Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:21])[N:11]=[C:10](F)[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[CH3:23][O-:24].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:21])[N:11]=[C:10]([O:24][CH3:23])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)cc2c1Oc1ccc(Br)cc1[C@@]21COC(N)=N1
Temperature: 65 °C

Procedure:
A 100 mL RBF containing a solution of (S)-7-bromo-3-chloro-1-fluoro-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (0.50 g, 1.30 mmol, prepared as described in Method BB33) in methanol (13 mL) was treated with sodium methoxide (0.36 mL, 6.50 mmol) and the resulting suspension was heated to 65° C. for 3 h on a hot-plate. The reaction was cooled to RT and concentrated to dryness under high vacuum. The resulting yellowish residue was taken up in dichloromethane (75 mL), water (25 mL), and the organic layer was separated. The organic layer was dried over sodium sulfate and concentrated to yield the crude product. The crude product was purified by silica gel flash column chromatography and eluted using DCM/MeOH gradient to provide (S)-7-bromo-3-chloro-1-methoxy-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine as an amorphous off-white solid. [MS: m/z=395.9 (M+H)].
Reaction SMILES: [F:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:3]1.CC([O-])(C)C.[K+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>C1COCC1>[F:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH2:3]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OCCCN1CCC(F)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OCCCN2CCC(F)C2)cc1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 82 %

Procedure:
The crude 3-(3-Fluoro-pyrrolidin-1-yl)-propan-1-ol (assumed 3.06 mmol) was dissolved in THF (8 mL) and was cooled to 0° C. The 0° C. solution was treated consecutively with KOtBu (1.5 g, 13.5 mmol) then 4-fluoronitrobenzene (423.3 mg, 3 mmol). The resulting reaction mixture was allowed to warm to room temperature and stir for an additional 4.5 h. The reaction mixture was quenched with the addition of ice water (50 mL) followed by extraction with EtOAc (75 mL). The organics were subsequently washed with room temperature H2O (75 mL), then saturated NaHCO3 (aq) (75 mL), and finally with brine (75 mL). The organics then were dried over anhydrous sodium sulfate, decanted and concentrated in vacuo to yield crude 3-Fluoro-1-[3-(4-nitro-phenoxy)-propyl]-pyrrolidine (660 mg) as a yellow oil. This material was carried on without further purification.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[CH:11]=[C:12]([O:15][CH2:16][CH3:17])[CH:13]=[CH:14][C:9]=3[NH:8][C:7]2=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[C:25]([O:33][CH3:34])[CH:24]=1)=[O:22]>>[CH:1]1([N:6]2[C:10]3[CH:11]=[C:12]([O:15][CH2:16][CH3:17])[CH:13]=[CH:14][C:9]=3[N:8]([S:29]([C:26]3[CH:27]=[CH:28][C:23]([C:21]([O:20][CH3:19])=[O:22])=[CH:24][C:25]=3[O:33][CH3:34])(=[O:31])=[O:30])[C:7]2=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOc1ccc2[nH]c(=O)n(C3CCCC3)c2c1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)c(OC)c1
Product: CCOc1ccc2c(c1)n(C1CCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)OC)cc1OC
Yield: 72.7 %

Procedure:
This compound is prepared by the procedure described in EXAMPLE 107 step A) starting from 1 g of 3- cyclopentyl-5-ethoxy-1,3-dihydro-2H-benzimidazol-2-one and 1.2 g of 4-methoxycarbonyl-2-methoxybenzenesulfonyl chloride. It is chromatographed on silica using a DCM/AcOEt mixture (95/5; v/v) as the eluent to give 1.4 g of the expected product. M.p.=151° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].O.Cl>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([NH:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCNC(=O)N1CCN(c2ccccc2C(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)NCCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.7 %

Procedure:
A mixture of ethyl N-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}-beta-alaninate obtained in Example 5 (470 mg), lithium hydroxide monohydrate (420 mg), water (50 mL), and tetrahydrofuran (50 mL) was stirred at room temperature for 3 h. 6 M hydrochloric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (298 mg, 69%) as a colorless solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[C:17]([N:19]([CH3:21])[CH3:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[Br:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[C:34]([O:42][C:43]([F:46])([F:45])[F:44])[CH:33]=1>C(Cl)Cl>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH:1][C@H:2]2[CH2:3][CH2:4][C@@H:5]([NH:8][C:9]3[N:18]=[C:17]([N:19]([CH3:21])[CH3:20])[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:6][CH2:7]2)(=[O:40])=[O:39])=[C:34]([O:42][C:43]([F:45])([F:44])[F:46])[CH:33]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: CN(C)c1nc(N[C@H]2CC[C@@H](N)CC2)nc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)c1nc(N[C@H]2CC[C@@H](NS(=O)(=O)c3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Reaction time: 6.5 h
Yield: 55.8 %

Procedure:
To a suspension of cis-N2-(4-amino-cyclohexyl)-N4,N4-dimethyl-quinazoline-2,4-diamine (680 mg, 2.38 mmol) in CH2Cl2 (7 mL) was added diisopropylethylamine (620 μL, 3.56 mmol). The mixture was cooled on an ice-bath and a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (849 mg, 2.50 mmol) in CH2Cl2 (3 mL) was added dropwise. The reaction mixture was stirred on an ice-bath for 6.5 hr. The reaction was quenched with saturated aqueous NaHCO3 The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 33% EtOAc in hexane) to give cis-4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzenesulfonamide (782 mg, 56%) as a pale yellow solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:29]([O-])([N+]([O-])=O)=[O:30]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:29]=[O:30])[C:5]([N:7]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CC(C)CN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)CN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 75.9 %

Procedure:
3.4 g of 1-(2-chloroethyl)-3-isobutyl-3-D-glucopyranosylurea are dissoved in a mixture of 70 ml of tetrahydrofuran and 70 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under stirring and ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.8 g of 1-(2-chloroethyl)-1-nitroso-3-isobutyl-3-D-glucopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: [BH4-].[Na+].[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH:19]4[CH2:27][C:26]5[C:21](=[CH:22][C:23]([O:28][CH3:29])=[CH:24][CH:25]=5)[C:20]4=[O:30])[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5][CH2:4]1>O1CCCC1>[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:14][CH2:15][N:16]([C@H:19]4[CH2:27][C:26]5[C:21](=[CH:22][C:23]([O:28][CH3:29])=[CH:24][CH:25]=5)[C@H:20]4[OH:30])[CH2:17][CH2:18]3)[C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: COc1ccc2c(c1)C(=O)C(N1CCN(c3cccc4c3OCCO4)CC1)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)[C@@H](O)[C@@H](N1CCN(c3cccc4c3OCCO4)CC1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.8 g (73.8 mmol) of sodium borohydride are added in fractions over the course of 15 minutes at room temperature to 28.0 g (73.6 mmol) of the compound obtained in Step 2 in 220 ml of tetrahydrofuran. The mixture is stirred overnight at room temperature, and then for 4 hours at reflux. After evaporation, the residue is taken up in 1 liter of dichloromethane, washed twice with 500 ml of water and then dried over magnesium sulphate. After concentration, the residue is chromatographed over silica (eluant: dichloromethane/methanol 99/1, then 98/2). The product eluted first corresponds to the cis isomer. Its stereochemistry was demonstrated by IR, in solution in chloroform, according to the method described by H. -J. Rimek et al. (Justus Liebigs Ann. Chem., 1969, 726, 25-29).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[Li]CCCC.CON(C)[C:15](=[O:19])[CH2:16][O:17][CH3:18]>O1CCCC1.CCCCCC>[CH3:18][O:17][CH2:16][C:15](=[O:19])[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: C#C[Si](C)(C)C
Reactant: COCC(=O)N(C)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCC(=O)C#C[Si](C)(C)C
Temperature: -70 °C
Reaction time: 0.42 h
Yield: 79.7 %

Procedure:
A solution of 14.75 ml of trimethylsilylacetylene (103.62 mmol) in 250 ml of tetrahydrofuran is cooled to −70° C. and then 64.76 ml of a 1.6 M solution of n-BuLi (103.62 mmol) in hexane are added. The mixture is stirred for 25 minutes at −70° C. and then a solution of 13.14 g of N-methoxy-N-methyl-2-methoxyacetamide (98.69 mmol) in 250 ml of tetrahydrofuran is added rapidly. During the addition, the temperature rises to −50° C., and then the cold bath is removed and the mixture is stirred for 2 hours at ambient temperature. A 1N solution of HClaq is added and then extraction is carried out 4 times with ethyl acetate. The organic phases are combined, dried over sodium sulphate, filtered, and concentrated under vacuum. 13.4 g of 1-methoxy-4-(trimethylsilyl)but-3-yn-2-one are obtained in the form of a light brown oil which is used without subsequent purification (crude yield=80%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([N:19]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([Br:35])[CH:29]=3)=[CH:24][CH:23]=2)[CH3:20])=[O:18])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:37][C:38]#[N:39].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([N:19]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:37][C:38]#[N:39])=[C:30]([Br:35])[CH:29]=3)=[CH:24][CH:23]=2)[CH3:20])=[O:18])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: CN(Cc1ccc(-c2ccc(O)c(Br)c2)cc1)C(=O)c1cn(Cc2ccccc2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(-c2ccc(OCC#N)c(Br)c2)cc1)C(=O)c1cn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
A mixture of 1-benzyl-N-[(3′-bromo-4′-hydroxy-1,1′-biphenyl-4-yl)methyl]-N-methyl-1H-indole-3-carboxamide (1.60 g, 3.05 mmol), prepared in the previous step, bromoacetonitrile (255 μL, 3.66 mmol) and potassium carbonate (2.11 g, 15.30 mmol) in 25 mL of DMF was stirred under nitrogen at room temperature for 16 h (overnight). The reaction was partitioned between ethyl acetate and water. The organic layer was separated, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 1-benzyl-N-{[3′-bromo-4′-(cyanomethoxy)-1,1′-biphenyl-4-yl]methyl}-N-methyl-1H-indole-3-carboxamide (1.69 g, 98%) as a yellow foam, MS (ESI) m/z 564 [M+H]+. Elemental Analysis for C32H26BrN3O2: Calc'd: C, 68.09; H, 4.64; N, 7.44; Found: C, 67.53; H, 4.57; N, 7.14
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([C:25]5[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=5)[CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cc(-c3cnn(C)c3)ccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2ccc(-c3cnn(C)c3)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20](OC)[O:21]C)[N:16]([C:25]([NH:27][C:28]1[CH:33]=[C:32]([O:34][CH2:35][CH2:36][O:37][CH3:38])[C:31]([C:39]#[N:40])=[CH:30][N:29]=1)=[O:26])[CH2:15][CH2:14][CH2:13]2)(C(C)(C)C)(C)C.Cl.C([O-])(O)=O.[Na+]>C1COCC1.O>[C:39]([C:31]1[C:32]([O:34][CH2:35][CH2:36][O:37][CH3:38])=[CH:33][C:28]([NH:27][C:25]([N:16]2[C:17]3[C:12](=[CH:11][C:10]([CH2:9][OH:8])=[C:19]([CH:20]=[O:21])[N:18]=3)[CH2:13][CH2:14][CH2:15]2)=[O:26])=[N:29][CH:30]=1)#[N:40]
Reactant: COCCOc1cc(NC(=O)N2CCCc3cc(CO[Si](C)(C)C(C)(C)C)c(C(OC)OC)nc32)ncc1C#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1cc(NC(=O)N2CCCc3cc(CO)c(C=O)nc32)ncc1C#N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-(2-methoxyethoxyl)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 37, 98 mg, 0.171 mmol) in THF (1 ml) and H2O (1 ml) was added conc. HCl (0.5 ml), the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was poured into sat. aq. NaHCO3 and extracted with DCM (2×). The organic phase was then dried over Na2SO4, filtered and evaporated. Trituration of the crude material in EtOAc/heptanes followed by drying under vacuum furnished the title compound as a colorless powder.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>CC#N>[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12]([CH:4]([OH:5])[CH2:3][CH2:2][Cl:1])(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: OCCCCl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)C(O)CCCl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.8 %

Procedure:
To 3-chloro-1-propanol (5.02 mL, 60 mmole) in CH3CN (200 mL) was added, p-toluenesufonyl chloride (17 g, 90 mmole) and pyridine (7.3 mL, 90 mmole). The reaction mixture was stirred at room temperature for 12 hours under an argon atmosphere. 200 mL of saturated NaHCO3 (aq) was added and the stirring was continued for 15 minutes. The mixture was extracted several times with CH2Cl2. The combine CH2Cl2 layers were dried over Na2SO4, the Na2SO4 was filtered and the filtrate was evaporated to give 12.35 g (83.8%) of the title compound: TLC (Rf: 0.5; 20% EtOAc/Hexane), 1H NMR (CDCl3) δ 2.1 (m, 2 H, CH2), 2.5 (s, 3 H, CH3), 3.6 (t, 2 H, CH2), 4.2 (t, 2 H, CH2), 7.6 (d & d, 4 H, Ar). 13C NMR (CDCl3): δ 21.4 (CH3), 31.5 (CH2), 40.2 (CH2), 66.7 (CH2), 127.8 (Ar), 129.8 (Ar), 132.5 (Ar), 144.9 (Ar).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:13])[CH:11]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[N:25]2[CH2:30][CH2:29][N:28](CCC3C=C(C=CC=3)N)[CH2:27][CH2:26]2)[N:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[N:25]2[CH2:30][CH2:29][N:28]([CH2:11][CH:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH3:13])[CH2:27][CH2:26]2)[N:16]=1
Reactant: CC(C=O)c1cccc([N+](=O)[O-])c1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc2c(N3CCN(CC(C)c4cccc([N+](=O)[O-])c4)CC3)cccc2n1
Reaction time: 1 h
Yield: 133.1 %

Procedure:
A mixture of 2-(3-nitrophenyl)propanal (1.2 equiv. 50 mg), 2-methyl-5-(1-piperazinyl)quinoline (D3) (52 mg) and DCM (2 mL) was stirred for 1 h. Sodium triacetoxyborohydride (1.2 equiv., 58 mg) was added and the resulting mixture was stirred for 18 h. The reaction mixture was concentrated in vacuo and purified using ion-exchange chromatography (SCX-2), eluting with methanol followed by ammonia in methanol (1M). The basic fractions were concentrated under vacuum and purified by chromatography (SPE, SiO2) using DCM-methanol (98:2) as eluent to afford the title compound as yellow liquid (78 mg, 78% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])/[C:11](=[CH:20]/[CH3:21])/[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH3:22].[BH4-].[Na+]>C1COCC1>[NH2:22][CH:20]([CH:11]1[CH2:10][C@@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[OH:19])[CH3:21]
Reactant: C/C=C1\C[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc2C1=O
Reactant: N
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(N)C1C[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc2C1O
Reaction time: 2 h
Yield: 78.7 %

Procedure:
To a solution of (S,E)-4-(3,4-dichlorophenyl)-2-ethylidene-3,4-dihydronaphthalen-1(2H)-one (42) (0.60 g, 1.89 mmol) in THF (8 mL) at ambient temperature was added ammonia solution (2.0 M in MeOH, 2.83 mL, 5.67 mmol). The reaction mixture was stirred for 4 h before NaBH4 (0.14 g, 3.78 mmol) was added. The reaction mixture was stirred for 2 h before being quenched by a saturated solution of NH4Cl (8 mL). The product was extracted with diethyl ether (30 mL×2), dried and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane/0.1% DEA=1:7 to 1:5) to give (4S)-2-(1-aminoethyl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-ol (43) (0.50 g, 50%).
Reaction SMILES: C([S:8][C:9]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[Cl:27])[CH:13]=[CH:12][C:10]=1[NH2:11])C1C=CC=CC=1.S(=O)(=O)(O)O.[N:33]([O-])=O.[Na+]>O>[Cl:27][C:18]1[CH:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:21]=[CH:22][C:17]=1[O:16][C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[N:33][S:8][C:9]=2[CH:15]=1
Reactant: Nc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1SCc1ccccc1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1ccc(Oc2ccc3nnsc3c2)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3 g of 1C was added to an ice-cold solution of 50% aqueous sulfuric acid, and the mixture maintained below 10° C. during the addition of a solution of 0.7 g of sodium nitrite in 10 ml of water. This mixture was then stirred for 1 hour, allowed to reach ambient temperature, and then extracted with ether. The organic layer was separated, solvent removed and the resulting red oil chromatographically purified and recrystallized to yield 1, as a crystalline solid, m.p.: 72°-73° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[O:16][C@H:15]([CH2:17][O:18]CC2C=CC=CC=2)[C@@H:6]1[O:7]CC1C=CC=CC=1)=[O:4].[H][H]>[OH-].[OH-].[Pd+2].CO>[CH3:1][O:2][C:3]([C@H:5]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:6]1[OH:7])=[O:4]
Reactant: [H][H]
Reactant: COC(=O)[C@H]1O[C@H](COCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@H]1O[C@H](CO)[C@@H]1O
Yield: 96.2 %

Procedure:
A slurry of 1.01 g of 2,4-anhydro-3,5-bis-O-(phenylmethyl)-D-lyxonic acid methyl ester (prepared by the procedure in Tetrahedron Letters, Vol 31, No. 33, p4787, 1990), 0.253 g of palladium hydroxide on carbon, and 30 ml of methyl alcohol is hydrogenated under a balloon of hydrogen (1 atm.) for 2.5 hours. The mixture is filtered through diatomaceous earth, washed with ethyl acetate and ethyl alcohol, and concentrated in vacuo to give 0.460 g of the desired product.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:29]=2)O1.Br[C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][C:33]=1[Cl:41]>>[C:36]([C:35]1[CH:39]=[CH:40][C:32]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:29]=2)=[C:33]([Cl:41])[CH:34]=1)(=[O:37])[NH2:38]
Reactant: NC(=O)c1ccc(Br)c(Cl)c1
Reactant: CC(C)OC(=O)N1CCC(c2nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3o2)CC1
Product: CC(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(C(N)=O)cc4Cl)ccc3o2)CC1
Yield: 37.7 %

Procedure:
Following the General Procedure-3, the titled compound (80 mg) was prepared from Intermediate 14 (200 mg, 0.48 mmol) and 4-bromo-3-chlorobenzamide (105 mg, 0.48 mmol) as a brown solid. M.P.: 178-182° C. MS (m/z): 442.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:16])[C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5]([O:7]C)=[O:6].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:16])[C:11]=1[O:12][CH:13]([CH3:14])[CH3:15])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(OC(C)C)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Oc1c(Cl)cc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of 1.88 g (7.15 mmol) of methyl 3,5-dichloro-4-isopropoxybenzoate (from Step A) in 20 mL of methanol was added 4 mL of 5.0 N sodium hydroxide solution. The mixture was stirred at rt overnight and concentrated. The residue was partitioned between EtOAc (30 mL) and 1 N NaOH (30 mL). The aqueous layer was separated, washed with EtOAc (2×30 mL), acidified using 5.0 N HCl until pH=1, and then extracted with EtOAc (3×30 mL). Organic layers were combined, dried over MgSO4, and concentrated to give 1.51 g of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.43 (d, J=6.2, 6H), 4.79 (m, 1H), 8.07 (s, 2H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[C:25]([O:29][C:30]([N:32]([C:40]1[C:45]([CH3:46])=[CH:44][C:43](CO)=[CH:42][N:41]=1)[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:31])([CH3:28])([CH3:27])[CH3:26]>ClCCl>[Br:24][CH2:20][C:43]1[CH:44]=[C:45]([CH3:46])[C:40]([N:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])=[N:41][CH:42]=1
Reactant: Cc1cc(CO)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(CBr)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 84.5 %

Procedure:
Triphenylphosphine (7.43 g, 28.3 mmol) and CBr4 (9.49 g, 28.6 mmol) was added to a solution of 2-[N,N-bis(tert-butoxycarbonyl)amino]-5-hydroxymethyl-3-methylpyridin (8.00 g, 23.6 mmol) in dichloromethane (220 mL) at 0° C. The reaction mixture was stirred for 3 h and was then concentrated under reduced pressure. Flash chromatography (hexane/EtOAc, 80:20) gave 5-bromomethyl-2-[N,N-bis(tert-butoxycarbonyl)amino]-3-methylpyridin (8.0 g,77%).