Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22].CCCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:13]([C:19]([OH:18])=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:26]=[N:12]2)=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(SCc2ccccc2)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2cc(SCc3ccccc3)ccc2c1O
Temperature: 265 °C
Reaction time: 0.75 h
Yield: 71.3 %

Procedure:
A mixture of 7.40 g of 3-(benzylsulfanyl)aniline from Preparation No. 28 and 7.70 g of diethyl ethoxymethylene malonate is heated at 135° C. under a gentle flow of argon for 2 h, then diluted with 30 mL of diphenyl ether and heated to 260-270° C. After 45 min, the solution was added to 500 mL of stirred heptane. The resulting solid was filtered, washed well with hexane, and dried under vacuum to afford 8.32 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][CH:11]=1>CO.C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH:10]1[CH2:11][CH2:12][C:13]2([O:14][CH2:15][CH2:16][O:17]2)[CH2:18][CH2:19]1
Reactant: Fc1cc(F)c(C2=CCC3(CC2)OCCO3)cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Fc1cc(F)c(C2CCC3(CC2)OCCO3)cc1F
Reaction time: 8 h

Procedure:
A solution of 8-(2,4,5-trifluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene in methanol (240 mL) and ethyl acetate (5 mL) was treated with 10% palladium on carbon (7.0 g) and stirred under an atmosphere of hydrogen gas (40 psig) overnight. The reaction mixture was filtered over Celite. The filtrate was concentrated and chromatographed (silica gel, gradient 5-7% ethyl acetate in hexane) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[S:31][CH:30]=[N:29][CH:28]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:8]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:5]2=[N:6][CH:7]=1.C([Li])CCC.[S:37]1[CH2:41][CH2:40][C:39](=[O:42])[CH2:38]1>O1CCCC1>[Cl:1][C:2]1[C:3]([C:27]2[S:31][C:30]([C:39]3([OH:42])[CH2:40][CH2:41][S:37][CH2:38]3)=[N:29][CH:28]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:8]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=3)(=[O:19])=[O:18])[C:5]2=[N:6][CH:7]=1
Reactant: O=C1CCSC1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(-c4cncs4)c(Cl)cnc32)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(-c4cnc(C5(O)CCSC5)s4)c(Cl)cnc32)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of Example 144A (0.095 g, 0.202 mmol) in tetrahydrofuran (2.5 mL) was cooled to −78° C. and treated with n-butyllithium (2.45 M in hexanes, 0.173 mL, 0.424 mmol) dropwise over 5 minutes. The reaction was stirred at −78° C. for 20 minutes, and dihydrothiophen-3(2H)-one (0.033 mL, 0.384 mmol) was added. The reaction was stirred 60 minutes at −78° C. and was quenched by addition of saturated aqueous sodium bicarbonate solution. The mixture was allowed to warm to ambient temperature and was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by flash chromatography on a silica gel column, eluting with 1% methanol in dichloromethane, to provide the title compound. MS ESI(+) m/z 572.3 [M+H]+.
Reaction SMILES: [ClH:1].C(NC1CCCCC1(C(C1C=CC2C(=CC=CC=2)C=1)C)O)C1C=CC=CC=1.[CH2:29]([NH:36][C:37](=O)[CH:38]([C:49]1([OH:55])[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1)[C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[ClH:1].[CH2:29]([NH:36][CH2:37][CH:38]([C:49]1([OH:55])[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54]1)[C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(NCc1ccccc1)C(c1ccc2ccccc2c1)C1(O)CCCCC1
Agent: CC(c1ccc2ccccc2c1)C1(O)CCCCC1NCc1ccccc1
Agent: Cl
Product: OC1(C(CNCc2ccccc2)c2ccc3ccccc3c2)CCCCC1

Procedure:
In an analogous manner to Example 1, step 2 1-[2-(benzylamino)[1-(2-naphthyl)ethyl]cyclohexanol hydrochloride was prepared from N-benzyl-2-(1-hydroxycyclohexyl)-2-(2-naphthyl)acetamide. HRMS: calcd for C25H29NO.HCl, 395.2016; found (ESI_FT), 360.23164.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([NH:19][C:20]([NH2:22])=[S:21])=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1.Cl[CH2:24][CH:25]=O>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([NH:19][C:20]2[S:21][CH:24]=[CH:25][N:22]=2)=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1
Reactant: O=CCCl
Reactant: COCCOc1cc(Oc2ccccc2)cnc1NC(N)=S
Solvent: CN(C)C=O
Product: COCCOc1cc(Oc2ccccc2)cnc1Nc1nccs1
Temperature: 100 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
[3-(2-Methoxy-ethoxy)-5-phenoxy-pyridine-2-yl]-thiourea (0.24 mmol) is dissolved in DMF (1 ml) and chloro-acetaldehyde (1.1 eq., 55% in water) is added and stirred 3 hours at 100° C. After cooling to room temperature the suspension is pored into ice-water and extracted with methyl-tert.-butyl ether. The combined organic phases are washed with brine and dried over MgSO4. The solvent is removed in vacuo. [3-(2-Methoxy-ethoxy)-5-phenoxy-pyridine-2-yl]-thiazole-2-yl-amine (“A20”) is obtained after reversed phase chromatography (water/acetonitrile 0.1% TFA) as yellow solid in a yield of 45%; mp. 140.6-140.9°; HPLC (method C): 1.73 min; LC-MS (method A): 1.589 min, 344.1 (M+H+);
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[O:20][C:19](=[O:21])[NH:18][N:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.O.O.Cl[Sn]Cl>CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[O:20][C:19](=[O:21])[NH:18][N:17]=3)[CH2:14][CH2:15]2)=[CH:8][CH:9]=1
Reactant: O=c1[nH]nc(C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)o1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: Nc1ccc(N2CCC(c3n[nH]c(=O)o3)CC2)cc1
Yield: 84.9 %

Procedure:
To a stirred solution of 4-fluoro nitrobenzene (1a, 3.1 g, 22 mmol) and methyl 4-piperidine carboxylate (2, 3.15 g, 22 mmol) in DMF solvent and K2CO3 (7.6 g, 55 mmol) as base and heated at 80° C. for 10 h, after completion of the reaction, reaction is poured into ice water and extracted into ethyl acetate finally purification by column chromatography to afford pure compound methyl 1-(4-nitrophenyl)-4-piperidinecarboxy-late (3a, 4.93 g, 85%). To a stirred solution of ester (3a, 4.75 g, 18 mmol) in ethanol, NH2NH2. H2O (2.25 g, 45 mmol) is added and refluxed for 24 h. After completion of the reaction ethanol is evaporated under vacuum and water is added and extracted into ethyl acetate finally purification by column chromatography to afford pure compound 1-(4-nitrophenyl)-4-piperidinecarbohydrazide (4a, 3.99 g, 84%). Addition N,N-dimethyl carbamyl chloride (1.29 g, 12 mmol) to hydrazide (4a, 3.17 g, 12 mmol) in pyridine at room temperature (27° C.) and followed by reflux at temperature 85° C. for 2.5 h. After completion of the reaction, the reaction mixture is cooled and filtered. The residue is recrystallized from water to get 5-[1-(4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5a, 1.39 g, 40%). Nitro compound (5a, 1.16 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (7a, 884 mg, 85%). To a stirred solution of 5-nitro2-furanoic acid (0.16 g, 1 mmol) in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide)) (0.19 g, 1 mmol) and amine compound (7a, 0.26 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-4-[4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2-furamide (8a, 323 mg, 81%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[CH:7]([C:8](=O)[C:9]([F:14])=[C:10]([F:13])[CH:11]=2)[CH2:6][CH2:5][CH2:4]1)[CH3:2].C1(Cl)C(=O)C(Cl)=C(Cl)C(=[O:19])C=1Cl>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([F:13])[CH:11]=2)[C:6](=[O:19])[CH:5]=[CH:4]1)[CH3:2]
Reactant: CCN1CCCC2C(=O)C(F)=C(F)C=C21
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Product: CCn1ccc(=O)c2cc(F)c(F)cc21
Yield: 68.3 %

Procedure:
1-Ethyl-6,7-difluoro-1,2,3,4-tetrahydro-5-oxoquinoline(10 g) and p-chloranil (23 g) were reacted in the same method as described in Preparation 1-B to give the white above-indicated compound(6.7 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[N:12]1([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[N:12]1([CH:17]2[CH2:22][CH2:21][N:20]([C:2]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:3]=3[CH:4]=[CH:5][N:6]=[CH:7]4)[CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Brc1cccc2cnccc12
Reactant: C1CCN(C2CCNCC2)C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1cc(N2CCC(N3CCCC3)CC2)c2ccncc2c1
Temperature: 130 °C
Yield: 62.1 %

Procedure:
To 5-bromoisoquinoline (1 g, 4.81 mmol), 4-(pyrrolidin-1-yl)piperidine (1.112 g, 7.21 mmol), and sodium tert-butoxide (0.647 g, 6.73 mmol), was added toluene (10 mL) and the mixture was degassed with argon. BINAP (0.090 g, 0.144 mmol) and Pd2(dba)3 (0.044 g, 0.048 mmol) were added and the reaction was heated to 130° C. in a microwave for 20 min. Purification by normal phase chromatography afforded 0.84 g (62.7%) of 80A as a tan solid. MS (ESI) m/z: 282.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O.[H][H].CO>C(OCC)(=O)C.[Pd]=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([NH:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)Nc2ccccc2)cc1
Reactant: [H][H]
Agent: O=[Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(CS(=O)(=O)Nc2ccccc2)cc1
Yield: 91 %

Procedure:
A solution of 4-Nitro-N-phenylbenzenemethanesulphonamide (11.0 g), in ethyl acetate (400 ml) was hydrogenated at room temperature and pressure over pre-reduced 10% palladium oxide on charcoal (1.0 g, 50% paste with water) for 4 h until hydrogen uptake ceased (2.7 l). Methanol (400 ml) was added, the catalyst filtered off, and the filtrate evaporated in vacuo to give the title compound as a white solid (8.98 g), m.p. 180°-182°.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=3)[N:13]=2)=[CH:7][C:6]=1[CH3:25].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C)C=O>[CH3:25][C:6]1[CH:7]=[C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=3)[N:13]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[O:4][CH2:3][CH2:2][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COc1ccc2nc(-c3cc(C)c(OCCBr)c(C)c3)[nH]c(=O)c2c1
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: COc1ccc2nc(-c3cc(C)c(OCCN4CCCC4)c(C)c3)[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-6-methoxy-3H-quinazolin-4-one (1.94 g, 4.80 mmol) in N,N-dimethylformamide (20 mL), pyrrolidine (4 mL) was added and the reaction mixture was stirred at room temperature for 16 hours. Solvent was evaporated in vacuo, water (50 mL) was added, and the separated solid was filtered. The solid was washed with ether to give the title compound as a light brown solid. Yield: 0.30 g (16%). MP 201.2-203.1° C. 1H NMR (400 MHz, CDCl3): δ 7.73 (m, 4H), 7.39 (m, 1H), 3.98 (t, J=6.0 Hz, 3H), 3.94 (s, 3H), 2.97 (t, J=6.0 Hz, 2H), 2.69 (br s, 4H), 2.41 (s, 6H), 1.86 (br s, 4H). MS (ES) m/z: 394.21 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:8])[CH:7]=1.[Mg].C1O[C:14]2([CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=O)[O:13]C1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:17]2[CH2:18][CH2:19][C:14](=[O:13])[CH2:15][CH2:16]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: O=C1CCCCC12OCCO2
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C1CCC(c2cc(F)cc(F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.1 %

Procedure:
To Grignard reagent prepared from 3,5-difluorobromobenzene 100 g (518 mmol) and magnesium in dried THF 300 ml at room temperature, a THF (300 ml) solution of cyclohexanedione monoethyleneketal 74.6 g (517 mmol) was added dropwise at room temperature, and the mixture was stirred for 3 hours at room temperature. The reactant was added to one liter of 2N-hydrochloric acid, and the product was extracted with diethylether. The extract was washed with water, a saturated sodium bicarbonate aqueous solution, and then water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the residue, para-toluene sulfonic acid 5 g and toluene 800 ml were added. The mixture was refluxed with heating while removing water formed with Dien-Stark. The reactant was washed with water, a saturated sodium bicarbonate aqueous solution, and then water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: heptane/ethyl acetate=3/1). Such obtained purified material was hydrogenated in the presence of 5% palladium carbon 5 g as a catalyst in ethanol 500 ml. The catalyst was filtered off, the solvent was distilled off under reduced pressure, formic acid 40 g and toluene 300 ml were added to the residue, and the mixture was refluxed for 3 hours. After cooling, water 500 ml was added to the reactant, and the organic layer was fractionated, washed with water, a saturated sodium bicarbonate aqueous solution, and then water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: heptane/ethyl acetate=3/1) to obtain 4-(3,5-difluorophenyl)cyclohexanone 29.4 g (140 mmol). The yield was 27.0% from 3,5-difluorobromobenzene.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:21])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:5](OC)=[O:6].[Li+].[BH4-].C1COCC1>CCOC(C)=O>[I:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:21])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH2:5][OH:6]
Reactant: COC(=O)c1cc(I)c(Oc2ccc(OC)cc2)c(I)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2c(I)cc(CO)cc2I)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To a dry 15 ml 2-necked flask fitted with a serum stopper and a reflux condenser under argon was added methyl 3,5-diiodo-4-(4′-methoxyphenoxy)benzoate (1.02 g; 2.0 mmol) followed by 2M LiBH4 in THF (2.0 ml; 4.0 mmol). The mixture was stirred at RT overnight. EtOAc (10 ml) was added to consume excess LiBH4, and the resulting mixture stirred at RT under argon. After approximately 20 min, a moderate exotherm was observed and the reaction became cloudy. The reaction was digested with saturated NH4Cl (20 ml), EtOAc added (20 ml) and the resulting layers partitioned and separated. The organic layer was washed with saturated NaCl (25 ml), then dried over Na2SO4, filtered and evaporated to give a pale amber oil. The crude product was applied to a filter pad of silica gel (10 g, 230-400 mesh) and eluted with EtOAc/hexanes (3:7). Fractions containing product were combined and evaporated to give 592 mg (61%) of the product as a white solid. Crystallization from EtOAc/hexanes afforded 347 mg of 3,5-diiodo-4-(4′-methoxyphenoxy)benzyl alcohol (9) as a crystalline white solid. NMR (CDCl3) d 3.78 (s, 3H), 4.52 (s, 2H), 6.72 (m, 2H), 6.83 (m, 2H), 7.82 (s, 2H). TLC: Rf0.47 (EtOAc/hexanes, 3:7)
Reaction SMILES: B.C1COCC1.[Cl:7][C:8]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=1[F:19]>C1COCC1>[Cl:7][C:8]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][C:9]=1[F:19]
Reactant: N#Cc1cc(F)c(Cl)c([N+](=O)[O-])c1
Agent: B
Solvent: C1CCOC1
Product: NCc1cc(F)c(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of BH3/THF (7.5 mL; 7.5 mmol) was added dropwise to a solution of 4-chloro-3-fluoro-5-nitrobenzonitrile (750 mg; 3.74 mmol) in THF (5 mL) at 0° C. The mixture was stirred at 0° C. for 3 h, it was acidified to pH ˜1 and stirred at rt for 1 h and then basicified to pH ˜8 and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was dissolved in Et2O and precipitated with PE to give the sub-title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][OH:7])[CH3:2].CC(C)([O-])C.[K+].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>C1COCC1>[CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][O:7][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCN(CC)CCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCN(CC)CCCOc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 71.2 %

Procedure:
A solution of 3-diethylamino-1-propanol (2.97 mL, 20 mmol) in THF (40 mL) at 0° C. is treated potassium tert-butoxide (2.36 g, 1.05 equiv.) in one portion. The reaction mixture is stirred at 0° C. for 5 min during which time it becomes reddish brown. Neat 1-fluoro-4-nitrobenzene (2.82 g, 1 equiv.) is added dropwise and the ice-bath is removed. The reaction mixture is stirred at room temperature for 15 min. The dark green reaction mixture is quenched with ice-water (300 mL), and extracted with EtOAc (2×200 mL). The combined organic extracts are washed with water (2×300 mL) and brine (1×300 mL) and dried over anhydrous Na2SO4. The oily brown residue obtained after evaporation, is purified by chromatography, (silica gel, 1:4 MeOH:CHCl3) to give the named compound as a brown oil (3.59 g, 71%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Cl)=[N:7][CH:6]=1)[CH3:2].[CH:13]1([NH2:16])[CH2:15][CH2:14]1>CCOC(C)=O>[CH:13]1([NH:16][C:8]2[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:12])=[CH:6][N:7]=2)[CH2:15][CH2:14]1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: NC1CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(NC2CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
A microwave vial is charged with ethyl-6-chloronicotinate (1 g, 5.39 mmol) and cyclopropylamine (1 mL, 14.43 mmol), sealed and stirred at 80° overnight. After cooling to RT, the yellow solid was stirred with EtOAc and filtered. The filtrate was preadsorbed on SiO2 and applied to the top of a SiO2 column and eluted with an EtOAc/hexane gradient (0 to 30% EtOAc) to afford 0.71 g of ethyl 6-cyclopropylamino-nicotinoate (332) as an off white solid (17).
Reaction SMILES: [OH:1][CH:2]1[C:11]2[N:10]=[CH:9][C:8]([NH:12][C:13](=[O:15])[CH3:14])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[O:1]=[C:2]1[C:11]2[N:10]=[CH:9][C:8]([NH:12][C:13](=[O:15])[CH3:14])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: CC(=O)Nc1cnc2c(c1)CCCC2O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cnc2c(c1)CCCC2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.7 %

Procedure:
Manganese dioxide (4.47 g, 51.4 mmol) was added to chloroform (26 ml) solution of N-(8-hydroxy-5,6,7,8-tetrahydro-3-quinolinyl)acetamide (1.06 g, 5.14 mmol) obtained in 2), which was stirred at room temperature for 1 day. After completion of the reaction, the insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. Diisopropyl ether and hexane were added to the resulting residue, to give the titled compound (858 mg) as a colorless powder.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH3:6])[CH2:3][CH3:4].Cl[C:8]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:11]([CH2:12][O:13][CH2:14][CH2:15][OH:16])=[C:10]([CH3:22])[C:9]=1[N+:23]([O-:25])=[O:24].Cl>C1(C)C=CC=CC=1>[CH2:3]([CH:2]([NH:1][C:8]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:11]([CH2:12][O:13][CH2:14][CH2:15][OH:16])=[C:10]([CH3:22])[C:9]=1[N+:23]([O-:25])=[O:24])[CH2:5][CH3:6])[CH3:4]
Reactant: CCC(N)CC
Reactant: Cc1c(COCCO)cc([N+](=O)[O-])c(Cl)c1[N+](=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: CCC(CC)Nc1c([N+](=O)[O-])cc(COCCO)c(C)c1[N+](=O)[O-]
Yield: 93.1 %

Procedure:
3-Aminopentane (1.74 g; 0.02 mol) is added to a solution of 2-(4-chloro-2-methyl-3,5-dinitrobenzyloxy)ethanol (0.5 g; 1.7×10-3 mol) in toluene. The reaction mixture is heated at reflux for 3 hours. Analysis by tlc (silica gel plate; eluent: methanol-benzene in a 1:9 ratio) shows the reaction to be complete. The reaction mixture is poured into 10% hydrochloric acid and extracted with methylene chloride. The organic phase is dried over calcium sulfate; and evaporated in vacuo to afford 0.54 g (91.8%) of an orange-colored oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5](N)=[C:4]([Br:12])[CH:3]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:22].[K+]>O.C(OCC)(=O)C>[I:22][C:5]1[C:4]([Br:12])=[CH:3][C:2]([F:1])=[CH:8][C:7]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1c(Br)cc(F)cc1[N+](=O)[O-]
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc(F)cc(Br)c1I
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Mix 4-fluoro-2-bromo-6-nitroaniline (15.5 g, 66.0 mmol) and 50% sulfuric acid (200 mL) and cool to 0°-5° C. Add, by dropwise addition, a solution of sodium nitrite (6.0 g, 86.4 mmol) in water (50 mL). Stir for 30 minutes and add solid potassium iodide (29 g, 173 mmol). Take up the product in ethyl acetate (300 mL), wash with saturated sodium hydrogen carbonate (2×200 mL), saturated sodium metabisulfite (2×200 mL) and water (200 mL). Dry (MgSO4), evaporate the solvent in vacuo and purify by silica gel chromatography to give 1-iodo-2-nitro-4-fluoro-6-bromobenzene as a yellow crystalline solid (17.81 g, 76%); mp 75°-76° C.
Reaction SMILES: S=C1[N:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:20])[CH3:19])=[C:13]([O:21][CH3:22])[CH:12]=2)=[O:8])[CH2:5][CH2:4]S1.[CH2:23](N)[CH2:24][CH2:25][CH2:26][CH2:27]CC.C(N(CC)CC)C>ClCCl>[C:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][C:7](=[O:8])[NH:6][CH2:5][CH2:4][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:12][C:13]=1[O:21][CH3:22])(=[O:20])[CH3:19]
Reactant: CCCCCCCN
Reactant: COc1cc(COC(=O)N2CCSC2=S)ccc1OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCNC(=O)OCc1ccc(OC(C)=O)c(OC)c1

Procedure:
A yellow solution of VII (87 mg, 0.255 mmol), n-heptylamine (31 mg, 1.05×0.255 mmol) and triethylamine (26 mg, 36 μL, 0.255 mmol) in 3 mL of dichloromethane was stirred at room temperature overnight. The reaction was worked up as described for 7. The product was purified by preparative thick layer chromatography using dichloromethane/diisopropyl ether, 9:1, v/v, as the developing solvent. The result was 58 mg (67%) of 6 as a clear oil: Rf=0.53 (dichloromethane/acetone, 97:3, v/v); 1HNMR (CDCl3) δ 6.98 (d, 3J=8.0 Hz, 1H), 6.94 (s, 1H), 6.91 (d, 3J=8.0 Hz, 1H), 4.98 (s, 2H), 4.73 (bs 1H, NH), 3.81 (s, 3H), 3.18-3.14 (m, 2H), 2.29 (s, 3H), 1.50-1.43 (m, 2H), 1.31-1.19 (m, 8H) and 0.85 (t, 3J=7.0 Hz, 3H). Exact mass (FAB+) calculated for C18H27NO5 [M+] 337.1889. found 337.1895.