Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.S(OS([O-])(=O)=O)([O-])(=O)=[O:3].[NH2:11][C:12]1[N:13]=[CH:14][C:15]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19](N)=[N:18][C:16]=2[N:17]=1>O>[NH2:11][C:12]1[N:13]=[CH:14][C:15]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]([OH:3])=[N:18][C:16]=2[N:17]=1
Reactant: O=S(=O)([O-])OS(=O)(=O)[O-]
Reactant: Nc1ncc2cc(-c3ccccc3)c(N)nc2n1
Agent: Cl
Solvent: O
Product: Nc1ncc2cc(-c3ccccc3)c(O)nc2n1
Reaction time: 8 h

Procedure:
To a solution of 2 L of concentrated HCl and 1 L of water is added 300 g of the disulfate salt of 2,7-diamino-6-phenylpyrido[2,3-d]pyrimidine and the resulting mixture refluxed with stirring overnight. The reaction mixture is cooled in an ice bath, filtered, and the insoluble product washed with water, followed by ethanol to give 149 g of the title compound 2-amino-6-phenyl-pyrido[2,3-d]pyrimidin-7-ol, mp 390°-395° C. (darkens slowly above 350° C.).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][CH3:28])=[CH:23][CH:22]=3)([CH3:20])[CH3:19])=[CH:14][CH:13]=2)([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[H][H]>>[CH3:28][NH:27][CH:24]1[CH2:23][CH2:22][CH:21]([C:18]([C:15]2[CH:14]=[CH:13][C:12]([C:9]([CH:6]3[CH2:5][CH2:4][CH:3]([NH:2][CH3:1])[CH2:8][CH2:7]3)([CH3:11])[CH3:10])=[CH:17][CH:16]=2)([CH3:20])[CH3:19])[CH2:26][CH2:25]1
Reactant: [H][H]
Reactant: CNc1ccc(C(C)(C)c2ccc(C(C)(C)c3ccc(NC)cc3)cc2)cc1
Product: CNC1CCC(C(C)(C)c2ccc(C(C)(C)C3CCC(NC)CC3)cc2)CC1
Yield: 99.8 %

Procedure:
100 g of α,α'-bis-(4-methylamino-phenyl)-p-diisopropylbenzene are hydrogenated in the presence of 1.0 g of the catalyst (2) (about 1% of ruthenium) at 180°- 200° C and 200° - 280° bars hydrogen pressure, until the absorption of hydrogen has ceased. Duration about 160 minutes. After cooling, the hydrogenation product is taken up in methanol, the solution is filtered and concentrated and the residue is distilled under reduced pressure. 103 g of α,α'-bis-(4-methylaminocyclohexyl)-p-diisopropylbenzene are obtained, corresponding to 100% of theory. Boiling range: 203° - 206° C/0.2 mm Hg, solidification point: 84° - 86° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1[O:12][CH3:13].C[O:15]C(OC)N(C)C.I([O-])(=O)(=O)=O.[Na+]>CN(C)C=O.O>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([CH:11]=[O:15])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: COc1cc(C)c([N+](=O)[O-])cc1Br
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)c([N+](=O)[O-])cc1Br
Temperature: 120 °C
Reaction time: 2 h
Yield: 19.2 %

Procedure:
The crude 1-bromo-2-methoxy-4-methyl-5-nitrobenzene (2.6 g, 11 mmol) was dissolved in N,N-dimethylformamide (15 mL) and N,N-dimethylformamide dimethylacetal (5 mL, 38 mmol) was added. The reaction was heated to 120° C. for 18 hours. The reaction was cooled to room temperature and the mixture was added directly to a 0° C. suspension of sodium periodate (12.2 g, 57.2 mmol) in water (20 mL) and N,N-dimethylformamide (5 mL). The reaction was stirred at 0° C. for 2 hours, then allowed to warm to room temperature and stir for another 6 hours. The reaction mixture was filtered, rinsing with ethyl acetate, toluene, and water. The filtrate was extracted with ethyl acetate (3×). The combined organics were washed with water and brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (0-50% ethyl acetate/heptanes) gave the title compound (550 mg, 19%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3, δ): 10.47 (s, 1 H), 8.41 (s, 1 H), 7.35 (s, 1 H), 4.05 (s, 3 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:17]([F:19])[F:18].C(=O)=O.Cl>O1CCOCC1.[OH-].[Na+].O>[F:18][CH:17]([F:19])[O:15][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=[CH:13][N:12]=1
Reactant: FC(F)Cl
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: Cl
Agent: O=C=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)Oc1cc(OCc2ccccc2)ccn1
Reaction time: 18 h
Yield: 56.4 %

Procedure:
4-Benzyloxy-2-pyridone (311.4 g, 1.55 mol) was mechanically stirred under nitrogen in a mixture of dioxane (6.2 L) and 50% sodium hydroxide (2.48 L) while chlorodifluoromethane (1,332.4 g, 15.5 mol) was condensed into the 22 L flask over a 4 h period using a dry-ice condenser that was attached to one of the necks of the 4-neck flask. The temperature inside the flask was maintained below 35° C. by means of an ice-bath. The mixture was then stirred for 18 h maintaining the temperature of the mixture between 25° C. and 35° C. The dry-ice condenser was in place during the 18 h reaction time. The mixture was then diluted with water, acidified to pH 1 with conc. HCl and extracted three times with ethyl acetate. If emulsions formed the whole mixture was filtered through a bed of celite. The combined organic layers were dried (MgSO4), filtered through silica gel and concentrated in-vacuo. The crude oil was chromatographed on a Prep-500 HPLC to give 2-difluoromethoxy-4-benzyloxypyridine (219.75 g, 56% yield) as a yellow oil, nD =1.5274. Anal. Calcd. for C13H11NO2F2 : C,62.15; H,4.41; N,5.58 Found: C,62.18; H,4.40; N,5.52.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40](=[O:46])[N:41]([CH2:43][CH2:44][F:45])[CH:42]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:45][CH2:44][CH2:43][N:41]1[C:40](=[O:46])[CH:39]=[CH:38][C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)=[CH:42]1
Reactant: O=c1ccc(Br)cn1CCF
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc(=O)n(CCF)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 20.8 %

Procedure:
To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (20 mg, 0.041 mmol), 5-bromo-1-(2-fluoroethyl)pyridin-2(1H)-one (9.2 mg, 0.041 mmol), and Cs2CO3 (2 N, 0.2 mL, 0.41 mmol) in 1,4-dioxane (2 mL) was added Pd(PPh3)2Cl2 (3 mg, 0.0041 mmol) under N2. The mixture was refluxed for 2 h, treated with EtOAc (10 mL) and water (10 mL). The organic layer was dried over Na2SO4, concentrated, and purified by preparative HPLC to give (S)-3-((S)-1-(4-(1-(2-fluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (4.20 mg, 20%). LC-MS Method 2 tR=1.01 min, m/z=515, 493; 1H NMR (CD3OD): δ 0.97 (s, 3H), 1.28 (s, 3H), 1.56 (d, 3H), 2.18 (s, 2H), 2.22 (m, 1H), 2.49 (m, 2H), 3.05 (m, 1H), 4.37 (t, 1H), 4.43 (t, 1H), 4.69 (t, 1H), 4.81 (t, 1H), 5.59 (q, 1H), 6.66 (d, 1H), 7.05 (d, 2H), 7.33 (m, 7H), 7.82 (m, 2H).
Reaction SMILES: [CH2:1]=[O:2].[C:3]1([CH3:12])[CH:8]=[CH:7][C:6]([S:9]([OH:11])=[O:10])=[CH:5][CH:4]=1>>[OH:2][CH2:1][S:9]([C:6]1[CH:7]=[CH:8][C:3]([CH3:12])=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: Cc1ccc(S(=O)O)cc1
Reactant: C=O
Product: Cc1ccc(S(=O)(=O)CO)cc1

Procedure:
Formaldehyde and p-toluenesulfinic acid were reacted together to produce hydroxymethyl-p-tolylsulfone according to the following procedure:
Reaction SMILES: B.CSC.[C:5]([CH2:8][C:9]1[C:10]([Cl:18])=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])(O)=[O:6]>C1COCC1>[Cl:18][C:10]1[C:11]([CH2:12][OH:13])=[CH:15][CH:16]=[CH:17][C:9]=1[CH2:8][CH2:5][OH:6]
Reactant: O=C(O)Cc1cccc(C(=O)O)c1Cl
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OCCc1cccc(CO)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of borane-methyl sulfide complex (2M in THF, 20 mL) was added portionwise over 5 minutes to a suspension of 3-(carboxymethyl)-2-chlorobenzoic acid (example 80, step b) (4.11 g) in dry THF (100 mL) at room temperature. The resulting effervescing suspension was stirred at room temperature for 30 minutes, then heated to reflux for 60 minutes, and allowed to cool to room temperature overnight. The mixture was quenched by the portionwise addition of methanol (15 mL) over 15 minutes. The mixture was diluted further with methanol to give a solution, which was then concentrated in vacuo to give a syrup. The syrup was purified by flash chromatography on silica eluted with 2% methanol in dichloromethane to the afford the crude subtitled compound as a white solid. Yield 1.44 g.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[OH:13])([CH3:4])([CH3:3])[CH3:2].[C:14]1([N:20]2[C:24](=[O:25])[CH:23]=[CH:22][C:21]2=[O:26])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(N(CC)CC)C>[C:14]1([N:20]2[C:24](=[O:25])[CH2:23][CH:22]([S:11][C:9]3[CH:8]=[C:7]([CH3:12])[C:6]([OH:13])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=3)[C:21]2=[O:26])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1C=CC(=O)N1c1ccccc1
Reactant: Cc1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Product: Cc1cc(SC2CC(=O)N(c3ccccc3)C2=O)cc(C(C)(C)C)c1O
Yield: 89 %

Procedure:
The procedure of Example 1 is repeated using 9.82 grams of 2-tert-butyl-6-methyl-4-mercaptophenol, 8.66 grams of N-phenylmaleimide, and 0.5 grams of triethylamine. The residue is recrystallized from a heptane-toluene mixture to give 16.44 grams of a white solid, m.p. 158°-160° C.
Reaction SMILES: C[O:2][C:3]1[C:38]([CH3:39])=[C:37]([CH3:40])[C:36]([O:41]C)=[C:35]([CH3:43])[C:4]=1[CH2:5][N:6]1[C:12](=[O:13])[C@H:11]2[CH2:14][CH2:15][CH2:16][C@H:10]2[N:9]([C:17](=[O:30])[CH2:18][N:19]2[C:23](=[O:24])[C:22]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]3[C:20]2=[O:29])[C:8]2[CH:31]=[CH:32][CH:33]=[CH:34][C:7]1=2.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(#N)C.O>[C:20]1(=[O:29])[N:19]([CH2:18][C:17]([N:9]2[C@@H:10]3[CH2:16][CH2:15][CH2:14][C@@H:11]3[C:12](=[O:13])[N:6]([CH2:5][C:4]3[C:3](=[O:2])[C:38]([CH3:39])=[C:37]([CH3:40])[C:36](=[O:41])[C:35]=3[CH3:43])[C:7]3[CH:34]=[CH:33][CH:32]=[CH:31][C:8]2=3)=[O:30])[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]12
Reactant: COc1c(C)c(C)c(OC)c(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)c1C
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CC1=C(C)C(=O)C(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)=C(C)C1=O
Yield: 63.2 %

Procedure:
In a mixture of acetonitrile (3 mL) and water (2 mL) was suspended (3aR*,10aS*)-9-(2,5-dimethoxy-3,4,6-trimethylbenzyl)-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (0.5 g, 0.86 mmol). To the suspension was added, while stirring, a solution of ammonium cerium (IV) nitrate (1.4 g, 2.55 mmol) in a mixture of acetonitrile (2 mL) and water (2 mL). The reaction mixture was stirred for one hour, which was diluted with water, followed by extraction with chloroform. The extract was washed with water and dried, then the solvent was distilled off. The residue was crystallized from ethyl acetate to give 300 mg (yield 63%) of the titled compound, m.p. 258°-260° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C.O>[N:11]([CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[N+:12]=[N-:13]
Reactant: COc1ccc(CCl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of p-methoxybenzyl chloride (4.26 mL, 31.4 mmol) in DMF (20 mL) was added sodium azide (2.04 g, 31.4 mmol). The reaction mixture was stirred at room temperature for 48 hours, diluted with H2O (200 mL), and then extracted with ether. The combined organic layers were washed w/H2O, dried over Na2SO4, filtered and conc. The clear oil obtained (4.9 g, 96%) was pure enough to use. 1H NMR (CDCl3, 400 MHz) 7.26-7.23 (m, 2H); 6.93-6.89 (m, H); 4.27 (s, 2H); 3.82 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:12][C:13]1[CH:28]=[CH:27][C:16]([O:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=1.C(N(CC)CC)C>C(O)(C)C>[F:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][N:24]([C:2]3[N:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)[CH2:25][CH2:26]2)=[CH:27][CH:28]=1
Reactant: Fc1ccc(OCCCN2CCNCC2)cc1
Reactant: Clc1ncc2ccccc2n1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Fc1ccc(OCCCN2CCN(c3ncc4ccccc4n3)CC2)cc1

Procedure:
2.5 g 2-Chloro-quinazoline, 3.8 g 1-[3-(4-fluorophenoxy)propyl]piperazine and 2.5 ml triethylamine in 15 ml isopropanol are stirred under reflux for 5 hours. The solvent is then evaporated in vacuo and the residue partitioned between water and methylene chloride. The organic phase is dried and evaporated. The residue is recrystallized from ethanol to yield the title compound, m.p. 126°-128° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([CH2:16][OH:17])[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[CH:28][C:29]([N:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)=[N:30][CH:31]=2)O1>>[OH:17][CH2:16][C:14]1[N:15]=[C:8]2[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[N:12][CH:11]=[C:10]([C:26]3[CH:27]=[CH:28][C:29]([N:32]4[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]4)=[N:30][CH:31]=3)[N:9]2[CH:13]=1
Reactant: OCc1cn2ccnc(N3CCOCC3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(CO)cn34)cn2)CC1

Procedure:
Compound 1d was subjected to Suzuki coupling reaction conditions with tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate using the method described in Example 1, Step G to obtain compound 30a. Mass Spectrum (LCMS, ESI pos.) Calcd. for C25H33N7O4: 496.2 (M+H). Found 496.3.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([CH2:7][CH2:8][CH3:9])=[N:4][C:3]=1[CH:10]=O.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[NH:13][NH2:14]>>[CH2:17]([O:16][C:12](=[O:15])[NH:13][N:14]=[CH:10][C:3]1[N:4]=[C:5]([CH2:7][CH2:8][CH3:9])[NH:6][C:2]=1[CH3:1])[CH3:18]
Reactant: CCCc1nc(C=O)c(C)[nH]1
Reactant: CCOC(=O)NN
Product: CCCc1nc(C=NNC(=O)OCC)c(C)[nH]1

Procedure:
A 12 gm. portion of 5-methyl-2-n-propyl-4-imidazolecarboxaldehyde and 9.06 gm. of ethyl carbazate are reacted as described in Example 32 giving the desired product, m.p. 184°-188° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH2:16]([NH2:22])[CH:17]1[O:21][CH2:20][CH2:19][CH2:18]1>O>[C:10]1([CH:8]([OH:9])[CH:7]([NH:22][CH2:16][CH:17]2[CH2:18][CH2:19][CH2:20][O:21]2)[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NCC1CCCO1
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Solvent: O
Product: OC(c1ccccc1)C(NCC1CCCO1)c1ccccc1
Temperature: 140 °C
Reaction time: 18 h
Yield: 76.7 %

Procedure:
A mixture of trans-stilbene oxide (1.96 g, 0.010 mol) and tetrahydrofurfurylamine (3.03 g, 0.030 mol) was heated at 140° C. for 2 hours. After standing at ambient temperature for 18 hours the mixture was diluted with water (150 mL). An oil separated from the solution but solidified on standing for an hour. NMR and mass spectral analyses showed stilbene oxide remaining. The solid was treated with another 3.03 g of tetrahydrofurfurylamine and the mixture heated at 150° C. for another 3 hours. The reaction mixture was treated with water (150 mL) as before to obtain 2.28 g (77%) of an off-white solid after drying under ambient conditions for 18 hours. The solid was recrystallized form toluene; mp 167°-168° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[CH:6]([OH:9])[CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1COc2cc(Br)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1COc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of 6-bromo-benzofuran-3-one (10.5 g, 49.28 mmol) in methanol (100 ml) was added NaBH4 (2.37 g, 64.07 mmol) at 0° C. The reaction mixture was then stirred for 2 hours at room temperature. It was subsequently quenched with saturated ammonium chloride solution (50 ml) and extracted twice with ethyl acetate (2×50 ml). The combined organic phases were dried over Na2SO4 and evaporated under reduced pressure to give 9.75 g (92%) of the title compound as colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH:13]=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O[CH:20]([CH:22]=[CH2:23])[CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:15]([C:12]([CH2:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])([CH2:21]/[CH:20]=[CH:22]/[CH3:23])[CH:13]=[O:14])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCC(C=O)CS(=O)(=O)c1ccc(C)cc1
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C/C=C/CC(C=O)(CCCC)CS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 2-(((4-methylphenyl)-sulfonyl)methyl)hexanal (5.63 g, 21 mmol) in 35 ml of toluene in a RBF fitted with a Dean-Stark trap is added 2-hydroxy-3-butene (10 mL, 115 mmol), followed by p-toluenesulfonic acid (0.13 g) at room temperature under nitrogen. The mixture is heated to reflux overnight. After cooling to room temperature, the toluene solution is washed with saturated NaHCO3 solution (2×10 mL), water (2×20 mL), brine (1×20 mL), and dried with MgSO4. After removing solvents, the product is obtained as a brownish oil in quantitative yield with a GC purity of 89%.
Reaction SMILES: [CH3:1][C:2]([CH3:14])=[CH:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]([CH3:14])=[CH:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][NH2:10]
Reactant: CC(C)=CCOc1cccc(C#N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=CCOc1cccc(CN)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
3-(3-Methyl-2-butenyloxy)-benzonitrile described in Preparation Example 133 (1.71 g, 10 mmol) was dissolved in tetrahydrofuran (20 mL), lithium aluminum hydride (0.57 g, 15 mmol) was added under stirring at room temperature, the solution was heated to 70° C., then stirring continued for 2 hours. The reaction solution was cooled on an ice bath, then, water (0.6 mL), an aqueous solution of 15% sodium hydroxide (0.6 mL) and water (1.8 mL) were added in this order, then, the solid was filtered, and washed with tetrahydrofuran (20 mL). The filtrate and the washings were combined, and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo, and the title compound (1.50 g, 8.52 mmol, 85.2%) was obtained as a colorless oil.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].Cl[CH2:30][CH2:31][CH2:32][C:33]#[N:34]>CC(C)CC(=O)C>[C:33]([CH2:32][CH2:31][CH2:30][N:12]1[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:11]1)#[N:34]
Reactant: N#CCCCCl
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: N#CCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1

Procedure:
The starting material for said product No. (4) is prepared as follows. The mixture of 4.63 g of 4-diphenylmethoxypiperidine, 4.63 g of anhydrous sodium carbonate, 0.3 g of sodium iodide, 1.81 g of 4-chlorobutyronitrile and 60 ml of 4-methyl-2-pentanone is stirred and refluxed for 22 hours. It is evaporated, the residue taken up in diethyl ether, the solution washed with 2N aqueous sodium hydroxide and saturated aqueous sodium chloride, dried and evaporated, to give the 1-(3-cyanopropyl)-4-diphenylmethoxypiperidine, which is sufficiently pure to be used directly for the reduction to the 1-(4-aminobutyl)-4-diphenylmethoxypiperidine previously described.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14])(=[O:3])[CH3:2].Cl.[CH:16]([CH:18]=[CH2:19])=[O:17]>>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:19][CH2:18][CH:16]=[O:17])(=[O:3])[CH3:2]
Reactant: C=CCCCCCCCCOC(C)=O
Reactant: C=CC=O
Agent: Cl
Product: CC(=O)OCCCCCCCCCCCCC=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.2 %

Procedure:
To a stirred 1.0 Molar solution of borane·tetrahydrofuran complex, 90 ml (0.09 mole), was added dropwise 57 grams (0.27 mole) of 9-decenyl acetate. The reaction mixture temperature was maintained at 20°-25° C. during the addition. Upon completion of addition, the reaction mixture stirred at ambient temperature for 18 hours. After this time 2 ml of aqueous 3M hydrochloric acid was added, and the reaction mixture was stirred for five minutes. To this was then added 5.0 grams (0.09 mole) of acrolein, during which time the reaction mixture temperature rose to 35° C. The reaction mixture was concentrated under reduced pressure to a residual oil. The oil was taken up in pentane and was washed with three 30 ml portions of an aqueous solution saturated with sodium bicarbonate. The organic layer was concentrated under reduced pressure to a residual oil. Volatile materials were removed from the oil by distillation under reduced pressure yielding 4.9 grams of 13-oxotridecyl acetate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:33]([OH:37])(=[O:36])[CH:34]=[CH2:35].C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2](/[CH:35]=[CH:34]/[C:33]([OH:37])=[O:36])=[CH:3][C:4]=1[CH3:10])#[N:7]
Reactant: C=CC(=O)O
Reactant: Cc1cc(Br)ccc1C#N
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc(/C=C/C(=O)O)ccc1C#N
Temperature: 200 °C
Reaction time: 2 h

Procedure:
9.0 g 4-bromo-2-methylbenzonitrile, 2.76 g tri-o-tolylphosphine, 3.11 ml acrylic acid and 25.1 ml triethylamine are dissolved in 80 ml acetonitrile. The reaction mixture is degassed, then 2.0 g palladium (II)acetate were added and the mixture stirred two hours under microwave irradiation at 200° C. The cooled reaction mixture was diluted by addition of 50 ml ethyl acetate. Thereby (E)-3-(4-Cyano-3-methyl-phenyl)-acrylic acid precipitated as a white solid. The precipitate was filtered off and dried in vacuo to obtain 2.5 g (E)-3-(4-Cyano-3-methyl-phenyl)-acrylic acid. The filtrate was washed with 1N HCl, thereby (E)-3-(4-Cyano-3-methyl-phenyl)-acrylic acid precipitated again as a white solid. The precipitate was filtered off and dried in vacuo to obtain 2.0 g (E)-3-(4-Cyano-3-methyl-phenyl)-acrylic acid. The filtrate was reduced in vacuo to one third of its volume, 150 ml diethyl ether were added, thereby (E)-3-(4-Cyano-3-methyl-phenyl)-acrylic acid precipitated again as a white solid. The precipitate was filtered off and dried in vacuo to obtain 840 mg (E)-3-(4-Cyano-3-methyl-phenyl)-acrylic acid