CH3:13])(=[O:16])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
To a 0° C. solution of 10 g (136.7 mmol) of t-butylamine and 15.2 g (150.4 mmol) of triethylamine in 350 mL of dichloromethane was added 15.7 g (136.7 mmol) of methanesulfonyl chloride in 20 mL of dichloromethane over 15 minutes. Continue stirring at 0° C. for 30 minutes then warm to room temperature over one hour. The mixture was washed once with 250 mL of 10% aqueous sodium bisulfate. The organic portion was separated and the aqueous portion was extracted two times with 100 mL each of dichloromethane. The combined organics were dried (Na2SO4), filtered and concentrated in vacuo. The residue was recrystallized from petroleum ether and dried in vacuo to afford 12.2g (59%) N-t-butyl methanesulfonamide.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[C:6](F)=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:4][C:5]1[C:6]([C:1]#[N:2])=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1
Reactant: [C-]#N
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: N#Cc1ncc(C(F)(F)F)cc1Cl
Reaction time: 23 h
Yield: 82.1 %

Procedure:
Solid sodium cyanide (0.29 g) was added to a stirred mixture of 3-chloro-2-fluoro-5-trifluoromethylpyridine (0.8 g) and tetrabutylammonium bromide (0.06 g) at 20-25° C., and stirred for 23 hours to give 3-chloro-2-cyano-5-trifluoromethylpyridine (0.68 g, 82% yield by hplc).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].[CH3:11][Mg]Br>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH3:11])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(C=O)ccc1Br
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1cc(C(C)O)ccc1Br
Reaction time: 2 h
Yield: 93 %

Procedure:
A solution of 4-bromo-3-methylbenzaldehyde (4 g, 20 mmol) in dry tetrahydrofuran (40 mL) was cooled to 0° C. under nitrogen atmosphere, and then methyl magnesium bromide (20 mL, 1N in tetrahydrofuran) was added dropwise. The ice bath was removed, and the mixture was stirred for 2 hours. Ammonium chloride aqueous (40 mL) was added and the mixture was extracted with dichloromethane (20 mL*3). The organic phase was dried by sodium sulphate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give 1-(4-bromo-3-methylphenyl)ethanol as a colorless oil (4.0 g, 93%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[C:11]1([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(O)c1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(O)c1cccc(-c2ccccc2)n1
Yield: 51.2 %

Procedure:
To a solution 1.0 g (4.9 mmol) of 6-bromo-pyridine-2-carboxylic acid, 0.9 g (7.4 mmol) of phenylboronic acid, 0.4 g (0.36 mmol) of palladium tetrakistriphenyl phosphine in 25 mL of DME was added 9.9 mL of 2 N Na2CO3 solutions under nitrogen. After 12 h reflux under nitrogen, the reaction mixture was cooled and filtered through a filter paper. The filtrate was acidified using 2 N HCl (pH=5). The resulting white precipitate was filtered, washed with water and dried to afford 0.5 g (51%) of 6-phenyl-pyridine-2-carboxylic acid. LCMS: 200 (M+1)+
Reaction SMILES: [OH:1][PH2:2]=[O:3].[OH2:4].[OH2:5].O.O.O.O.[N+]([O-])([O-])=O.[Zn+2:14].[N+]([O-])([O-])=O.[Zn]>O>[P:2]([O-:5])([O-:4])([O-:1])=[O:3].[Zn+2:14].[P:2]([O-:5])([O-:4])([O-:1])=[O:3].[Zn+2:14].[Zn+2:14]
Reactant: O
Reactant: O=[PH2]O
Agent: O=[N+]([O-])[O-]
Agent: [Zn+2]
Agent: [Zn]
Product: O=P([O-])([O-])[O-]

Procedure:
An aqueous solution of 13.67 g 50 wt % H3PO2 was combined with 5.00 g deionized water to form a clear, colorless solution contained in a 250 ml Pyrex beaker. To this solution was added 46.23 g zinc nitrate hexahydrate salt, Zn(NO3)26H2O (Aldrich Chemical Co., Inc. #22,873-7, CAS #10196-18-6), equivalent to 21.97 wt. % Zn. The molar ratio of [Zn]2+/[PO4]−3 in this mixture was 3/2 and the equivalent solids level [as Zn3(PO4)2] was 27.5 wt. %.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[H-].[Na+].Br[C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11].C(=O)(O)[O-].[Na+]>C1COCC1>[C:3]([CH:2]([C:1]#[N:5])[C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])#[N:4]
Reactant: COC(=O)C(C)(C)Br
Reactant: N#CCC#N
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)C(C#N)C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In THF (91 ml), 3 g (45.411 mmol) of malononitrile were added slowly to 1.816 g (45.411 mmol) of sodium hydride (60% in mineral oil). Subsequently, 5.876 ml (45.411 mmol) of methyl 2-bromo-2-methylpropanoate were added and the mixture was stirred at RT overnight. Thereafter, another 5.876 ml (45.411 mmol) of methyl 2-bromo-2-methylpropanoate were added and the mixture was heated at 50° C. overnight. Then yet another 1.762 ml (13.623 mmol) of methyl 2-bromo-2-methylpropanoate were added and the mixture was heated at 50° C. for a further 4 h. Saturated aqueous sodium bicarbonate solution was then added to the reaction, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness. This gave 8.9 g of crude product, which was purified by chromatography on silica gel (cyclohexane-ethyl acetate 4:1).