Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:22][NH2:23])[N:15]([C:24]3[C:25]4[CH:32]([CH:33]([CH3:35])[CH3:34])[CH2:31][CH2:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]1(=O)[CH2:40][CH2:39][CH2:38][CH2:37]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:22][NH:23][CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[N:15]([C:24]3[C:25]4[CH:32]([CH:33]([CH3:35])[CH3:34])[CH2:31][CH2:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCC1
Reactant: CC(C)C1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CN)cccc43)c21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)C1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CNC5CCCC5)cccc43)c21
Reaction time: 0.33 h
Yield: 91 %

Procedure:
A stirring solution of (1′-benzyl-1-(5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methanamine (0.250 g, 0.433 mmol) in DCE (3 mL) was treated with cyclopentanone (0.192 mL, 2.17 mmol). The reaction was allowed to stir for 20 minutes, followed by the addition of NaBH(OAc)3 (0.184 g, 0.867 mmol). The reaction was stirred at room temperature overnight. An additional 2.5 equivalents of cyclopentanone and 1.0 eq of NaBH(OAc)3 were added to the reaction and stirred an additional 2 hours. The reaction was quenched by the addition of saturated NaHCO3 and diluted with DCM. The combined organics were washed with brine, dried Na2SO4, filtered, and concentrated under reduced pressure to yield N-((1′-benzyl-1-(5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)cyclopentanamine (0.211 g, 91%), which was used without further purification. LCMS (APCI+) m/z 536.4 [M+H]+; Rt=3.61 min.
Reaction SMILES: C(C1C=C(CC)[NH:5][C:4]=1[CH:10]=[O:11])C.[CH3:12][CH:13]([C:15](=O)[CH2:16][C:17](=O)[CH:18]([CH3:20])[CH3:19])[CH3:14]>>[CH:13]([C:15]1[CH:16]=[C:17]([CH:18]([CH3:20])[CH3:19])[NH:5][C:4]=1[CH:10]=[O:11])([CH3:14])[CH3:12]
Reactant: CCc1cc(CC)c(C=O)[nH]1
Reactant: CC(C)C(=O)CC(=O)C(C)C
Product: CC(C)c1cc(C(C)C)c(C=O)[nH]1

Procedure:
The procedure was the same as the one for the preparation of 3,5-diethylpyrrol-2-carboxaldehyde except starting with 2,6-dimethyl-3,5-heptanedione.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.Cl.[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1>CN(C=O)C>[F:21][C:20]([F:23])([F:22])[C:17]1[N:15]2[N:16]=[C:11]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]4[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=4)[CH2:27][CH2:26]3)[CH:12]=[CH:13][C:14]2=[N:19][N:18]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: Oc1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Oc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
DIPEA (5.84 mL, 33.54 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (2.99 g, 13.41 mmol) and 4-(piperidin-4-yl)phenol hydrochloride (CAS 263139-27-1, 3.01 g, 14.08 mmol) in DMF (30 mL). The resulting solution was stirred at 80° C. for 1 hour. The mixture was cooled to room temperature, evaporated to dryness and re-dissolved in DCM (200 mL). The solution was washed with water (200 mL) and saturated brine (200 mL), dried over MgSO4 and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 50 to 70% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford 4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenol (4.47 g, 92%) as a solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH2:8])=[O:7].[C:9](OC(=O)C)(=[O:11])[CH3:10]>O>[C:9]([NH:8][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][Br:1])(=[O:11])[CH3:10]
Reactant: NC(=O)CCCCBr
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)NC(=O)CCCCBr
Temperature: 25 °C
Yield: 53 %

Procedure:
A stirred solution of 100 g. (0.55 mole) of 5-bromovaleramide, 62.4 g. (0.61 mole) of acetic anhydride, and 5.4 g. (0.055 mole) of concentrated sulfuric was heated on a steam bath under nitrogen for 1.5 hours (internal temperature 93°). The mixture was then cooled to room temperature diluted with 250 ml. of water. The resultant tan granular precipitate was collected by filtration and dissolved in 600 ml. of methylene chloride. The solution was washed with saturated sodium bicarbonate (100 ml.) and saturated brine (100 ml.), was dried (anhydrous magnesium sulfate), treated with Darco, and filtered. Hexane was added to effect crystallization which afforded 64.8 g. (53.0% yield) of N-acetyl-5-bromovaleramide melting at 88°-90° .
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][S:48](Cl)(=[O:50])=[O:49])=[C:43]([N+:52]([O-:54])=[O:53])[CH:42]=1>>[CH:27]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2)[C:12]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[C:4]1[CH2:3][CH2:2][NH:1][S:48]([CH2:47][C:44]1[CH:45]=[CH:46][C:41]([Cl:40])=[CH:42][C:43]=1[N+:52]([O-:54])=[O:53])(=[O:50])=[O:49])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(OCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccc(Cl)cc3[N+](=O)[O-])n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 74 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 6, Example 1)was added (4-chloro-2-nitro-phenyl)-methanesulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 74% yield.
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:44]([NH:46][C:47]3[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:48]=3[O:55][CH3:56])=[O:45])[CH2:20][CH2:21][C:22](=[O:43])[NH:23][C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.[NH:57]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH:59]=[C:58]1[C:66]([OH:68])=O>>[NH:57]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH:59]=[C:58]1[C:66]([NH:18][C@H:19]([C:44]([NH:46][C:47]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:48]=1[O:55][CH3:56])=[O:45])[CH2:20][CH2:21][C:22](=[O:43])[NH:23][C:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:68]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: COc1ccc(OC)c(NC(=O)[C@H](CCC(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)OCC2c3ccccc3-c3ccccc32)c1
Product: COc1ccc(OC)c(NC(=O)[C@H](CCC(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)c2cc3ccccc3[nH]2)c1

Procedure:
The title compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-Nδ-trityl-L-glutaminyl]-2,5-dimethoxyaniline (620 mg, 0.83 mmol, example 82, step A) as described for example 82 (step B) using indole-2-carboxylic acid (201 mg, 1.25 mmol) instead of caffeic acid. The crude material was purified by flash chromatography using initially 10% then 20% EtOAc/CH2Cl2. The title compound was obtained as white crystals (200 mg, 36%).
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[C:13]1[CH:26]=[CH:25][C:16]([CH:17]=[C:18]([CH3:24])[C:19]([O:21]CC)=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])O.[Na+]>Cl>[CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[C:13]1[CH:26]=[CH:25][C:16]([CH:17]=[C:18]([CH3:24])[C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(C)=Cc1ccc(C(C2=C(C)C(=O)C(C)=C(C)C2=O)c2cccnc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=Cc1ccc(C(C2=C(C)C(=O)C(C)=C(C)C2=O)c2cccnc2)cc1)C(=O)O
Yield: 85.6 %

Procedure:
Ethyl 4-[3,5,6-trimethyl-1,4-benzoquinon-2-yl-(3-pyridyl)methyl]-α-methylcinnamate, 1.2 g (2.8 mmol), was dissolved in 20 ml of concentrated hydrochloric acid, and refluxed by heating for 2 hours. After cooling, the reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and the resulting substance was extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was evaporated off. The residue was purified with silica gel column chromatography (ethyl acetate-ethanol (9:1)), and recrystallized from ethyl acetate, to give 0.96 g (85.6%) of 4-[3,5,6-trimethyl-1,4-benzoquinon-2-yl(3-pyridyl)methyl]-α-methylcinnamic acid. The physical data are shown in Table 1.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH2:23][O:24][CH3:25])=O)=[CH:7][C:6]=1[CH2:27][CH3:28])(=O)C.[NH2:29][C:30]([NH2:32])=[O:31].Cl>O1CCOCC1>[CH2:27]([C:6]1[CH:7]=[C:8]([C:11]2[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH2:22][CH2:23][O:24][CH3:25])[NH:32][C:30](=[O:31])[N:29]=2)[CH:9]=[CH:10][C:5]=1[NH2:4])[CH3:28]
Reactant: CCc1cc(C(=O)CC(=O)c2ccccc2OCCOC)ccc1NC(C)=O
Reactant: NC(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: CCc1cc(-c2cc(-c3ccccc3OCCOC)[nH]c(=O)n2)ccc1N
Temperature: 110 °C

Procedure:
A flask was charged with 1-(4-acetamido-3-ethylphenyl)-3-(2-(2-methoxyethoxy)phenyl)propane-1,3-dione (4.0 g, 10.4 mmol), urea (3.0 g, 50 mmol) and 4 N HCl in dioxane (80 mL). The mixture was heated to 110° C. overnight. The reaction was cooled down, concentrated, neutralized with sodium bicarbonate, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to result in 4-(2-ethylanilin-4-yl)-6-[2-(2-methoxyethoxy)phenyl]pyrimidin-2(1H)-one as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].S(C1C=CC(C)=CC=1)(O[CH2:14][C:15]([F:18])([F:17])[F:16])(=O)=O>>[F:16][C:15]([F:18])([F:17])[CH2:14][NH:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: Cc1ccc(O)cc1N
Product: Cc1ccc(O)cc1NCC(F)(F)F
Reaction time: 5 h

Procedure:
3-Amino-4-methylphenol (9.84 g; 0.08 mole) and trifluoroethyl tosylate (20.32 g; 0.08 mole) were mixed in a 500 ml round-bottomed flask and the flask purged with nitrogen. A short air condenser was added, the nitrogen stream was slowed and located towards the top of the condenser, and the flask was immersed in an oil bath at 200° C. A temperature in the range of 150°-250° C. is acceptable. After the molten reagents had been swirled to complete mixing, the heating was continued for five hours. The flask was allowed to cool and before the mixture had solidified, it was dispersed and dissolved in 200 ml of chloroform. Over four days a light brown precipitate of the tosylate salt of 3-amino-4-methylphenol appeared which was filtered off and recovered. The chloroform was extracted with 10% aqueous sodium hydroxide and the dark brown aqueous phase was extracted with chloroform 50 ml. Ice and concentrated hydrochloric acid (21 ml) were added to the aqueous phase and the brown oil was extracted into chloroform 100 ml plus 50 ml. The chloroform solution was washed with 1N hydrochloric and the chloroform layer was separated, dried with sodium sulfate, filtered and evaporated to give a brown gum that crystallized over a day 8.0 g (49%). Recrystallization from petroleum ether 60/80 gave white, fluffy needles mp. 64°-65°. NMR (deuterodimethylsulfoxide): δ8.86 (s, 1H, OH); 6.8-5.9 (m, 3H, ring protons) resolved as AB quartet at 6.74 (C-5 CH) and 6.01 (C-6 CH), J=8.0 Hz together with 6.13 (d, 1H, J=1.0 Hz, C-2 CH) which in turn coupled with the high-field half of the AB quartet; 5.33 (t, 1H, J=6.8 Hz, N-H); 4.0-3.7 (m, 2H, CH2) resolved as two quadruplets, JCF3, CH2 =9.6 Hz, JCH2, NH=6.8 Hz; 1.99 (s, 3H, CH3). Anal. calc. for C9H10F3NO: C, 52.68; H, 4.91; N, 6.83. Found: C, 52.58; H, 4.99; N, 6.80.
Reaction SMILES: C(N)=[O:2].[CH3:4][O:5][C:6]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[C:7]=1[CH2:8]NC=O>C(O)=O>[CH3:4][O:5][C:6]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[C:7]=1[CH:8]=[O:2]
Reactant: NC=O
Reactant: COc1cc(OC)c(CNC=O)c(OC)c1
Solvent: O=CO
Product: COc1cc(OC)c(C=O)c(OC)c1
Temperature: 200 °C
Reaction time: 0.05 h

Procedure:
1.96 g (10 mmol) of XII, 20 ml of formamide, and 2 ml of formic acid were placed in the GreenChem reaction vessel. The GreenChem reaction vessel was placed into the MARS-5 reaction system and the reaction mixture was quickly heated to 200° C. The reaction mixture was kept at 200° C. for 3 minutes and then cooled to 100° C. The GreenChem reaction vessel was removed from the MARS 5 system, the residual pressure was released, and the reaction vessel was opened. TLC showed that the reaction was complete. The reaction mixture was cooled to room temperature; the precipitated crystals were separated by filtration, rinsed with water and dried with vacuum. The filtrate was used as solvent in the next reaction. The reaction was repeated 10 times. The total of 9.6492 g of formic acid, and 34.5680 g of formamide were added to the reaction mixture over the ten cycles to compensate the losses. The total yield of 2,4,6-trimethoxybenzylformamide (XIII) is quantitative.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[N:21][C:7]1=2)=[O:5].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CC(N(C)C)=O.C(O)C>[N:22]1([CH2:2][CH2:3][C:4]([N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[NH:9][C:8]3[CH:18]=[CH:19][CH:20]=[N:21][C:7]2=3)=[O:5])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: C1CNCCN1
Reactant: O=C1Nc2cccnc2N(C(=O)CCCl)c2ccccc21
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: O=C1Nc2cccnc2N(C(=O)CCN2CCNCC2)c2ccccc21
Yield: 70 %

Procedure:
A warm solution of 6.0 g of 11-(3-chloropropionyl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one in 12 ml of dimethylacetamide and 40 ml of ethanol was added dropwise with stirring to a refluxing solution of 8.6 g of piperazine in 50 ml of ethanol. Then, the reaction mixture was refluxed for 1 hour and the mixture was evaporated to dryness in vacuo. The residue was chromatographed over silica gel and the eluent was then evaporated to dryness in vacuo. The residue was crystallized from acetonitrile to obtain a 70% yield of 5,11-dihydro-11-[3-(1-piperazinyl)-propionyl]-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one with a melting point of 280°-282° C. with decomposition.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH2:13]>>[CH3:12][NH:13][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CN
Product: CNS(=O)(=O)c1ccc(Br)cc1

Procedure:
Entry 54: 4-Bromobenzenesulfonyl chloride was reacted with methylamine according to Method A15, Step 1 to afford N-methyl-4-bromobenzenesulfonamide. N-Methyl-4-bromobenzenesulfonamide was coupled with phenol according to Method A15, Step 2 to afford 4-(4-(N-methylsulfamoyl)phenoxy)benzene. 4-(4-(N-Methylsulfamoyl)phenoxy)benzene was converted into 4-(4-(N-methylsulfamoyl)phenoxy)-1-nitrobenzene according to Method A15, Step 3. 4-(4-(N-Methylsulfamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(4-N-methylsulfamoyl)phenyloxy)aniline according to Method A15, Step 4. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-N-methylsulfamoyl)phenyloxy)aniline to afford the urea.
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Br:20][C:21]1[C:26]([C:27](Cl)=[O:28])=[C:25]([Br:30])[C:24]([Br:31])=[C:23]([Br:32])[C:22]=1[Br:33]>C1C=CC=CC=1>[Br:20][C:21]1[C:26]([C:27]([N:7]2[C:8](=[O:9])[CH:3]3[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]3[C:5]2=[O:6])=[O:28])=[C:25]([Br:30])[C:24]([Br:31])=[C:23]([Br:32])[C:22]=1[Br:33]
Reactant: O=C(Cl)c1c(Br)c(Br)c(Br)c(Br)c1Br
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(c1c(Br)c(Br)c(Br)c(Br)c1Br)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Pentabromobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(pentabromobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]2)=[O:18])=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH3:34][S:35]([O:24][CH:21]1[CH2:22][CH2:23][N:19]([C:17](=[O:18])[C:14]2[CH:13]=[CH:12][C:11]([CH2:10][C:2]3[NH:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:1]=3)=[CH:16][CH:15]=2)[CH2:20]1)(=[O:37])=[O:36]
Reactant: O=C(c1ccc(Cc2nc3ccccc3[nH]2)cc1)N1CCC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OC1CCN(C(=O)c2ccc(Cc3nc4ccccc4[nH]3)cc2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
A portion of [4-(1H-benzoimidazol-2-ylmethyl)-phenyl]-(3-hydroxy-pyrrolidin-1-yl)-methanone (1.00 g, 3.1 mmol) was dissolved in dichloromethane, treated with diisopropylethylamine (0.60 g, 4.6 mmol), cooled to 0° C., treated dropwise with a solution of methanesulfonyl chloride (0.49 g, 4.3 mmol) in dichloromethane, stirred at 0° C. for 10 min. and concentrated under vacuum to provide a solid residue. Purification of this residue by column chromatography (silica, chloroform:methanol 0→5%) gave the title product as a yellow solid (62%). 1H NMR (400 MHz, CDCl3): 7.58 (m, 2H), 7.56 (m, 4H), 7.22 (m, 2H), 5.27 (d, J=5.4 Hz 1H), 4.35 (s, 2H), 3.93 (s, 1H), 3.80 (s, 1H), 3.63 (m, 4H), 3.09 (m, 3H), 2.31 (m, 2H). [M+H] 400.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[NH3:15].CO>>[N+:12]([C:11]1[C:2]([NH2:15])=[N:3][C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1)([O-:14])=[O:13]
Reactant: N
Reactant: O=[N+]([O-])c1cc2c(nc1Cl)CCCC2
Solvent: CO
Product: Nc1nc2c(cc1[N+](=O)[O-])CCCC2
Temperature: 120 °C
Reaction time: 12 h

Procedure:
A mixture of intermediate (9) (0.0658 mol) in NH3/CH3OH 7N (60 ml) was stirred at 120° C. for 12 hours in an autoclave. The solvent was evaporated till dryness. The residue was taken up in 2-propanone. The precipitate was filtered off and dried, yielding 8.6 g 5,6,7,8-tetrahydro-3-nitro-2-quinolinamine (intermediate 10). d) A mixture of intermediate (10) (0.031 mol) in methanol (100 ml) was hydrogenated at room temperature under a 3.105 Pa (3 bar) pressure for 30 minutes in a Parr apparatus. After uptake of hydrogen (3 equivalents), the catalyst was filtered through celite, rinced with methanol and the filtrate was evaporated till dryness. The product was used with further purification, yielding 5.07 g 5,6,7,8-tetrahydro-2,3-quinolinediamine (intermediate 11).
Reaction SMILES: [Na].[C:2]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])[CH2:3][C:4]([O-:6])=[O:5].[CH:13]12[CH2:20][CH2:19][CH:16]([CH:17]=[CH:18]1)[CH2:15][CH:14]2[C:21](Cl)=[O:22]>>[C:4]([O:6][C:21]([CH:14]1[CH2:15][CH:16]2[CH2:19][CH2:20][CH:13]1[CH:18]=[CH:17]2)=[O:22])(=[O:5])[CH2:3][C:2]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: O=C(Cl)C1CC2C=CC1CC2
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Agent: [Na]
Product: CC(C)(C)OC(=O)CC(=O)OC(=O)C1CC2C=CC1CC2
Yield: 84.8 %

Procedure:
To a solution of sodium salt of mono-tert-butyl malonate (20.4 g) prepared according to the same procedure as in Example 4, bicyclo[2,2,2]oct-5-ene-2-carbonyl chloride (17.1 g) obtained in Preparation Example 2 is slowly added, and the reaction mixture is reacted at −20° C. in a nitrogen atmosphere for 1 hour, and further reacted at 40° C. for 6 hours. Then, the mixture is worked up as in the procedure of Example 1, to obtain 25 g of the pure title compound (purity: 99%, yield: 84%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[CH3:15][C:16]([CH3:18])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)C.C(O)(=O)C>[CH:16]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1)([CH3:18])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C

Procedure:
Commercially available tert-butyl (3R)-3-aminopiperidine-1-carboxylate (6.67 g) was dissolved in ethanol (100 ml), and thereto were added acetone (12.2 ml) and acetic acid (2.0 ml), and the mixture was heated at 60° C. with stirring. Seven hours later, to the mixture was added sodium triacetoxyborohydride (9.67 g), and the mixture was stirred at room temperature for 14 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium hydrogen sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: chloroform/methanol=30/1, 15/1, 10) to give the title compound (7.78 g) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[CH:4]=1.C([O-])(=O)C.[Na+].[H][H]>CCOCC.[Pd]>[F:9][C:7]1[CH:8]=[C:3]([CH3:2])[CH:4]=[C:5]([F:10])[CH:6]=1
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Product: Cc1cc(F)cc(F)c1
Yield: 98.1 %

Procedure:
A mixture of 1-bromomethyl-3,5-difluoro-benzene (75 g, 0.362 mol), Pd/C (5%, 5 g), and sodium acetate (208 g, 2.54 mol) in ether (300 mL) was treated with hydrogen gas (50 psi) in a Parr shaker for 2 days. The mixture was filtered through Celite and the organic solution washed three times with saturated aqueous sodium bicarbonate solution. The aqueous layers were washed with ether and the combined organic layers dried (MgSO4), filtered, and partially concentrated by evaporation using a cold water bath. The volatile product was obtained as a mixture with ether and the ratio (˜3:2, ether:product, g:g) calculated based on 1H NMR integration to determine actual yield (45.5 g, 0.355 mol, 98%) of product for scaling reagents in the ensuing reaction. 1H NMR (400 MHz, CDCl3) δ 2.25 (s, 3H), 6.51-6.56 (m, 1H), 6.58-6.60 (m, 2H) ppm.