Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:13][C:14]1[CH:15]=[C:16]2[C:21]3=[C:22]([CH2:24][CH2:25][N:20]3[CH2:19][C@@H:18]3[CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C@H:17]23)[CH:23]=1>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]([F:12])([F:11])[F:10])=[CH:3][C:2]=1[NH:13][C:14]1[CH:15]=[C:16]2[C:21]3=[C:22]([CH2:24][CH2:25][N:20]3[CH2:19][C@@H:18]3[CH2:26][NH:27][CH2:28][C@H:17]23)[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN3CCc4cc(N)cc(c43)[C@H]2C1
Reactant: FC(F)(F)c1ccc(Cl)c(Br)c1
Product: FC(F)(F)c1ccc(Cl)c(Nc2cc3c4c(c2)[C@H]2CNC[C@H]2CN4CC3)c1

Procedure:
Using 3-bromo-4-chlorobenzotrifluoride and following the procedures described in EXAMPLE 17, Parts B and C, (±)-cis tert-butyl 2-amino-4,5,7a,8,10,10a-hexahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinoline-9(7H)-carboxylate was converted into (±) -cis-N-[2-chloro-5-(trifluoromethyl)phenyl]-4,5,7,7a,8,9,10,10a-octahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinolin-2-amine, bis-trifluoroacetic acid salt, after HPLC purification (c18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA). This material was free-based with aq ammonium hydroxide, extracted with chloroform, washed with brine, dried (K2CO3) and concentrated to the title compound of EXAMPLE 114 as the free base. LRMS (ES)+: 394.4 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[O:28]([CH2:35][C:36](Cl)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:25]([N:24]([CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:27])=[O:2])[CH:6]=1)[C:36](=[O:37])[CH2:35][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:26]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: O=C(Cl)COc1ccccc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)COc1ccccc1

Procedure:
(2′-{[Ethyl-(2-phenoxy-acetyl)-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (Compound 1-48) was prepared by following the procedures outlined in Example 1 and using (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and phenoxyacetyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CO.[CH2:19]1[O:22][C@H:20]1[CH3:21]>>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:19][C@@H:20]([OH:22])[CH3:21])[CH2:13][CH2:12]1
Reactant: C[C@H]1CO1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)c(F)c1
Solvent: CO
Product: C[C@H](O)CN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Reaction time: 19 h
Yield: 92.7 %

Procedure:
1-(2-Fluoro-4-nitro-phenyl)-piperazine (0.500 g, 0.00222 mol) was dissolved in Methanol (11.0 mL, 0.272 mol) and the reaction mixture was placed in a sealed tube. (S)-(−)-Propylene Oxide (0.235 mL, 0.00335 mol) was then added at room temperature and the reaction was stirred for 19 hours. The reaction was concentrated to yield a yellow solid, (S)-1-[4-(2-Fluoro-4-nitro-phenyl)-piperazin-1-yl]-propan-2-ol (583 mg, 93%). LCMS: m/z=284.10 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ 8.00 (d, 2H, J=11.3 Hz), 7.16 (m, 1H), 4.36 (d, 1H, J=4.0 Hz), 3.80 (m, 1H), 3.28 (m, 4H), 2.57 (m, 4H), 2.26 (m, 2H), 1.06 (d, 3H, J=6.2 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:2].Cl.[NH2:20][OH:21].C(=O)(O)[O-].[Na+]>C(O)C>[OH:21][NH:20][C:1](=[NH:2])[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: NO
Reactant: CCOC(=O)CCn1ncc2c(C#N)cccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCn1ncc2c(C(=N)NO)cccc21
Yield: 70.4 %

Procedure:
Ethyl 3-(4-cyano-1H-indazol-1-yl)propanoate (D96) (0.95 g, 3.91 mmol), hydroxylamine hydrochloride (1.086 g, 15.62 mmol), and sodium bicarbonate (3.28 g, 39.1 mmol), were heated in ethanol (20 ml) at 50° C. for 3 hours. The mixture was filtered and evaporated to give the title compound (760 mg) as a white powder. MS (ES): C13H16N4O3 requires 276; found (MH+) 277.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:39])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH3:36])=[O:28])=[C:22]([O:37][CH3:38])[CH:21]=3)=[CH:13][CH:12]=2)[CH2:9][N:8]([C:40](=[O:48])[CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])[CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C>[C:43]([CH2:42][CH2:41][C:40]([N:8]1[CH2:9][CH:10]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:39])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH3:36])=[O:28])=[C:22]([O:37][CH3:38])[CH:21]=3)=[CH:13][CH:12]=2)[CH:6]([C:4]([OH:5])=[O:3])[CH2:7]1)=[O:48])([OH:45])=[O:44]
Reactant: CCOC(=O)CCC(=O)N1CC(C(=O)OCC)C(c2ccc(NC(=O)Cc3ccc(NC(=O)Nc4ccccc4C)c(OC)c3)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(CC(=O)Nc2ccc(C3CN(C(=O)CCC(=O)O)CC3C(=O)O)cc2)ccc1NC(=O)Nc1ccccc1C
Temperature: 20 °C
Reaction time: 20 h
Yield: 47.4 %

Procedure:
A stirred solution of 1-(3-ethoxycarbonyl-propionyl)4-(4-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (0.3 g, Reference Example 10) in ethanol (3 ml) was treated dropwise with aqueous sodium hydroxide solution (1.8 ml and then 0.9 ml after 20 hours, 1N). After stirring at 20° C. for a further 2 hours the mixture was evaporated (40° C. and 2.7 kPa). The residue was treated with water (50 ml), then cooled to 5° C. and the pH of the mixture adjusted to 2 by dropwise addition of hydrochloric acid (10 ml, 1 N). The aqueous solution was triturated with ethyl acetate (50 ml), affording the title compound (130 mg) as a white solid, m.p. 184° C. TLC: RF=0.5 (on silica eluting with a mixture of dichloromethane and methanol, 50:50).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][NH:11]3)=[CH:4][C:3]=2[O:2]1.Cl[C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:4][C:3]=2[O:2]1
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)NCC3
Reactant: Clc1ncccn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1cnc(N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)nc1

Procedure:
1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (2.3 g, 8.0 mmol) (prepared according to the process as disclosed in WO97/43287, Intermediate 7, page 24) and 2-chloropyrimidine (0.914 g, 8.0 mmol) were stirred in anhydrous DMF (15 mL) at 140° C. for 24 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated aqueous NH4Cl solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (2×80 mL) and dried with MgSO4. The solvents were evaporated and the product was isolated by column chromatography (silica gel, EtOAc:Hexane=1:9) as a yellowish solid.
Reaction SMILES: CO[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[N:6][CH:5]=1.Cl.[CH3:13][NH:14][O:15][CH3:16].C([Mg]Cl)(C)C>O1CCCC1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([N:14]([O:15][CH3:16])[CH3:13])=[O:11])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(Cl)nc1
Temperature: -30 °C
Yield: 88.4 %

Procedure:
6-Chloro-nicotinic acid methyl ester (6 g, 34.97 mmol) is dissolved into anhydrous tetrahydrofuran (THF) (200 mL) and then cooled to −30° C. while stirring under nitrogen. N,O-dimethylhydroxylamine hydrochloride (5.12 g, 52.46 mmol) is then added to the solution in one portion. Isopropyl magnesium chloride (52 mL, 2M in THF, 105 mmol) is slowly added to the cooled suspension over 1 h. After complete consumption of starting material, then 30% solution of ammonium chloride is added with stirring. The reaction is diluted with diethyl ether and extracted. The organic layer is collected and washed with cold water (2×) and brine. The solution is then dried over anhydrous sodium sulfate, filtered, and concentrated. The 6-chloro-N-methoxy-N-methyl-nicotinamide (6.20 g, 30.90 mmol) is obtained in pure form after flash column chromatography. 1H NMR (CDCL3, 400 MHz): δ 8.78 (d, J=1.5 Hz, 1H), 8.02 (dd, J=1.5 and 8.3 Hz, 1H), 7.40 (d, J=8.3 Hz, 1H), 3.57 (s, 3H), 3.40 (s, 3H); MS m/z 218, 201, 188, 171.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:20]([O-:22])=[O:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:28]O>>[CH3:28][O:8][C:7](=[O:9])[C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:11]([N+:20]([O-:22])=[O:21])[CH:10]=1
Reactant: CO
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Oc2ccccc2)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(Oc2ccccc2)c([N+](=O)[O-])c1
Reaction time: 3 h

Procedure:
30 g of 3,5-dinitro-4-phenoxy-benzoic acid in 200 ml of methanol are combined with 3 ml of concentrated sulphuric acid and the whole is boiled for 3 hours under reflux. After evaporation of the solvent, the residue is dissolved in ethyl acetate, and traces of unreacted acid are destroyed with dilute sodium bicarbonate solution. After drying of the ethyl acetate solution, the solvent is eliminated by evaporation, the residue is recrystallised from ethyl acetate/methanol. The desired ester melting at 171°-173 ° C. is obtained with a very good yield.
Reaction SMILES: [CH:1]1([CH:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[O:31])=[CH:26][CH:25]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:28][CH:29]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OCCOC)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCOc1ccc2oc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C)c2c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
Ethyl 3-[{[4-({cyclohexyl[5-(2-methoxyethoxy)-3-methyl-1-benzofuran-2-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (5.4 g) synthesized in the above-mentioned (4) was dissolved in ethanol (150 mL), 1N aqueous sodium hydroxide solution (15 mL) was added at room temperature, and the mixture was stirred at 50° C. for 0.5 hr. Ethanol was evaporated under reduced pressure, 1N hydrochloric acid (20 mL) was added to the residue, and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give the title object compound (3.0 g, 59%) as a white solid.
Reaction SMILES: [Mg].[CH2:2]([O:4][CH:5]([O:10][CH2:11][CH3:12])[CH2:6][C:7]([OH:9])=O)[CH3:3].C(N1[CH:24]=[CH:23]N=C1)(N1C=CN=C1)=O>O1CCCC1>[CH2:11]([O:10][CH:5]([O:4][CH2:2][CH3:3])[CH2:6][C:7](=[O:9])[CH2:6][C:5]([O:10][CH2:23][CH3:24])=[O:4])[CH3:12]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(CC(=O)O)OCC
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(OCC)OCC
Temperature: 80 °C
Reaction time: 72 h

Procedure:
To a solution of 16 mL of 3-ethoxy-3-oxomalonic acid (135 mmol) in 40 mL of tetrahydrofuran there are added, under argon, 21.9 g of powdered magnesium (90.4 mmol). The mixture obtained is then heated at 80° C. for 7 hours. After returning to ambient temperature, this mixture is transferred by cannula to a solution of 10 g of the compound obtained in Step A (61.7 mmol) in 64 mL of tetrahydrofuran to which there has previously been added, in portions, 11 g of carbonyldiimidazole (66 mmol). The reaction mixture is stirred for 3 days at ambient temperature. After concentration, the residue is taken up in a mixture of ethyl acetate and aqueous sodium hydrogen sulphate (NaHSO4) solution. The mixture is stirred vigorously until no more gas is evolved. After separation of the phases, the organic phase is washed successively with water, saturated aqueous NaHCO3 solution and finally brine. After drying over MgSO4 and concentrating to dryness, the title product is obtained in the form of an oil which is used in the next Step without being otherwise purified.
Reaction SMILES: [O:1]1[C:5](=[O:6])[CH:4]=[CH:3][C:2]1=[O:7].[CH:8]1[CH2:14][CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1(C)C(C)=CC=CC=1>[CH:9]12[CH:8]=[CH:14][CH:13]([CH:12]3[CH:10]1[CH2:11]3)[CH:4]1[CH:3]2[C:2](=[O:7])[O:1][C:5]1=[O:6]
Reactant: C1=CC=CCC=C1
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1C
Product: O=C1OC(=O)C2C3C=CC(C4CC34)C12
Temperature: 144 °C
Reaction time: 5 h
Yield: 8.5 %

Procedure:
Furan-2,5-dione (5.32 g, 54.26 mmol) was partially dissolved in xylene (100 mL). Cyclohepta-1,3,5-triene (5 g, 54.26 mmol) was added. The reaction was stirred at 144° C. for 5 h. The mixture was allowed to cool to 25° C. and concentrated in vacuo. Purification by flash column chromatography (Teledyne Isco RediSep column; 0 to 20% ethyl acetate in hexanes) afforded the desired products, rac-(1R,2R,6S,7S,8S,10R)-4-Oxatetracyclo[5.3.2.02,6.08,10]dodec-11-ene-3,5-dione (7.46 g, 39.22 mmol, 72%) and rac-(1R,2S,6R,7S,8S,10R)-4-Oxatetracyclo[5.3.2.02,6.08,10]dodec-11-ene-3,5-dione (0.88 g, 4.63 mmol, 8%), as white solids. 1H NMR (400 MHz, CDCl3) 6: exo: 0.27-0.42 (2H, m), 1.11-1.15 (2H, m), 3.25 (2H, t, J=1.6 Hz), 3.46-3.50 (2H, m), 5.89 (2H, dd, J1=4.8 Hz, J2=3.2 Hz); endo: 0.14-0.26 (2H, m), 1.12-1.16 (2H, m), 3.09 (2H, s), 3.40-3.44 (2H, m), 5.94 (2H, dd, J1=4.8 Hz, J2=3.2 Hz). LC-MS (ESI) calcd for C11H10O3 190.20, found exo 191.0; endo 191.3 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11](O)[C:12]([F:15])([F:14])[F:13].COC1C=CC(C([Br:30])C(F)(F)F)=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]([Br:30])[C:12]([F:15])([F:14])[F:13]
Reactant: COc1ccc(C(Br)C(F)(F)F)cc1
Reactant: COc1ccc(C(O)C(F)(F)F)c(OC)c1
Product: COc1ccc(C(Br)C(F)(F)F)c(OC)c1

Procedure:
This compound was prepared from Compound 82 in the same manner of Compound 44.
Reaction SMILES: [C:1]([C:4]1[CH:5]2[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:8]([CH2:9][C:10]=1[CH3:11])[CH:7]=[CH:6]2)(=[O:3])[CH3:2].[H][H]>C(O)C>[C:1]([C:4]1[CH:5]2[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:8]([CH2:9][C:10]=1[CH3:11])[CH2:7][CH2:6]2)(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)CC2C=CC1N2C(=O)OC(C)(C)C
Reactant: [H][H]
Solvent: CCO
Product: CC(=O)C1=C(C)CC2CCC1N2C(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
A solution of 2-acetyl-3-methyl-8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octa-2,6-diene (0.74 g, 2.81 mmol) and RhCl(PPh3)3 (0.026 g, 0.028 mmol) in 50 ml ethanol was pressurized with 45 psi hydrogen gas and shaken for about 12 hours. The solvent was then evaporated and the residue was purified by silica gel column chromatography (using 3 parts diethyl ether and 7 parts petroleum ether) to give 2-acetyl-3-methyl-8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]oct-2-en.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:8]=2)[CH2:3]1.Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[CH:25][CH:24]=1)=[O:22].[BH4-].[Na+].C(O)C>CN(C)C=O>[OH:22][CH:21]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[CH:27][CH:28]=1)[CH2:20][NH:1][C@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:8]=2)[CH2:3]1
Reactant: O=C(CBr)c1ccc(OC2CCCCO2)cc1
Reactant: CCOC(=O)COc1ccc2c(c1)C[C@@H](N)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)COc1ccc2c(c1)C[C@@H](NCC(O)c1ccc(OC3CCCCO3)cc1)CC2
Temperature: 0 °C
Yield: 82.8 %

Procedure:
Ethyl (S)-(2-amino-1,2,3,4-tetrahydronaphthalen-7-yl-oxy)acetate (1.14 g) was dissolved in N,N-dimethylformamide (15 ml), and 2-bromo-4'-((2RS)-2-tetrahydropyranyloxy)-acetophenone (600 mg) was added to the solution under ice-cooling with stirring, followed by reaction at room temperature for an hour. Sodium borohydride (380 mg) and ethanol (10 ml) were added to the reaction mixture under ice-cooling with stirring. After reaction for an hour, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. The resulting residue was dissolved in tetrahydrofuran (20 ml), triethanolamine (2 ml) was added to the solution and the mixture was heated under reflux for 17 hours. After cooling, water was poured into the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: ethyl acetate) gave ethyl 2-[(2S)-2-[[(2RS)-2-hydroxy-2-[4-((2RS)-2-tetrahydropyranyloxy)phenyl]ethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]acetate (780 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br.Br[CH2:26][C:27]([C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][N:30]=1)=[O:28]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:26]=1[C:27]([C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][N:30]=1)=[O:28]
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reactant: O=C(CBr)c1cc(Cl)ccn1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2cc(Cl)ccn2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-4-chloropyridine hydrobromide (Preparation is described in Example 33).
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:25]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH2:33])=[CH:27][CH:26]=1>>[C:25]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][NH:33][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)=[CH:18][CH:19]=2)=[CH:29][CH:30]=1
Reactant: CCCCCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Reactant: NCCc1ccc(-c2ccccc2)cc1
Product: CCCCCCCCCCCc1noc(-c2ccc(CNCCc3ccc(-c4ccccc4)cc3)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 2-(1,1′-biphenyl-4-yl)ethylamine gave the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:27][CH:26]([N:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[CH3:37])[CH3:29])[CH2:25]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[OH-].[Na+]>C1OCCOC1.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:25][CH:26]([N:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[CH3:37])[CH3:29])[CH2:27]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(N(C)c4ccc(F)cc4C)C3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(F)ccc1N(C)C1CN(c2ncc(Cl)cc2C(=O)NC2(c3ccc(C(=O)O)cc3)CC2)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of starting from methyl 4-(1-(5-chloro-2-(3-((4-fluoro-2-methylphenyl)(methyl)amino)azetidin-1-yl)nicotinamido)cyclopropyl)benzoate (D171) (56 mg, 0.107 mmol). in a mixture 1-4 dioxane/water (3 ml/1 ml), 1N NaOH (0.16 ml) was added. The reaction mixture was stirred 2 h at 60° C. Organic solvent was evaporated in vacuo and the reaction mixture was acidified with 2N HCl (pH=2) and the resulting mixture was extracted with ethylacetate (3×5 ml). Combined organics were evaporated in vacuo to afford the title (E37) (53 mg).
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:5][CH:4]([C:6]([O:8]CC2C=CC=CC=2)=[O:7])[CH2:3]1>C(O)C.[Pd]>[F:1][C:2]1([F:16])[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1
Reactant: O=C(OCc1ccccc1)C1CC(F)(F)C1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)C1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.2 %

Procedure:
To a solution of benzyl 3,3-difluorocyclobutanecarboxylate (1.4 g, 6.2 mmol) in ethanol (50 mL) was added palladium on activated carbon (500 mg) and the reaction mixture was stirred at RT under an atmosphere of hydrogen (1 atm) for 12 h. The reaction mixture was filtered through a pad of CELITE® and the filtrate was concentrated to afford Intermediate 291A as pale yellow liquid (550 mg, 65% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.97-12.76 (m, 1H), 3.04-2.91 (m, 1H), 2.89-2.64 (m, 4H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=O)=[CH:2]1.[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][N:22]([CH:32]1[C:41]2[N:40]=[CH:39][CH:38]=[CH:37][C:36]=2[CH2:35][CH2:34][CH2:33]1)[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=1.[BH4-].[Na+]>CO>[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][N:22]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[CH:26][CH:25]=1)[CH:32]1[C:41]2[N:40]=[CH:39][CH:38]=[CH:37][C:36]=2[CH2:35][CH2:34][CH2:33]1
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: O=Cc1c[nH]c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1cnc2c(c1)CCCC2N(Cc1ccc(CNCc2c[nH]c3ccccc23)cc1)Cc1nc2ccccc2[nH]1

Procedure:
Using General Procedure B: 1H-Indole-3-carbaldehyde (73 mg, 0.50 mmol) and N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (200 mg, 0.50 mmol) were stirred at 40° C. in MeOH (5 mL) for 4 hours. NaBH4 (38 mg, 1.0 mmol) was added and the resultant mixture stirred at room temperature for an additional 15 minutes. Purification of the crude white foam by column chromatography on silica gel (200:1:1—EtOAc:MeOH:NH4OH) afforded AMD9673 (80 mg, 31%) as a white foam. 1H NMR (CDCl3) δ 1.59–1.75 (m, 1H), 1.81–2.09 (m, 2H), 2.16–2.30 (m, 1H), 2.64–2.76 (m, 1H), 2.76–2.91 (m, 1H), 3.69 (s, 2H), 3.78 (s, 2H), 3.92–3.98 (m, 3H), 4.04–4.09 (m, 1H), 4.15 (d, 1H, J=16.5 Hz), 7.02–7.07 (m, 2H), 7.11–7.21 (m, 6H), 7.25–7.34 (m, 3H), 7.41 (d, 1H, J=7.2 Hz), 7.54–7.57 (m, 3H), 8.68 (d, 1H, J=3.9 Hz), 8.75 (br s, 1H); 13C NMR (CDCl3) δ 21.74, 23.88, 29.60, 44.05, 48.89, 52.95, 54.06, 60.72, 111.68, 113.70, 119.08, 119.77, 121.97, 122.30, 122.66, 123.71, 127.40, 128.84, 129.07, 135.15, 136.70, 137.66, 138.60 (2 carbons), 147.27, 156.70, 157.79. ES-MS m/z 532.4 (M-C9H8N). Anal. Calcd. for C34H34N6.0.7H2O.0.2CH2Cl2: C, 73.84; H, 6.49; N, 15.11. Found: C, 73.95; H, 6.60; N, 14.81.