Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][C:15]([O:24][CH3:25])=[CH:16][C:17]=3[O:22][CH3:23])[N:12]=2)=[CH:7][CH:6]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C=O)C>[CH3:23][O:22][C:17]1[CH:16]=[C:15]([O:24][CH3:25])[CH:14]=[C:13]2[C:18]=1[C:19](=[O:21])[NH:20][C:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:6][CH:7]=1)=[N:12]2
Reactant: C1CCNC1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OCCBr)cc3)nc2c1
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OCCN4CCCC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 2-[4-(2-bromo-ethoxy)-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.25 g, 0.61 mmol) in anhydrous DMF (10 mL) was added pyrrolidine (0.20 mL, 2.45 mmol) and the reaction mixture was stirred at room temperature under nitrogen for about 20 hours. Solvent was removed under reduced pressure and the residual solid was triturated with water. The resulting slurry was filtered and washed with ether and hexanes. The crude product was purified by column chromatography (silica gel 230-400 mesh; 10% methanol in dichloromethane as eluent) to give the title compound as a white solid. Yield: 0.11 g (44%). MP 226-227° C. 1H NMR (400 MHz, CDCl3): δ 10.08 (br s, 1H), 8.07 (d, J=8.4 Hz, 2H), 7.06 (d, J=8.8 Hz, 2H), 6.81 (d, J=1.95 Hz, 1H), 6.45 (d, J=1.95 Hz, 1H), 4.21 (t, J=5.6 Hz, 2H), 3.99 (s, 3H), 3.93 (s, 3H), 2.97 (t, J=5.6 Hz, 2H), 2.68 (br s, 4H), 1.84 (br s, 4H). MS (ES+): m/z 198.65 (100%), 396.10 (M+1, 70%).
Reaction SMILES: [BH4-].[Li+].O1CCCC1.Cl.C[O:10][C:11]([CH2:13][CH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[F:28])[CH2:17][CH2:16]1)=O>>[OH:10][CH2:11][CH2:13][CH2:14][C@H:15]1[CH2:16][CH2:17][C@H:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[F:28])[CH2:19][CH2:20]1
Reactant: COC(=O)CC[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC[C@H]1CC[C@H](c2cccc(F)c2F)CC1

Procedure:
First, 1.4 g of lithium borohydride and 50 ml of dry tetrahydrofuran were placed in a 200 ml flask whose content was replaced with argon. Then, 25 ml of a tetrahydrofuran solution in which 12.1 g of 1-[trans-4-(2-methoxycarbonylethyl)cyclohexyl]-2,3-difluorobenzene was dissolved was added dropwise to the reaction mixture at room temperature, and the resultant reaction mixture was stirred under reflux for 1 hour. Diluted hydrochloric acid was added to the reaction mixture, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=3/1) and recrystallized from hexane to obtain 9.3 g of 1-[trans-4-(3-hydroxypropyl)cyclohexyl]-2,3-difluorobenzene (Y: 85.1%). The compound thus obtained had a purity of 99.1% by GC and 99.0% by HPLC.
Reaction SMILES: [CH:1](/[C:9]1[N:13]=[CH:12][O:11][N:10]=1)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O>C(O)C.[Hg]>[CH:1](/[C:9]1[N:13]=[CH:12][O:11][N:10]=1)=[CH:2]/[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C(=C/c1ncon1)\c1ccccc1
Agent: [Hg]
Solvent: CCO
Solvent: O
Product: C(=C\c1ncon1)\c1ccccc1

Procedure:
3-(trans-Styryl)-1,2,4-oxadiazole (0.75 g.) in absolute ethanol (750 ml.) was irradiated at room temperature, under nitrogen for a total of 31 hr. using a medium pressure mercury vapour arc tube contained in a water cooled glass well immersed in the solution. The ultraviolet spectra of suitably diluted aliquots showed a reduction in the intensity of absorption at ca. 274 nm over the period of irradiation. The colourless solution was evaporated to a low volume when the trans isomer (0.11 g.), m.p. 84° , λmax. (EtOH) 274 nm (ε 26,200) separated. Evaporation of the mother liquors to dryness gave a solid and an oil. The oil was separated and thoroughly dried to give 3-(cis-styryl)-1,2,4-oxadiazole contaminated with ca. 25% by weight of the trans-isomer, λmax. (EtOH) 272-273 nm (ε 14,300), pmr. shows cis-protons at 2.92 and 3.50 (J = 12.5) and confirms the presence of the transisomer.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:11][C:10](=[O:12])[O:9][C:8]([CH2:17][NH2:18])([C:13]([F:16])([F:15])[F:14])[C:7]=2[CH:19]=1.C(N(CC)CC)C.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1>C1COCC1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:11][C:10](=[O:12])[O:9][C:8]([CH2:17][NH:18][C:35]([NH:34][C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)=[O:36])([C:13]([F:15])([F:16])[F:14])[C:7]=2[CH:19]=1
Reactant: NCC1(C(F)(F)F)OC(=O)Nc2ccc(Cl)cc21
Reactant: O=C=Nc1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCC1(C(F)(F)F)OC(=O)Nc2ccc(Cl)cc21)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of [6-chloro-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methylamine hydrochloride (60 mg, 0.20 mmol) in THF (1 mL), triethylamine (66 μL, 0.47 mmol) and 4-fluorophenyl isocyanate (32 mg, 0.24 mmol) were sequentially added at room temperature. The reaction solution was stirred overnight at room temperature and then concentrated. The residue was purified by thin-layer silica gel column chromatography (ethyl acetate/hexane=1/1), whereby the objective compound (24 mg, 28%) was obtained as a white solid.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[NH2:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[OH:34])[N:17]=2)[CH2:12]1.Cl[C:36]([O:38][C@H:39]1[CH2:43][CH2:42][O:41][CH2:40]1)=[O:37]>C1COCC1>[F:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([OH:34])[C:27]=1[C:18]1[N:17]=[C:16]([N:13]2[CH2:14][CH2:15][C@@H:11]([NH:10][C:36](=[O:37])[O:38][C@H:39]3[CH2:43][CH2:42][O:41][CH2:40]3)[CH2:12]2)[C:25]2[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=2)[N:19]=1
Reactant: O=C(Cl)O[C@H]1CCOC1
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3c(O)cccc3F)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)O[C@H]4CCOC4)C3)nc(-c3c(O)cccc3F)nc2c1
Temperature: 25 °C
Yield: 88.4 %

Procedure:
At room temperature, N-ethyl-N-isopropylpropan-2-amine (155 mL, 0.88 mmol) was added to a solution of 2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol (150 mg, 0.40 mmol) in THF. The mixture was cooled in an ice bath, and (S)-tetrahydrofuran-3-yl chloroformate (63 mg, 0.42 mmol) was added slowly over a period of 10 minutes. After warming to room temperature, the reaction was quenched with water and extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in CH2Cl2/hexanes (1:1) gave (S)-tetrahydrofuran-3-yl (R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (160 mg, 84%). LC/MS: m/z 453.3 (M+H)+ at 2.12 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J=8.6 Hz, 1H), 7.70 (d, J=6.3 Hz, 1H), 7.58 (s, 1H), 7.29-7.38 (m, 2H), 6.76 (d, J=8.3 Hz, 1H), 6.67-6.72 (m, 1H), 5.14 (s, 1H), 4.23-4.24 (m, 1H), 3.99-4.13 (m, 3H), 3.64-3.85 (m, 5H), 2.50 (s, 3H), 2.07-2.22 (m, 2H), 2.00-2.03 (m, 1H), 1.85-1.90 (m, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:33])[CH2:9][N:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[S:27][C:28]([CH:31]=[O:32])=[CH:29][CH:30]=3)=[CH:22][CH:21]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.OO.Cl([O-])=[O:37].[Na+]>C(#N)C.C(OCC)(=O)C>[C:13]([O:12][C:11]([N:10]([CH2:9][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:33])[CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[S:27][C:28]([C:31]([OH:37])=[O:32])=[CH:29][CH:30]=2)=[CH:24][CH:25]=1)=[O:17])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(C=O)s2)cc1)C[C@H](O)c1cccc(Cl)c1
Reactant: [O-][Cl+][O-]
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(C(=O)O)s2)cc1)C[C@H](O)c1cccc(Cl)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
To a solution of tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-[4-(5-formyl-2-thienyl)phenyl]ethyl]-carbamate (180 mg) in acetonitrile (2 ml) and pH 4 buffer solution (sodium dihydrogenphosphate) (1 ml) was added 30% hydrogen peroxide solution (30 μl) and 80% sodium chlorite (67 mg) below 10° C. The reaction mixture was stirred at 50° C. for 3 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give 5-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyl]-2-thiophenecarboxylic acid (160 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].Cl[C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[C@@H:20]([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1>>[CH3:22][N:21]1[C:14]2[N:15]([C:16](=[O:18])[N:17]=[C:12]([O:1][CH2:2][C:3]3[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=3)[C:6]#[N:7])[CH:13]=2)[CH2:19][C@@H:20]1[CH3:23]
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Reactant: N#Cc1cccc(CO)c1
Product: C[C@H]1Cn2c(cc(OCc3cccc(C#N)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 3-(hydroxymethyl)benzonitrile and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidaz-o[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:15]=[N:16][N:17]=2)[CH:5]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:7]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:3]3[N:4]([CH:15]=[N:16][N:17]=3)[CH:5]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:7]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c2nncn2c1
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCO
Product: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cn3cnnc23)cc1
Temperature: 85 °C
Reaction time: 18 h
Yield: 16.9 %

Procedure:
To a solution of tert-butyl 8-chloro[1,2,4]triazolo[4,3-a]pyridine-6-carboxylate (1.7 g, 6.7 mmol) in n-propanol (53.6 mL) and water (13.4 mL) were added (4-methylphenyl)boronic acid (1.37 g, 10.1 mmol), tetrakistriphenylphosphinepalladium (0) (0.39 g, 0.34 mmol) and potassium carbonate (2.78 g, 20.1 mmol). The mixture was purged with nitrogen and heated to 85° C. After 18 h, the mixture was cooled to ambient temperature and filtered with Celite. The filtrate was concentrated to remove n-propanol. The aqueous mixture was extracted with ethyl acetate (3×). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol). The product obtained was purified again by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.025% trifluoroacetic acid) gave the title compound (0.35 g): LC-MS [M+1]=310.2.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[CH3:27][O:28][CH2:29]Cl>ClCCl>[CH3:27][O:28][CH2:29][O:1][CH:2]1[CH2:3][CH2:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][CH2:7]1
Reactant: COCCl
Reactant: CCOC(=O)C1(C(=O)OCC)CCC(O)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(C(=O)OCC)CCC(OCOC)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
12.3 g of diethyl 4-hydroxycyclohexane-1,1-dicarboxylate was dissolved in 160 ml of dichloromethane and 26.3 ml of diisopropylethylamine was added thereto followed by ice-cooling. Next, 9.6 ml of chloromethyl methyl ether was added thereto and the reaction mixture was stirred at room temperature for 15 hours. Then the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 11.10 g of the title compound as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1.[CH2:16]([C:18]([O-:20])=[O:19])[CH3:17].[Cl:21][C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([S:28]([NH:1][C:2]2[CH:11]=[CH:10][C:9]3[NH:8][C:7](=[O:12])[C:6]4[NH:13][CH:14]=[CH:15][C:5]=4[C:4]=3[CH:3]=2)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1.[CH2:16]([C:18]([O-:20])=[O:19])[CH3:17]
Reactant: Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: CCC(=O)[O-]
Product: O=c1[nH]c2ccc(NS(=O)(=O)c3cccc(Cl)c3)cc2c2cc[nH]c12
Yield: 27.5 %

Procedure:
This compound is prepared according to synthesis 37, from 60 mg (0.22 mmol) of 8-amino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate (synthesis 64) and 34 μL (0.24 mmol) of 3-chloro-benzenesulfonyl chloride. After recrystallization from methanol then trituration in hot methanol, 27 mg (27%) of 8-(3-chloro-benzenesulfonylamino)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[Cl:29][C:30]1[CH:31]=[C:32]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:33]=[CH:34][C:35]=1[Cl:36]>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:3]=1[C:14]([N:40]1[CH2:39][CH2:38][N:37]([C:32]2[CH:33]=[CH:34][C:35]([Cl:36])=[C:30]([Cl:29])[CH:31]=2)[CH2:42][CH2:41]1)=[O:16]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: Nc1onc(-c2ccccc2F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2ccccc2F)c1C(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Yield: 81 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(2-fluorophenyl)isoxazol-4-carboxylic acid (409 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3,4-dichlorophenyl)piperazine (425 mg, 1.84 mmol), a white solid required compound (613 mg, 1.49 mmol, 81%) was obtained.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[K+].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(Cl)(Cl)Cl>C(O)C.O>[CH2:12]([O:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:4][CH:3]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCBr
Reactant: Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCOc1ccc(OCCCCCCCC)cc1

Procedure:
Hydroquinone (10.00 g, 9.08×10−2 mol) was dissolved in 100 ml of ethanol. After addition of KOH (10.79 g, 0.192 mol), the solution was stirred under reflux for 20 min. 1-Bromooctane (33.0 ml, 0.191 mol) was added dropwise to the light brown solution over 1 h, followed by stirring under reflux for 3 h. After cooling, CHCl3 and H2O were added to the reaction mixture and the organic layer was collected. The aqueous layer was further washed with CHCl3. The combined organic layers were washed with aqueous NaHCO3 and dried over Na2SO4. After the solvent was evaporated, the residue was chromatographed on silica gel with 1:1 hexane:CHCl3 as the eluent. Yield=27.33 g (90% based on 10.00 g of hydroquinone). 1H NMR (300 MHz, CDCl3): δ 6.82 (s, 4H, Ph-H), 3.90 (t, 4H, J=6.6 Hz, —OCH2—), 1.75 (quint, 4H, J=7.0 Hz, —OCCH2—), 1.37-1.51 (m, 4H, —OCCCH2), 1.17-1.37 (m, 16H, —CH2—), 1.20-1.49 (m, 24H, —CH2—), 0.88 (t, 6H, J=6.6 Hz, —CH3). CI MS m/z: 334.287 (M+) (calcd 334.287).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1.[CH:10]1([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23](O)=[O:24])[CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C.C(Cl)Cl>CN(C=O)C>[CH:10]1([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=3[CH3:9])=[O:24])[CH:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Reactant: Cc1cc(O)ccc1N
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(O)ccc1NC(=O)c1cc(NC2CCCCC2)ncn1
Reaction time: 16 h

Procedure:
A mixture of 4-amino-m-cresol (Fluka, 40.00 mg; 0.32 mmol), 6-(cyclohexylamino)pyrimidine-4-carboxylic acid, Intermediate 4 (86.2 mg; 0.39 mmol) and triethylamine (136 μl; 0.97 mmol) in dry DMF (5.00 mL) was treated with polymer-supported Mukaiyama reagent (520 mg; 0.65 mmol) and stirred for 16 hours. DCM was added to the reaction mixture and the solution was filtered through a SPE-NH2 column (2 g). The DCM was evaporated in vacuo, the resulting solution was diluted with EtOAc, washed three times with brine, then the organic phase was dried over magnesium sulfate, filtered and evaporated in vacuo. The solid obtained was triturated in acetonitrile to afford the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][NH2:36])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC(C)=CC=1C>CN(C)C=O>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][NH:36][C:13](=[O:15])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C(N[C@H](C(=O)O)C1CCCCC1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)[C@@H](NC(=O)OCc2ccccc2)C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (S)-benzyloxycarbonylamino-cyclohexyl-acetic acid (5.4 g, 18.66 mmol) and 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (4.0 g, 18.66 mmol) in dimethylformamide were added HATU (7.09 g, 18.66 mmol) and collidine (2.46 ml, 18.66 mmol) at 0° C. The mixture was stirred for 1 hour and then allowed to warm to room temperature. The mixture was evaporated and separated between ethyl acetate and sodium bicarbonate solution. The organic layer was washed with aqueous solution (pH 4), dried and evaporated. The resulting residue was taken up in ethyl acetate and washed with potassium hydrogen sulfate solution, dried and evaporated to give the desired product. Yield: 8.29 g (91%), MS m/z: 488.3 (M+H)+.
Reaction SMILES: Cl.Cl.[CH:3]1([C:7]2[N:8]=[N:9][C:10]([O:26][CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][CH:14]=2)[CH2:6][CH2:5][CH2:4]1.[CH2:33]=O.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:36]>C(Cl)Cl>[CH:3]1([C:7]2[N:8]=[N:9][C:10]([O:26][CH:27]3[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]3)=[CH:11][C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:17][CH:18]=2)[CH2:6][CH2:36][CH2:35][CH2:5][CH2:4]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: c1cc(-c2cc(OC3CCNCC3)nnc2C2CCC2)ccc1OC1CCCCC1
Reactant: C=O
Agent: Cl
Solvent: ClCCl
Product: CN1CCC(Oc2cc(-c3ccc(OC4CCCCC4)cc3)c(C3CCCCC3)nn2)CC1
Reaction time: 12 h

Procedure:
To a solution of 3-cyclobutyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (0.17 mmol, 0.08 g) and aqueous formaldehyde (37%, 0.83 mmol, 0.07 mL) in dry DCM (1 mL) was added macroporous resin-bound triacetoxyborohydride (loading 2.36 mmol/gram, 1.0 mmol, 0.42 g). The mixture was shaken for 12 hours. The reaction was placed directly onto a 4 g SiO2 cartridge and the column was eluted with 0-6% (2N NH3 in MeOH) in DCM to give 3-cyclohexyl-4-(4-cyclohexyloxy-phenyl)-6-(1-methyl-piperidin-4-yloxy)-pyridazine. The neutral amine was treated with 2N HCl in diethyl ether (1 mL) and DCM (1 mL). The volatiles were removed under reduced pressure and the salt was triturated with diethyl ether and filtered to provide the title compound (0.05 g). LCMS: m/z 423 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.26-7.47 (3 H, m), 7.02-7.11 (2 H, m), 5.35-5.60 (1 H, m), 4.37-4.48 (1 H, m), 3.97-4.13 (1 H, m), 3.67 (1 H, d), 3.23-3.53 (2 H, m), 2.92 (3 H, s), 1.95-2.62 (12 H, m), 1.75-1.92 (3 H, m), 1.29-1.68 (6 H, m).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-:14].[Na+]>CC(=O)CC>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][I:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [I-]
Reactant: BrCCCCCCc1ccccc1
Agent: [Na+]
Solvent: CCC(C)=O
Product: ICCCCCCc1ccccc1

Procedure:
6-Phenylhexyl iodide [VIa; Ar is C6H5, R is H] was prepared from 16 g. of 6-phenylhexyl bromide (Preparation C12) and 10.95 g. of sodium iodide in 325 ml. of 2-butanone, to give 19.1 g. of product as an oil.
Reaction SMILES: B(Br)(Br)[Br:2].[C:5]([CH2:9][CH2:10][C:11]1[C:20]2[C:15](=[C:16]([O:25][CH3:26])[C:17]([O:23]C)=[C:18]([O:21]C)[CH:19]=2)[C:14]([CH3:27])=[N:13][C:12]=1[OH:28])([O:7]C)=[O:6].CO>C(Cl)Cl>[BrH:2].[C:5]([CH2:9][CH2:10][C:11]1[C:20]2[C:15](=[C:16]([O:25][CH3:26])[C:17]([OH:23])=[C:18]([OH:21])[CH:19]=2)[C:14]([CH3:27])=[N:13][C:12]=1[OH:28])([OH:7])=[O:6]
Reactant: BrB(Br)Br
Reactant: COC(=O)CCc1c(O)nc(C)c2c(OC)c(OC)c(OC)cc12
Solvent: ClCCl
Solvent: CO
Product: Br
Product: COc1c(O)c(O)cc2c(CCC(=O)O)c(O)nc(C)c12
Temperature: -50 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
Boron tribromide (25.0 grams, 99.8 mmol) was added dropwise to a solution of 2.14 grams 4-carbomethoxyethyl-3-hydroxy-6,7,8-trimethoxy-1-methylisoquinoline (6.38 mmol) (Compound J) in 35 ml methylene chloride cooled to -50° C. (in a dry ice-acetone slush bath) under a nitrogen atmosphere. A gummy residue formed immediately. The reaction mixture was warmed to room temperature, stirred for 4 hours and then was cooled to 0°-5° C. Methanol (30 ml) was added dropwise over a 45 minute period and a clear solution was obtained. The solvent was removed in vacuo to provide a brown solid residue which was triturated with ether for 64 hours and then filtered. The solid was washed with ether and dried in vacuo at room temperature to provide 2.14 grams of Compound N (89.7% yield) having a melting point of 172° to 174° C.