Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12]1([CH2:18][CH2:19][CH:20]=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>ClCCl>[OH:23][N:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:20](=[O:21])[CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Nc1ccccc1
Reactant: O=CCCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=C(CCc1ccccc1)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (15 mg, 0.1 mmol) was added under argon to a solution of 3-phenylpropanal (134 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (36.4 mg, 0.1 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: [Cl-].[CH3:2][NH:3][CH3:4].[C:5]([C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([OH:18])([CH2:11]3)[CH2:9]1)[CH2:15]2)(O)=[O:6]>CN(C)C=O>[CH3:2][N:3]([CH3:4])[C:5]([C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([OH:18])([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:6]
Reactant: O=C(O)C12CC3CC(CC(O)(C3)C1)C2
Reactant: CNC
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CN(C)C(=O)C12CC3CC(CC(O)(C3)C1)C2
Reaction time: 2 h
Yield: 95 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1-carboxy-3-adamantanol obtained by the method of Example 2 was dissolved in 10 ml of N,N-dimethylformamide (DMF). To the mixture, 15 mmole of tionyl chloride was added dropwise over 30 minutes while heating the mixture to the reflux temperature so as to begin to reflux at about the time the addition is finished. After refluxing for 2 hours, the mixture was cooled. To the mixture, 25 mmole of dimethylamine was added dropwise over 30 minutes while keeping the temperature of the solution at 10° C. or below, and the mixture was stirred for another 2 hours. As a result, the conversion of 1-carboxy-3-adamantanol was 99%, and 1-(N,N-dimethylcarbamoyl)-3-adamantanol (yield 95%) was formed.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]([CH2:19][C@H:20]3[O:24]C(C)(C)[N:22]([C:27]([O:29][C@@H:30]4[C@H:37]5[C@H:33]([O:34][CH2:35][CH2:36]5)[O:32][CH2:31]4)=[O:28])[C@H:21]3[CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=4)=[CH:41][CH:40]=3)[CH2:15][CH:16]([CH3:18])[CH3:17])(=[O:13])=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)(C)C.Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:19][C@@H:20]([OH:24])[C@@H:21]([NH:22][C:27](=[O:28])[O:29][C@@H:30]3[C@H:37]4[C@H:33]([O:34][CH2:35][CH2:36]4)[O:32][CH2:31]3)[CH2:38][C:39]3[CH:40]=[CH:41][C:42]([O:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=4)=[CH:43][CH:44]=3)(=[O:13])=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(OCc2ccccn2)cc1)S(=O)(=O)c1ccc2c(c1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCc2ccccn2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCCO2
Reaction time: 2 h
Yield: 101.2 %

Procedure:
70 mg of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (4S,5R)-5-{[(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)(isobutyl)amino]methyl}-2,2-dimethyl-4-[4-(2-pyridinylmethoxy)benzyl]-1,3-oxazolidine-3-carboxylate were dissolved in 15 mL of isopropanol and 5 mL of concentrated hydrochloric acid. After 2 h, the reaction was treated with excess 3N sodium hydroxide and extracted with ethyl acetate. Evaporation of the solvent gave 67 mg of the desired product. 1H NMR: 0.83(6H,dd), 1.4-1.8(4H,m), 2.6-3.2(7H,m), 3.6(2H,m), 3.75(2H,m), 3.9(2H,m), 4.25(4H,bs), 4.95(1H,d), 5.0(1H,m), 5.6(1H,d), 6.9(2H,d), 6.95(2H,d), 7.1(2H,d), 7.2(2H,m), 7.45(1H,d), 7.7(1H,t), 8.58(1H,d).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19](I)[CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][C:8](=[O:24])[NH:7][C:6]=2[CH:25]=1.[CH2:26]([N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)[C:27]#[CH:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:28]#[C:27][CH2:26][N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)[CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][C:8](=[O:24])[NH:7][C:6]=2[CH:25]=1
Reactant: C#CCN1CCCC1
Reactant: O=C1Cc2cnc(Nc3cccc(I)c3)nc2-c2ccc(Cl)cc2N1
Product: O=C1Cc2cnc(Nc3cccc(C#CCN4CCCC4)c3)nc2-c2ccc(Cl)cc2N1

Procedure:
In a manner similar to that described for Method O, 9-chloro-2-(3-iodo-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (v-j) and 1-(prop-2-ynyl)pyrrolidine were converted to I-89 (46%): MS (AA) Rt═1.32 min, m/z═444 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-])=O>CCO.C1COCC1.[Pd]>[NH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[NH2:1])[C:6]#[N:7]
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1ccc(N)c(N)c1
Reaction time: 12 h
Yield: 96.5 %

Procedure:
To a mixed solution of 4-amino-3-nitrobenzonitrile (8 g) in EtOH/THF (40 ml/40 ml) was added Pd—C(50% wet) (0.8 g), followed by stirring under an H2 atmosphere for 12 hours. The reaction solution was filtered through celite, and concentrated. The residue was powdered/washed with a mixed solvent of IPE and IPA, and collected by filtration to obtain 3,4-diaminobenzonitrile (6.3 g) as orange powders.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[C:11](=[C:12]([CH3:26])[N:13]([CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:14]=2)[C:10](=O)[CH2:9]1.[C:28]([NH:31][NH2:32])([NH2:30])=[NH:29].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[C:11](=[C:12]([CH3:26])[N:13]([CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:14]=2)[C:10](=[N:32][NH:31][C:28]([NH2:30])=[NH:29])[CH2:9]1
Reactant: N=C(N)NN
Reactant: Cc1c2c(nn1CCCc1ccccc1)CC(c1ccccc1Cl)CC2=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1c2c(nn1CCCc1ccccc1)CC(c1ccccc1Cl)CC2=NNC(=N)N
Yield: 154.3 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-methyl-2-(3-phenylpropyl)-4,5,6,7-tetrahydroindazol-4-one (0.25 g), aminoguanidine hydrochloride (0.11 g), concentrated hydrochloric acid (0.16 ml), water (0.16 ml) and ethanol (15 ml) was refluxed for 8 hours. Under reduced pressure, the solvent was evaporated, and the resulting crystals were recrystallized from ethanol-water to give 6-(2-chlorophenyl)-4-guanidinoimino-3-methyl-2-(3-phenylpropyl)-4,5,6,7-tetrahydroindazole hydrochloride (Compound 154) (0.24 g) as colorless crystals.
Reaction SMILES: [BH:1]([OH:3])[OH:2].BrC1C=C(N2C3N=C(NC4C=CC(OC)=CC=4)N=CC=3C3=NN=C(O)C3=C2)C=CC=1.C([O-])([O-])=O.[Na+].[Na+].FC1C=CC(C2C=CC=C([N:53]3[C:58]4[N:59]=[C:60](NC5C=CC(OC)=CC=5)[N:61]=[CH:62][C:57]=4[C:56]4=[N:72][NH:73][CH:74]=[C:55]4[C:54]3=[O:75])C=2)=CC=1>C1(C)C=CC=CC=1.CCO>[BH:1]([OH:3])[OH:2].[N:72]1[NH:73][CH:74]=[C:55]2[C:54](=[O:75])[NH:53][C:58]3[N:59]=[CH:60][N:61]=[CH:62][C:57]=3[C:56]=12
Reactant: COc1ccc(Nc2ncc3c4n[nH]cc4c(=O)n(-c4cccc(-c5ccc(F)cc5)c4)c3n2)cc1
Agent: COc1ccc(Nc2ncc3c4nnc(O)c-4cn(-c4cccc(Br)c4)c3n2)cc1
Agent: O=C([O-])[O-]
Agent: OBO
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=c1[nH]c2ncncc2c2n[nH]cc12
Temperature: 100 °C
Yield: 22 %

Procedure:
Boronic acid solution 0.1 M was prepared in Toluene/EtOH (1/1). Boronic acid solution (100 mmol, 1000 μL) was added to vials. A suspension of 5-(3-bromophenyl)-7-((4-methoxyphenyl)amino)-5H-pyrazolo[3′,4′:4,5]pyrido[2,3-d]pyrimidin-3-ol (16) 0.1 M was prepared in Toluene/EtOH (1/1). Suspension of intermediate 56 (500 μL, 50 mmol) was added into each vial. Saturated Na2CO3 (500 μL) was added to each vial. Add catalytic amount of BDtBFPdCl2 to each vial at a time followed by purging with N2 with pipette and cap the vial immediately. The reactions were shaken at 100° C. for at least 16 h. EtOAc (2 mL) was added to each vial. Water (0.5 mL) was added to each vial. Vortex vials and water layer was removed. Additional water (1500 μL) was added to each vial, vortex and remove the water layer. Repeat water washing sequence again. Solvents were removed to dryness. Residue was dissolved in DMSO (1 mL) (may need heat to dissolve or add one drop TFA) and purified by reverse phase HPLC. To obtain 5-(4′-fluoro-[1,1′-biphenyl]-3-yl)-7-(4-methoxyphenyl)amino)-2H-pyrazolo[3′,4′:4,5]pyrido[2,3-d]pyrimidin-4(5H)-one (Compound 133) (11.2 mmol, 22%) LC-Mass: m/e 479 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH:8]=O.Cl.[NH2:18][OH:19]>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH:8]=[N:18][OH:19]
Reactant: NO
Reactant: O=Cc1ccc(-c2ccc(O)cc2)cc1F
Agent: Cl
Product: ON=Cc1ccc(-c2ccc(O)cc2)cc1F

Procedure:
The title compound was prepared by reacting 3-fluoro-4′-hydroxy-1,1′-biphenyl-4-carbaldehyde (154 mg, 0.713 mmol) with hydroxylamine hydrochloride (99 mg, 1.43 mmol) according to Method C to yield 156 mg (95%) of yellowish solid: mp 181-183° C.; 1H NMR (DMSO-d6): δ 6.84-6.87 (2H, m), 7.48-7.53 (2H, m), 7.57-7.60 (2H, m), 7.76 (1H, t, J=8.14 Hz), 8.22 (1H, s), 9.74 (1H, s), 11.56 (1H, s); MS (ESI) m/z 230 (M−H)−, 232 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[CH:16]([CH2:17][C:18](=[O:28])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C1([Se](O[Se](C2C=CC=CC=2)=O)=O)C=CC=CC=1>ClC1C=CC=CC=1>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH:19]=[CH:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Se](O[Se](=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 3 h
Yield: 64 %

Procedure:
Cholestan-3-one (100 mg) was dissolved in chlorobenzene (5 ml), benzeneseleninic anhydride (188 mg, 2 equiv.) added and the solution heated to reflux with stirring under nitrogen in the dark. After 3 hours tlc showed almost complete reaction. The mixture was allowed to cool before filtering down a short silica column, washing with petrol containing 10% methylene chloride followed by releasing the crude product by washing with methanol. On evaporation an oil (107.1 mg) was obtained which crystallised on cooling in cardice. mp. 50°-57° C. Plc of the resulting impure product yielded 63.3 mg (63%) of cholesta-1,4-dien-3-one mp. 110°-112° C. (literature melting point 112° C.). λmax. 242 nm (ε 14500) (literature U.V. absorption 242 nm (ε 15000)). I.R. spectrum identical to previously prepared pure samples. The results of several runs are tabulated below:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH3:10])=[O:8])[C@@H:3]1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C.[F:27][C:28]([F:43])([F:42])[C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[C:32](Cl)=[O:33].Cl>C(Cl)Cl.O>[F:27][C:28]([F:42])([F:43])[C:29]1[CH:30]=[C:31]([C:32]([NH:1][C@H:2]2[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH3:10])=[O:8])[C@@H:3]2[C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)=[O:33])[CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=1
Reactant: COC(=O)[C@@H]1CC[C@H](N)[C@H]1c1ccc(F)cc1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
To a solution of 100 mg of amine from Example 62 in 5 mL of methylene chloride was added 0.2 mL of DIPEA and 175 mg of 3,5-bis(trifluoromethyl)benzoyl chloride. The reaction was stirred at room temperature for 1 h and was then poured into water and 2N HCl and extracted twice with methylene chloride. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography eluting with 30 to 50% ethyl acetate in hexanes to obtain 100 mg of title compound. NMR (CDCl3): δ 1.8-1.9 (m, 1H), 2.05-2.2 (m, 1H), 2.2-2.4 (m, 2H), 3.08 (q, 1H), 3.42 (t, 1H), 3.67 (s, 3H), 4.65 (p, 1H), 6.80 (d, 1H), 6.99 (t, 2H), 7.22 (dd, 2H), 7.96 (s, 1H), 8.15 (s, 2H).
Reaction SMILES: [OH-].[K+].[CH2:3](Br)[CH2:4][CH2:5][CH3:6].O.[CH2:9]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:24])[C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1)[CH:10]=[C:11]([CH3:13])[CH3:12]>CN(C)P(=O)(N(C)C)N(C)C.C(O)C>[CH2:9]([C:14]1[CH:15]=[CH:16][C:17]([CH:20]([CH3:24])[C:21]([O:23][CH2:3][CH2:4][CH2:5][CH3:6])=[O:22])=[CH:18][CH:19]=1)[CH:10]=[C:11]([CH3:13])[CH3:12]
Reactant: CCCCBr
Reactant: CC(C)=CCc1ccc(C(C)C(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCO
Solvent: O
Product: CCCCOC(=O)C(C)c1ccc(CC=C(C)C)cc1
Temperature: 25 °C
Yield: 63.1 %

Procedure:
Six grams of powdered potassium hydroxide was dissolved in a mixture of 21.8 g of 2-(p-prenylphenyl)propionic acid in 125 ml of hexamethylphosphoric triamide and 125 ml of ethyl alcohol with stirring at room temperature. To the solution was added 27.4 g of n-butyl bromide and the mixture was stirred at room temperature for 24 hours. The mixture was poured into 500 ml of water and extracted with n-hexane. The extract was washed with 2 N hydrochloric acid, water, 5% aqueous sodium hydroxide and water successively, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 17.3 g of n-butyl 2-(p-prenylphenyl)propionate. b.p. 131°-133° C./0.15 mmHg, IR νmaxneat ; 1730 cm-1.
Reaction SMILES: C(OC(COC1C=CC(F)=CC=1)CCC1N(CCCCCCC(OCC2C=CC=CC=2)=O)C(=O)CS1(=O)=O)C1C=CC=CC=1.C([O:52][CH2:53][C:54]#[C:55][C@@H:56]([O:62][C:63](=[O:65])[CH3:64])[CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])C1C=CC=CC=1>>[C:63]([O:62][C@@H:56]([CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:55][CH2:54][CH2:53][OH:52])(=[O:65])[CH3:64]
Reactant: CCCCC[C@@H](C#CCOCc1ccccc1)OC(C)=O
Agent: O=C(CCCCCCN1C(=O)CS(=O)(=O)C1CCC(COc1ccc(F)cc1)OCc1ccccc1)OCc1ccccc1
Product: CCCCC[C@@H](CCCO)OC(C)=O

Procedure:
This compound is prepared essentially by the method as described in Example 5, Step E, except that the benzyl 7-{2-(3-benzyloxy-4-[4-fluorophenoxy]butyl)-1,1,4-trioxo-3-thiazolidinyl}heptanoate is replaced by 1-benzyloxy-4(S) acetyloxy-2-nonyne and no chromatographic purification is needed. The title compound is obtained as a mobile oil which is used immediately in Step A-6 below.
Reaction SMILES: [CH:1]1[C:2]([C:10]([OH:12])=[O:11])=[CH:3][N:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][CH2:5]2.[CH3:13]N(C=O)C.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>CO.C(Cl)Cl>[CH:1]1[C:2]([C:10]([O:12][CH3:13])=[O:11])=[CH:3][N:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][CH2:5]2
Reactant: O=C(O)c1cc2n(c1)CCCC2
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc2n(c1)CCCC2
Temperature: 0 °C
Reaction time: 5 h
Yield: 58 %

Procedure:
A 500-mL round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was purged with nitrogen and charged with 5,6,7,8-tetrahydroindolizine-2-carboxylic acid (30.4 g, 184 mmol), DMF (1.00 g, 13.6 mmol) and methylene chloride (300 mL). The solution was cooled to 0° C. using an ice bath. Oxalyl chloride (28.0 g, 221 mmol) was added dropwise, and the reaction mixture was warmed to room temperature over 30 min and stirred for 5 h. After this time, the resulting solution was concentrated to afford a brown solid. This solid was dissolved in anhydrous methanol (400 mL), and the solution was cooled to 0° C. Triethylamine (57 g, 552 mmol) was added to the reaction mixture, and it was stirred for a further 2 h at room temperature. After this time, the reaction mixture was concentrated to dryness under reduced pressure. The residue was diluted with methylene chloride (300 mL) and washed with water (200 mL) and saturated aqueous sodium bicarbonate (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was titrated with hexane (200 mL) to afford 112a in 58% yield (19.1 g) as a white solid: mp 72-74° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.13 (s, 1H), 6.23 (s, 1H), 3.93 (t, 2H, J=6.0 Hz), 3.77 (s, 3H), 2.75 (t, 2H, J=6.0 Hz), 1.93 (m, 2H), 1.80 (m, 2H); (APCI+) m/z 180.1 (M+H)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[CH:12]=[N:13][OH:14].[CH2:15]([C:17](=[CH2:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:16].Cl[O-].[Na+].O>ClCCl.C(N(CC)CC)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[C:12]1[CH2:23][C:17]([CH2:15][CH3:16])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:14][N:13]=1
Reactant: C=C(CC)C(=O)OCC
Reactant: Cc1c(C=NO)n(C)c2ccccc12
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1(CC)CC(c2c(C)c3ccccc3n2C)=NO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 35.3 %

Procedure:
1,3-Dimethyl-1H-indol-2-aldehyde oxime derivative (356 mg, 2.07 mmol) was dissolved in dichloromethane (20 ml), and the mixture was kept at 0□. Ethyl 2-ethylacrylate (345 mg, 1.3 Eq) and triethylamine (6 drops) were dissolved in dichloromethane (5 ml), thus obtained solution was slowly added to the above, and sodium hypochlorite solution (5.5 ml) was further added. The reaction solution was warmed to room temperature and stirred for 4 hours. Water (20 ml) was added, and the mixture was extracted with dichloromethane (40 ml×2), washed with aqueous sodium chloride solution (20 ml), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (15% ethyl acetate-hexane) to give the title compound (230 mg, Yield 35%).
Reaction SMILES: [N:1]1([C:6]2[CH:18]=[CH:17][C:9]([O:10][CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)C(C)C.C([Sn](Cl)(Cl)CCCC)CCC.[C:35]1([SiH3])[CH:40]=[CH:39][CH:38]=[CH:37]C=1>C1COCC1>[CH:37]1([N:14]2[CH2:13][CH2:12][CH:11]([O:10][C:9]3[CH:8]=[CH:7][C:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)=[CH:18][CH:17]=3)[CH2:16][CH2:15]2)[CH2:38][CH2:39][CH2:40][CH2:35]1
Reactant: c1cn(-c2ccc(OC3CCNCC3)cc2)cn1
Reactant: [SiH3]c1ccccc1
Agent: CC(C)C=O
Agent: CCCC[Sn](Cl)(Cl)CCCC
Solvent: C1CCOC1
Product: c1cn(-c2ccc(OC3CCN(C4CCCC4)CC3)cc2)cn1
Reaction time: 16 h

Procedure:
A solution of the product of Example 6 (130 mg), isobutyraldehyde (0.06 mL), and dibutyltin dichloride (3 mg) in THF (0.1 mL) was treated with phenylsilane (0.07 mL). After 16 h, the resulting mixture was chromatographed (0-8% 2M methanolic ammonia/DCM), giving the title compound as a waxy solid (57 mg). 1H NMR (400 MHz, CDCl3): 7.75 (t, J=1.2 Hz, 1H), 7.28 (d, J=9.0 Hz, 2H), 7.20 (t, J=1.2 Hz, 1H), 7.17 (t, J=1.2 Hz, 1H), 6.99 (d, J=9.0 Hz, 2H), 4.39-4.29 (m, 1H), 2.87-2.77 (br m, 1H), 2.57-2.48 (m, 1H), 2.40-2.30 (m, 2H), 2.08-1.99 (m, 2H), 1.94-1.82 (m, 5H), 1.75-1.64 (m, 2H), 1.61-1.61 (m, 2H), 1.47-1.37 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:11]2[CH:7]1[CH2:8][CH2:9][C:10]2=[O:12])=[O:5])[CH3:2].CCN(CC)CC.O([Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])S(C(F)(F)F)(=O)=O>ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH:11]2[CH:7]1[CH2:8][CH:9]=[C:10]2[O:12][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])=[O:5])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)C1C2CCC(=O)C21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1C2CC=C(O[Si](C)(C)C(C)(C)C)C21
Temperature: 22 °C

Procedure:
To a solution of (1RS,5SR,6RS)-2-oxo-bicyclo[3,1,0]hexane-6-carboxylic acid ethyl ester (28.93 g, 172 mmole) in dichloromethane (430 ml) was added at 22° C. NEt3 (36.0 ml, 258 mmole), the mixture was cooled to 0° C. and treated with tert-butyldimethylsilyl triflate (43.5 ml, 189.2 mmole) keeping the temperature below 10° C. The mixture was allowed to warm to 22° C. over 2 h, washed with saturated aqueous NaHCO3, the organic layer was dried, evaporated and the residue purified over aluminiumoxide (100 g) using cyclohexane/AcOEt (9:1) to give the title compound as a yellow oil which was used without further purification in the next step.
Reaction SMILES: CC1C=CC=CC=1C.[Cl:9]Cl.[CH3:11][C:12]1[C:17]([Cl:18])=[C:16]([Cl:19])[C:15]([Cl:20])=[C:14]([Cl:21])[C:13]=1[CH3:22]>C(Cl)(Cl)(Cl)Cl.[Hg]>[CH3:22][C:13]1[C:14]([Cl:21])=[C:15]([Cl:20])[C:16]([Cl:19])=[C:17]([Cl:18])[C:12]=1[CH2:11][Cl:9]
Reactant: ClCl
Reactant: Cc1c(C)c(Cl)c(Cl)c(Cl)c1Cl
Agent: [Hg]
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1C
Product: Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1CCl
Reaction time: 6 h
Yield: 78.7 %

Procedure:
530 g of o-xylene in 5 liters of CCl4 was chlorinated in the nucleus in the presence of 10 g of FeCl3 by passing chlorine over the reaction solution while stirring the latter, at a pressure of 0.06 atmospheres excess pressure, with the exclusion of light. The first half of the amount of chlorine calculated for dimethyltetrachlorobenzene was introduced into the gas chamber of the reaction vessel at a liquid phase temperature of 20° C, and the remainder at 40° C. The reaction time was about 6 hours. Then, while irradiating the gas chamber in the reaction vessel with a 250-watt mercury vapor lamp at a liquid phase temperature of 70° C and 0.06 atmospheres excess pressure, the side-chain chlorination was performed, which required about 6 hours. Total chlorine consumption: 110% of the calculated amount, with respect to xylene. The reaction solution was stirred with 400 g of calcium hydroxide, which rendered the solution neutral and iron-free. The calcium hydroxide containing iron and chloride was removed on a suction filter and, after the CCl4 had been removed by distillation, the solution was fractionated at 12 Torr in a packed column. The main fraction distilled at 179°-189° C. 1242 g of 1-methyl-2-chloromethyl-3,4,5,6-tetrachlorobenzene was obtained in a purity of 88.3% (yield 78.7%). After recrystallization from isopropanol + 1,2-dichloroethane (1:1), the product had a purity of 96.4% and melted at 102°-103° C.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)[CH2:9][CH3:10].S(Cl)([Cl:22])=O>N1C=CC=CC=1>[CH2:8]([C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([Cl:22])=[O:19])[CH2:13][CH2:12]1)[CH2:9][CH3:10]
Reactant: CCC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H](C(=O)Cl)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Toluene (1,000 ml) was added to trans-4-propylcyclohexanecarboxylic acid (1) (500.0 g) in a reaction vessel under an atmosphere of nitrogen, and the mixture was heated to 50° C. Pyridine (0.70 ml) and thionyl chloride (360.0 g) were then added, and the stirring was continued for 3 hours. The unreacted thionyl chloride and the toluene were distilled off at atmospheric pressure. The residue was distilled under reduced pressure (83° C., 3 mmHg) to give trans-4-propylcyclohexanecarboxylic acid chloride (2) (531.7 g) in 98% yield.