Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([NH2:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]=O.[CH3:13][C:14]1[C:15]2[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[C:16]=2[C:17]2[CH2:18][CH2:19][C:20](=[O:24])[NH:21][C:22]=2[CH:23]=1>C(O)C>[ClH:1].[CH3:13][C:14]1[C:15]2[CH2:28][CH2:27][CH:26]([CH2:11][NH:10][CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:25](=[O:29])[C:16]=2[C:17]2[CH2:18][CH2:19][C:20](=[O:24])[NH:21][C:22]=2[CH:23]=1
Reactant: Cc1cc2c(c3c1CCCC3=O)CCC(=O)N2
Reactant: NCCc1ccccc1
Reactant: C=O
Agent: Cl
Solvent: CCO
Product: Cc1cc2c(c3c1CCC(CNCCc1ccccc1)C3=O)CCC(=O)N2
Yield: 25 %

Procedure:
Phenethylamine hydrochloride (4.7 g), 2.7 g of paraformaldehyde and 4.6 g of 6-methyl-1,2,3,4,7,8,9,10-octahydro-benzo[f]quinoline-3,10-dione are added to 200 ml of ethanol, and the mixture is stirred under reflux for 2 days. The reaction mixture is then cooled, and the precipitated crystals are collected by filtration and recrystallized from 60% ethanol to give 2.0 g of 6-methyl-1,2,3,4,7,8,9,10-octahydro-9-phenethylaminomethylbenzo[f]quinoline-3,10-dione hydrochloride as colorless needles, melting at 190°-192° C.
Reaction SMILES: Cl[C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][C:6]([C:19]([O:21][CH3:22])=[O:20])=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1>C(O)(C)C>[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH:38][C:2]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](=[O:18])[C:9]3[C:4](=[CH:5][C:6]([C:19]([O:21][CH3:22])=[O:20])=[CH:7][CH:8]=3)[N:3]=2)=[CH:35][CH:34]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc2c(=O)n(-c3ccccc3)c(Cl)nc2c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(=O)n(-c3ccccc3)c(NCc3ccc(Cl)cc3)nc2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 28.6 %

Procedure:
To a suspension of methyl 2-chloro-4-oxo-3-phenyl-3,4-dihydroquinazoline-7-carboxylate (0.10 g, 0.25 mmol) in isopropyl alcohol (2.8 mL) was added N,N-diisopropylethylamine (93 μL, 0.53 mmol) and p-chlorobenzylamine (77.3 μL, 0.64 mmol). The reaction mixture was heated to 100° C. and stirred for 1 h. The mixture was then cooled to rt and concentrated. The residue was purified by flash silica gel chromatography (0% to 30% EtOAc/hexanes) to afford methyl 2-[(4-chlorobenzyl)amino]-4-oxo-3-phenyl-3,4-dihydroquinazoline-7-carboxylate (30 mg, 30%). LC-MS: (FA) ES+ 420.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][C@H:10]([NH:12][C:13]1[C:14]2[S:31][C:30](=[O:32])[NH:29][C:15]=2[N:16]=[C:17]([S:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[F:28])[N:18]=1)[CH3:11].CC([Si](C)(C)[O:38][CH2:39][CH:40]=O)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C1COCC1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:28][C:22]1[C:23]([F:27])=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][S:19][C:17]1[N:18]=[C:13]([NH:12][C@H:10]([CH3:11])[CH2:9][NH:8][CH2:40][CH2:39][OH:38])[C:14]2[S:31][C:30](=[O:32])[NH:29][C:15]=2[N:16]=1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: C[C@H](CN)Nc1nc(SCc2cccc(F)c2F)nc2[nH]c(=O)sc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: C[C@H](CNCCO)Nc1nc(SCc2cccc(F)c2F)nc2[nH]c(=O)sc12
Reaction time: 1 h

Procedure:
To a solution of the product from example 12 step f) (100 mg) in dry THF (5 ml) was added [[(1,1-dimethylethyl)dimethylsilyl]oxy]-acetaldehyde (49 mg) followed by sodium triacetoxyborohydride (61 mg) and the mixture stirred for 1 hour. The mixture was acidified with concentrated hydrochloric acid, stirred at room temp for 1 hour then evaporated to dryness. The product was purified (HPLC, Novapak® C18 column, 0.1% aqueous TFA:acetonitrile, gradient elution 75:25 to 5:95 over 15 minutes) to afford the title compound (0.021 g).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:15]C[C:17](Cl)=[O:18].[CH3:20][NH:21][CH3:22]>>[ClH:15].[ClH:15].[N:8]1([CH2:6][C:17]([N:21]([CH3:22])[CH3:20])=[O:18])[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CNC
Reactant: O=C(Cl)CCl
Product: CN(C)C(=O)CN1CCCNCC1
Product: Cl

Procedure:
prepared from [1,4]diazepane-1-carboxylic acid tert-butyl ester, chloroacetylchloride and dimethylamine in an analogous manner as described in example 15.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]([O:17][CH3:18])=[CH:16][C:11]=3[CH2:10][CH2:9][C@H:8]([NH:23][C:24](=[O:38])[CH2:25][NH:26][C:27](=[O:37])[CH2:28][NH:29]C(OCCCC)=O)[C:7]=2[CH:39]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]([O:17][CH3:18])=[CH:16][C:11]=3[CH2:10][CH2:9][C@H:8]([NH:23][C:24](=[O:38])[CH2:25][NH:26][C:27](=[O:37])[CH2:28][NH2:29])[C:7]=2[CH:39]=1
Reactant: CCCCOC(=O)NCC(=O)NCC(=O)N[C@H]1CCc2cc(OC)c(OC)c(OC)c2-c2ccc(OC)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)[C@@H](NC(=O)CNC(=O)CN)CCc1cc(OC)c(OC)c(OC)c1-2
Yield: 65 %

Procedure:
A solution of N-[(5S)-3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]-2-[2-(butoxycarbonylamino)acetylamino]acetamide (0.9 g ; 0.64 mmol) in dichloromethane (6 ml) was treated with TFA (6 ml) at ambient temperature for 0.5 hour. After evaporation to dryness, the residue was neutralised to pH 6.5 with solid sodium hydrogen carbonate and purified on reverse phase silica eluting with a gradient of 30-40% methanol/ammonium carbonate buffer (2 g/l, pH 7). The appropriate fractions were evaporated to dryness and triturated in ether to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1.S(O)(O)(=O)=O.[Cl:25][C:26]1[NH:27][CH2:28][CH2:29][N:30]=1>>[ClH:25].[NH:27]1[CH2:28][CH2:29][NH:30][C:26]1=[N:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: ClC1=NCCN1
Reactant: COc1ccc(NC(=O)Cc2ccc(N)cc2)cc1
Agent: O=S(=O)(O)O
Product: COc1ccc(NC(=O)Cc2ccc(N=C3NCCN3)cc2)cc1
Product: Cl
Yield: 10 %

Procedure:
2-(4-Amino-phenyl)-N-(4-methoxy-phenyl)-acetamide (732 mg) was treated with 2-chloroimidazoline sulfate using the procedure of Example 1 above, to yield 2-[4-(Imidazolidin-2-ylideneamino)-phenyl]-N-(4-methoxy-phenyl)-acetamide hydrochloride (10%); Mass Spec M+H: 314.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: OCC1CCNCC1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)ccc1N1CCC(CO)CC1
Temperature: 80 °C
Yield: 81.1 %

Procedure:
A mixture of 2,5-dichloronitrobenzene (0.7 g), 4-piperidinemethanol (0.6 g) and potassium carbonate (1 g) in N,N-dimethylformamide (10 mL) was heated at 80° C. for 1 hour. The reaction mixture was cooled, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (DCM/Acetone, 90/10) to afford 0.8 g of [1-(4-chloro-2-nitro-phenyl)-piperidin-4-yl]-methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C(=O)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][C:33]=1[N+:42]([O-:44])=[O:43]>C1COCC1.O.CC(C)=O>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:11][N:10]=[CH:9][N:8]=1)[S:38]([C:35]1[CH:36]=[CH:37][C:32]([F:31])=[C:33]([N+:42]([O-:44])=[O:43])[CH:34]=1)(=[O:39])=[O:40]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1F
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c([N+](=O)[O-])c2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.2 %

Procedure:
A round-bottom flask was charged with N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (851 mg, 3.39 mmol) and THF (10 mL) to give a clear, light yellow solution. The flask was cooled in a dry ice and acetone bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (3387 μl, 3.39 mmol) was added dropwise over 1 minute to give a suspension. The flask was removed from the cooling bath for 10 min, then re-cooled for 5 min. A solution of 4-fluoro-3-nitrobenzene-1-sulfonyl chloride (737.72 mg, 3.08 mmol) in THF (3 mL with a 1 mL flask/syringe wash) was added dropwise over 2 min. The mixture was stirred for another 5 min, then the mixture was warmed to room temperature. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic extract was dried over sodium sulfate, filtered and concentrated. The crude product was purified by chromatography on silica gel (0 to 30% EtOAc/heptane) to give N-(2,4-dimethoxybenzyl)-4-fluoro-3-nitro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (758 mg, 1.668 mmol, 54.2% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=8.24 (s, 1 H), 8.18 (dd, J=2.4, 6.7 Hz, 1 H), 7.99 (ddd, J=2.4, 3.9, 8.8 Hz, 1 H), 7.33-7.28 (m, 1 H), 7.09 (d, J=8.4 Hz, 1 H), 6.32 (dd, J=2.3, 8.4 Hz, 1 H), 6.21 (d, J=2.4 Hz, 1 H), 5.37 (s, 2 H), 3.76 (s, 3 H), 3.63 (s, 3 H). m/z (ESI) 477.0 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH3:20])[C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:6]=[N:7][CH:8]=1)=O.[F:21][C:22]([F:28])([F:27])[S:23]([NH2:26])(=[O:25])=[O:24]>>[C:18]([C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:20])[C:9]=1[C:5]1[CH:4]=[C:3]([CH2:1][NH:26][S:23]([C:22]([F:28])([F:27])[F:21])(=[O:25])=[O:24])[CH:8]=[N:7][CH:6]=1)#[N:19]
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccccc21
Reactant: NS(=O)(=O)C(F)(F)F
Product: Cn1c(-c2cncc(CNS(=O)(=O)C(F)(F)F)c2)c(C#N)c2ccccc21

Procedure:
2-(5-Formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 127) and trifluoromethanesulfonamide are processed according to the method described in Example 170 to give trifluoromethanesulfonic acid [5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]amide. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.79 (s, 3H), 4.58 (s, 2H), 7.34-7.39 (m, 1H), 7.42-7.47 (m, 1H), 7.72 (d, J=7.7 Hz, 1H), 7.77 (d, J=8.3 Hz, 1H), 8.10 (t, J=2.1 Hz, 1H), 8.78 (d, J=2.1 Hz, 1H), 8.85 (d, J=2.1 Hz, 1H), 10.19 (br. s, 1H). HRMS (ESI) m/z 395.0779 [(M+H)+ Calcd for C17H14F3N4O2S: 395.0790].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([O:13]C)=[O:12])=[C:6]2[C:10]=1[O:9][CH2:8][CH2:7]2.[OH-].[Li+].O>CO.O1CCCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([OH:13])=[O:12])=[C:6]2[C:10]=1[O:9][CH2:8][CH2:7]2
Reactant: COC(=O)c1ccc(N)c2c1CCO2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Nc1ccc(C(=O)O)c2c1OCC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.7 %

Procedure:
Methyl 7-amino-2,3-dihydrobenzofuran-4-carboxylate 1g (2.30 g, 11.90 mmol) was dissolved in 80 mL of the mixture solvent of methanol and tetrahydrofuran (V/V=1:1) followed by the addition of a 1 M solution of lithium hydroxide solution (47.6 mL, 47.60 mmol) in tetrahydrofuran. The reaction solution was heated to reflux for 5 hours, then cooled down to room temperature, stirred for 12 hours. The reaction solution was added with 20 mL of water and concentrated under reduced pressure. The resulting residue was added with 100 mL of water, extracted with ethyl acetate (50 mL×2), the combined aqueous phase was added dropwise with 1 M hydrochloric acid to adjust pH to 3 resulting in the formation of precipitate. The precipitate was filtered to obtain the title compound 7-amino-2,3-dihydrobenzofuran-4-carboxylic acid 22e (1.70 g, yield: 80.0%) as a gary solid.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:20])[N:7](CCN3CCCCC3)[C:8]2=[O:11])=[CH:4][C:3]=1S(N)(=O)=O.ClC1C=C2C(=O)NC(=O)C2=CC=1S(=O)(=O)N.N1(CCN)CCCCC1>C(O)C>[O:20]=[C:6]1[C:5]2[C:9](=[CH:10][CH:2]=[CH:3][CH:4]=2)[C:8](=[O:11])[NH:7]1
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)N(CCN1CCCCC1)C2=O
Agent: NCCN1CCCCC1
Agent: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)NC2=O
Solvent: CCO
Product: O=C1NC(=O)c2ccccc21
Yield: 71 %

Procedure:
6-Chloro-2,3-dihydro-2-[2-(1-piperidinyl)ethyl]-1,3-dioxo-1H-isoindole-5-sulfonamide. Reaction of a mixture of 4-chloro-5-sulfamoylphthalimide and 2-(1-piperidinyl)ethylamine according to the procedure of Example 1(a) afforded a 71% yield of the 1,3-dioxoisoindole intermediate, m.p. 200°-202° from ethanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:33]=[C:32]([OH:34])[CH:31]=[CH:30][C:10]=1[C:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:17][CH:18]=2)[O:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:42][C:43]([Si:46](Cl)([CH3:48])[CH3:47])([CH3:45])[CH3:44]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:33]=[C:32]([O:34][Si:46]([C:43]([CH3:45])([CH3:44])[CH3:42])([CH3:48])[CH3:47])[CH:31]=[CH:30][C:10]=1[C:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:17][CH:18]=2)[O:13][CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c(-c2ccc(O)cc2OCc2ccccc2)coc2cc(OCc3ccccc3)ccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2coc3cc(OCc4ccccc4)ccc3c2=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 2′,7-dibenzyloxy-4′-hydroxy-isoflavone (0.450 g, 1 mmol) in 10 mL of DCM was added triethylamine (0.25 mL, 2 mmol) and TBDMSCl (0.225 g, 1.5 mmol). The reaction mixture was stirred at room temperature for ca. 6 hrs. After disappearance of starting material (TLC) the reaction was quenched with 1N HCl (ca. 2 mL). The mixture was extracted with DCM:water (2×10 mL:10 mL). The organic layer was dried over sodium sulfate and evaporated to give 0.507 g (90%) of fluffy, white solid: mp 132-133° C.; TLC Rf0.89 in hexanes:EtOAc (1:1); 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H, OCH═), 8.04-8.02 (d, 1H, J=8.8 Hz, Ar—H5), 7.50-7.13 (m, 10+3H, C6H5, Ar—H6, H6′, H8), 6.53-6.48 (m, 2H, Ar—H3′/Ar—H5′), 5.27 (s, 2H, Ph-CH2), 5.08 (s, 2H, PhCH2), 0.93 {s, 9H, Si(CH3)3}, 0.16 {s, 6H, Si(CH3)2}; 13C NMR (100 MHz, DMSO-d6) δ 175.1, 163.3, 158.1, 157.9, 157, 155, 137.9, 136.8, 132.7, 129.2, 128.9, 128.8, 128.6, 128.1, 127.7, 127.6, 122.7, 118.4, 115.9, 115.3, 112.1, 105.9, 102.4, 70.8, 70.1, 26.2, 18.6; analysis calcd. for C35H36O5Si.0.25H2O: C, 73.78; H, 6.42. found: C, 73.85; H, 6.38.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][CH:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH2:29][O:30][CH3:31])=[CH:25][CH:26]=2)[O:21][CH2:20][C:19]1([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][O:41][CH3:42])=[CH:35][CH:34]=1)[CH3:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(OCC)(=O)C>CO.O1CCCC1.[Pd]>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH2:29][O:30][CH3:31])=[CH:25][CH:26]=2)[O:21][CH2:20][C:19]1([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][O:41][CH3:42])=[CH:35][CH:34]=1)[CH3:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2C#CCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 8884.4 %

Procedure:
To a solution of 4-[9-(t-butyldimethylsilyloxy)-1-nonynyl]-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman (150 g, 2.51 mmol) in methanol (100 ml) and tetrahydrofuran (10 ml) was added 10% Pd—C (570 mg), which was then stirred at room temperature under hydrogen (atmospheric pressure) for 1 day. Ethyl acetate was added to the reaction solution, which was then filtered, extracted several times with ethyl acetate, and concentrated under reduced pressure to give the title compound (134 g, yield 89%, 3RS/4RS:3RS/4SR=6:1) as a colorless oil.
Reaction SMILES: [C:1]([CH:3]([C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1)C(OC(C)(C)C)=O)#[N:2]>FC(F)(F)C(O)C(F)(F)F.C(OCC)C>[CH3:16][N:15]1[C:11]([CH2:3][C:1]#[N:2])=[CH:12][CH:13]=[N:14]1
Reactant: Cn1nccc1C(C#N)C(=O)OC(C)(C)C
Solvent: OC(C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Product: Cn1nccc1CC#N
Yield: 95.9 %

Procedure:
A mixture of tert-butyl 2-cyano-2-(1-methyl-1H-pyrazol-5-yl)acetate (130 mg, 0.588 mmol) in hexafluoroisopropanol (1 mL) was submitted to microwave radiation at 130° C. for 15 minutes. The reaction mixture was diluted with diethyl ether (30 mL), washed with water (5 mL) and brine (5 mL), dried over magnesium sulfate, filtered, concentrated under reduced pressure and dried under high vacuum to afford 2-(1-methyl-1H-pyrazol-5-yl)acetonitrile (68.3 mg) as a pale yellow oil. 1H NMR (500 MHz, CDCl3) δ 3.77 (s, 2H), 3.89 (s, 3H), 6.30 (s, 1H), 7.45 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][NH:9][CH2:8][CH2:7]2.Cl[C:13](Cl)(Cl)[CH:14]([OH:16])O.Cl.[NH2:20][OH:21]>>[CH2:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][C:14](=[O:16])[CH:13]=[N:20][OH:21])[CH2:7][CH2:8][NH:9]1
Reactant: NO
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: Nc1cccc2c1CNCC2
Agent: Cl
Product: O=C(C=NO)Nc1cccc2c1CNCC2

Procedure:
Reacting an 8-amino-1,2,3,4-tetrahydro-isoquinoline (Compound 9) derivative with chloral hydrate and hydroxylamine hydrochloride to give an N-(1,2,3,4-tetrahydro-isoquinolin-8-yl)-2-hydroxyimino-acetamide (Compound 10) derivative (Step 9);
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:17]2[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=2[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.7 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (3.62 g), 2-methyl-4-nitrophenol (2.55 g) and triphenylphosphine (5.25 g) in dichloromethane (100 ml) was added dropwise diethyl azodicarboxylate (3.2 ml) in an ice bath and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using dichloromethane as an eluant to give the crude desired compound (4.07 g) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:12]#[N:13])[C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1)=[O:4].[BH4-].[Na+].[H][H]>CO>[CH3:1][O:2][C:3]([C:5]1([CH2:12][NH2:13])[C:7]2([CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:6]1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)C1(C#N)CC12CCCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(CN)CC12CCCC2
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
To a solution of 1-cyano-spiro[2.4]heptane-1-carboxylic acid methyl ester (3.45 g, 19.3 mmol) in methanol (240 mL) was added CoCl2-6H2O (9.16 g, 38.5 mmol) to give a deep purple colored solution. Sodium borohydride (7.30 g, 193 mmol) was added portionwise over 10 minutes with caution to control the evolution of hydrogen and the exothermic reaction that ensued to give a black solution. The reaction mixture was stirred for 30 minutes under nitrogen after the addition was completed. The reaction was quenched carefully by the addition of 0.5N HCl (1.3 L). The solution was made alkaline (pH˜9) by the addition of concentrated ammonium hydroxide. The mixture was extracted with ethyl acetate (4×400 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to afford 3.07 g (87%) of 1-aminomethyl-spiro[2.4]heptane-1-carboxylic acid methyl ester as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 0.74 (br d, 1H), 1.4–1.7 (m, 10H), 1.9 (m, 1H), 2.58 (d, J=13.8 Hz, 1H), 3.16 (d, J=13.8 Hz, 1H), 3.48 (s, 3H); MS (APCI) m/z 184 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][O:6][C@@H:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C@@H:3]1[OH:21].[OH:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH:8]([C@H:5]1[CH2:4][C@H:3]([OH:21])[C@@H:2]([NH:1][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([OH:22])=[CH:24][CH:25]=2)[CH2:7][O:6]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N[C@H]1CO[C@@H](C(c2ccccc2)c2ccccc2)C[C@@H]1O
Reactant: O=Cc1ccc(O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Oc1ccc(CN[C@H]2CO[C@@H](C(c3ccccc3)c3ccccc3)C[C@@H]2O)cc1

Procedure:
(2R,4S,5S)-5-amino-2-benzhydryl-tetrahydropyran-4-ol 31b (0.02 g, 0.07 mmol) was reacted with 4-hydroxybenzaldehyde (0.009 g, 0.071 mmol), glacial acetic acid (0.004 g, 0.071 mmol) and NaCNBH3 (0.005 g, 0.085 mmol) (Procedure H) to give (2R,4S,5S)-2-benzhydryl-5-(4-hydroxy-benzylamino)-tetrahydropyran-4-ol, (+)-32a, 0.023 g (85%, [α]D=(+)72.4, c=1, MeOH).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[Cl:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21].[Cl-:23].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:16][CH2:17][CH2:18][CH2:19][C:20]([C:7]1[CH:6]=[CH:5][C:4]2[N:3]([CH2:1][CH3:2])[C:15]3[C:10]([C:9]=2[CH:8]=1)=[CH:11][C:12]([C:20](=[O:21])[CH2:19][CH2:18][CH2:17][Cl:23])=[CH:13][CH:14]=3)=[O:21]
Reactant: CCn1c2ccccc2c2ccccc21
Reactant: [Cl-]
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Solvent: ClCCl
Product: CCn1c2ccc(C(=O)CCCCl)cc2c2cc(C(=O)CCCCl)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 78.0g (0.4 mole) of N-ethylcarbazole and 141 g (1.0 mole) of 4-chlorobutyrylchloride in 1 l of methylene chloride, previously cooled to 0°C, 127.0 g (0.95 mole) of aluminum chloride was added portionwise. The mixture was stirred at room temperature for 16 hours, and the resulting complex was decomposed with concentrated HCl/ice. The organic layer was separated, washed with water, dried over magnesium sulfate and treated with pentane to precipitate the desired product which was recrystallized from acetone and then acetone-methanol. M.P. 106°-108°C, λmaxEtOH 259, E1cm1% 1030.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])=[CH:12][CH:11]=1)[C:6]([O-:8])=[O:7])[CH3:2].[BH4-].[Na+].[C:29](O)(=O)[CH3:30]>C(O)C>[CH2:1]([O:3][C:4](=[O:26])[CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])=[CH:12][CH:11]=1)[C:6]([O:8][CH2:29][CH3:30])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)C(=O)[O-]
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)C(=O)OCC
Yield: 88 %

Procedure:
T a stirred solution of ethyl[4-(2,6-dichlorobenzyloxy)benzylidene]malonate (8.35 g, 19,2 mmol) in ethanol at 0° C. under argon was added sodium borohydride in small portions. Upon completion of the addition, the reaction mixture was adjusted to pH 6 with acetic acid. The mixture was filtered, concentrated in vacuo then partitioned between ether and water. The organic extract was washed successively with 1N hydrochloric acid, saturated sodium bicarbonate solution, water, brine and dried (MgSO4). Removal of volatiles in vacuo afforded the title compound (7.47 g, 88%).