Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([N+:14]([O-])=O)[CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1.C1CCCCC=1>[Pd].C(O)C>[NH2:14][C:9]1[CH:8]=[C:7]([C:2]2([CH3:1])[O:3][CH2:4][CH2:5][O:6]2)[CH:12]=[CH:11][C:10]=1[OH:13]
Reactant: CC1(c2ccc(O)c([N+](=O)[O-])c2)OCCO1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CC1(c2ccc(O)c(N)c2)OCCO1
Temperature: 25 °C
Yield: 76 %

Procedure:
A stirred mixture of 4-(2-methyl-1,3-dioxolan-2-yl)-2-nitrophenol D61 (2.40 g, 10.66 mmol), cyclohexene (4.38 g, 53.3 mmol) and 10% palladium on carbon (0.227 g, 0.213 mmol) in ethanol (75 mL) was heated to reflux for 6 hr under argon. The mixture was cooled to rt and the catalyst was removed by filtration through celite. The filtrate was concentrated to dryness in vacuo and the reside dissolved in 10% MeOH in DCM (20 mL) and passed through a SCX-2 cartridge (25 g) which was then eluted with further 10% MeOH in DCM to wash through any unreacted starting material and then with 2M ammonia in MeOH. The basic eluate was concentrated under vacuum to give the title compound as a yellow-brown solid (1.58 g, 76%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[C:6]([NH:8][S:9]([C:12]2[C:17]3=[N:18]S[N:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1.CN(C(ON1N=N[C:39]2C=CC=N[C:38]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1SN=C2C(S(NC3C=C(I)C=CC=3C(O)=O)(=O)=O)=CC=CC=12.N1CCOCC1>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[C:6]([NH:8][S:9]([C:12]2[C:17]3[N:18]=[CH:38][CH:39]=[N:20][C:16]=3[CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12)N1CCOCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Solvent: C1COCCN1
Product: O=C(c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12)N1CCOCC1

Procedure:
Benzo[1,2,5]thiadiazole-4-sulfonic acid [5-iodo-2-(morpholine-4-carbonyl)-phenyl]-amide. The title compound was prepared from the HATU-mediated coupling of 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodobenzoic acid and morpholine and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C17H15IN4O4S2, 530.0; m/z found, 531 [M+H]+, 553 [M+Na]+. HPLC (reverse phase): RT=8.50 min. 1H NMR (400 MHz, CDCl3): (rotameric broadening) 8.91 (s, 1H), 8.31 (dd, J=7.0, 0.9 Hz, 1H), 8.27 (dd, J=8.8, 0.9 Hz, 1H), 7.97 (d, J=1.5 Hz, 1H), 7.74 (dd, J=8.8, 7.0 Hz; 1H), 7.41 (dd, J=8.1, 1.6 Hz, 1H), 6.78 (d, J=8.1 Hz, 1H), 3.75-3.05 (br m, 8H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]([NH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(NC(C)C)(C)C.[I-].[Na+]>CN(C)C=O.O>[CH:1]1([CH2:7][CH2:8][N:22]2[CH2:23][CH2:24][CH:19]([NH:18][C:10](=[O:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:20][CH2:21]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: BrCCC1CCCCC1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1CCN(CCC2CCCCC2)CC1)c1ccccc1
Temperature: 70 °C

Procedure:
2-Cyclohexylethyl bromide (1.9 g.) in dimethylformamide (10 ml.) was added to 4-benzamidopiperidine (2.2g.), diisopropylamine (4 ml.) and a trace of sodium iodide in dimethylformamide (10 ml). The mixture was heated at 70° C. for 16 hours, cooled, poured into water, and extracted with methylene chloride. The washed and dried extracts were evaporated and the solid residue was recrystallised from ethanol to give the product (1.25 g.), m.p. 174°-5° C. (Found: C, 76.4; H, 9.5; N, 8.9 C20H30N2O requires C, 76.4; H, 9.6; N, 8.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[Cl:40])[C:5]([NH:7][CH2:8][C:9]1[N:13]2[C:14]3[S:34][C:33]([CH2:35][CH3:36])=[CH:32][C:15]=3[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])=[N:17][CH:18]([CH2:19][C:20]([O:22]CC)=[O:21])[C:12]2=[N:11][N:10]=1)=[O:6].[OH-:41].[Na+]>CO>[CH:2]([O-:41])([CH3:3])[CH3:39].[Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[Cl:40])[C:5]([NH:7][CH2:8][C:9]1[N:13]2[C:14]3[S:34][C:33]([CH2:35][CH3:36])=[CH:32][C:15]=3[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])=[N:17][CH:18]([CH2:19][C:20]([OH:22])=[O:21])[C:12]2=[N:11][N:10]=1)=[O:6]
Reactant: [OH-]
Reactant: CCOC(=O)CC1N=C(c2ccccc2Cl)c2cc(CC)sc2-n2c(CNC(=O)c3ccc(Cl)c(Cl)c3)nnc21
Agent: [Na+]
Solvent: CO
Product: CC(C)[O-]
Product: CCc1cc2c(s1)-n1c(CNC(=O)c3ccc(Cl)c(Cl)c3)nnc1C(CC(=O)O)N=C2c1ccccc1Cl

Procedure:
Ethyl 9-((3,4-dichlorobenzoylamino)methyl)-4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine-6-acetate (0.4 g) was dissolved in methanol (4 ml). 2N Sodium hydroxide (1 ml) was added and the mixture was stirred. The solvent was evaporated. Water was added and the mixture was washed with ethyl acetate. Citric acid was added to the aqueous layer to make the layer acidic. The solution was extracted with ethyl acetate and the extract was dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from a mixed solvent of diisopropyl alcohol and methanol to give 0.17 g of 9-((3,4-dichlorobenzoylamino)methyl)-4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]-diazepine-6-acetic acid isopropyl alcoholate.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH2:16][C:17]1([CH3:22])[O:21][CH2:20][CH2:19][O:18]1)[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15].[C:24](OC)(OC)(OC)[CH2:25][CH2:26][CH3:27]>>[CH3:1][C:2]([CH3:23])([CH2:16][C:17]1([CH3:22])[O:21][CH2:20][CH2:19][O:18]1)[CH2:3][N:4]1[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=[C:24]1[CH2:25][CH2:26][CH3:27]
Reactant: CCCC(OC)(OC)OC
Reactant: CC(C)(CNc1c(N)cnc2ccccc12)CC1(C)OCCO1
Product: CCCc1nc2cnc3ccccc3c2n1CC(C)(C)CC1(C)OCCO1
Yield: 29.2 %

Procedure:
The general method described in Part F of Example 39 was used to cyclize N4-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]quinoline-3,4-diamine (9.1 g, 28.9 mmol) by reaction with trimethyl orthobutyrate (4.4 g, 30 mmol) to provide 1-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-2-propyl-1H-imidazo[4,5-c]quinoline (3.10 g) as a solid after chromatography on silica gel (elution with a solution of 7% methanol in dichloromethane that contained about 5 mL of ammonium hydroxide solution per liter of eluent).
Reaction SMILES: [O:1]=[C:2]([CH2:10][C@@H:11]1[C@@H:15](/[CH:16]=[CH:17]/[C@@H:18]([O:25]C2CCCCO2)[CH:19]([CH3:24])[CH2:20][C:21]#[C:22][CH3:23])[C@H:14]([O:32]C2CCCCO2)[CH2:13][C:12]1=[O:39])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]>C(O)(=O)C.O.O1CCCC1>[O:1]=[C:2]([CH2:10][C@@H:11]1[C@@H:15](/[CH:16]=[CH:17]/[C@@H:18]([OH:25])[CH:19]([CH3:24])[CH2:20][C:21]#[C:22][CH3:23])[C@H:14]([OH:32])[CH2:13][C:12]1=[O:39])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CC#CCC(C)[C@@H](/C=C/[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1CC(=O)CCCCC(=O)O)OC1CCCCO1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC#CCC(C)[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CC(=O)CCCCC(=O)O
Yield: 97.5 %

Procedure:
160 mg of (13E)-(11R,15S,16RS)-6,9-Di-oxo-11,15-bis-(tetrahydropyran-2-yloxy)-16-methyl-18,18,19,19-tetradehydro-13-prostenoic acid was mixed with 88 ml of a mixture of acetic acid:water:tetrahydrofuran (65:35:10) and allowed to react for 15 h at room temperature. It was concentrated by evaporation in a vacuum and the residue portions of acetic acid and water were removed by addition of toluene by azeotropic vacuum distillations repeated several times. The resulting raw oil was purified by chromatography on glass plates coated with silica gel. A mixture of dichloromethane and methanol was used as mobile solvent. 108 mg (98%) the title compound was isolated as colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[N-:13]=[N+:14]=[N-:15].[Na+].O>CS(C)=O>[N:13]([CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CCCCl)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCCC(=O)c1ccccc1
Temperature: 55 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
To a solution of 4-chloro-1-phenylbutan-1-one (26.4 mL, 164 mmol) in DMSO (200 mL) was added sodium azide (12.8 g, 197 mmol). The solution was warmed to 55° C. and stirred for 16 hours. The cooled mixture was then treated with water (600 mL) and extracted with ether (3×200 mL). The combined organics were washed with water (8×100 mL) and brine (100 mL) then dried over MgSO4 and concentrated to provide the product as an orange oil (30.7 g, 99%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]([NH:7][C:8]1[CH:9]=[C:10]([O:30][CH3:31])[C:11]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[C:13]2[CH3:18])[CH3:6].[CH3:32][C:33]([CH3:35])=O.[C:36]([OH:43])(=[O:42])[CH2:37][CH2:38][C:39]([OH:41])=[O:40]>CCO.[Pt]=O>[C:36]([OH:43])(=[O:42])[CH2:37][CH2:38][C:39]([OH:41])=[O:40].[CH:33]([NH:1][CH2:2][CH2:3][CH2:4][CH:5]([NH:7][C:8]1[CH:9]=[C:10]([O:30][CH3:31])[C:11]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=2)=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[C:13]2[CH3:18])[CH3:6])([CH3:35])[CH3:32]
Reactant: CC(C)=O
Reactant: COc1cc(NC(C)CCCN)c2nccc(C)c2c1Oc1cccc(C(F)(F)F)c1
Agent: O=[Pt]
Agent: O=C(O)CCC(=O)O
Solvent: CCO
Product: COc1cc(NC(C)CCCNC(C)C)c2nccc(C)c2c1Oc1cccc(C(F)(F)F)c1
Reaction time: 5 h

Procedure:
A solution of 8-(4-amino-1-methylbutylamino)-6-methoxy-4-methyl-5-(3-trifluoromethylphenoxy)quinoline as the free base (4.7 g, 10.8 mmol) prepared as in Example 1 in EtOH (60 mL) containing acetone (1.8 mL), prereduced platinum oxide (0.6 g) and molecular sieves (3A) was reduced on a Parr apparatus at 45 psig for 5 hours. An additional quantity of acetone (0.9 mL) was added and the reduction was continued an additional 18 hours. The catalyst and molecular sieves were filtered (celite) and the solvent was removed in vacuo. The residue was dissolved in acetonitrile (50 mL) and succinic acid (1.35 g, 1 mol equivalent) was added with stirring. The solid was filtered after cooling in the refrigerator overnight to yield the title compound 5, 5.8 g (91%), mp 143°-146°. Recrystallization from acetonitrile (75 mL) yielded pure title compound, 5.2 g, (81%), mp 145°-147.5°.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.O>CN(C)C=O>[CH2:3]([O:10][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: BrCCCCCOCc1ccccc1
Yield: 100.9 %

Procedure:
60% Sodium hydride (1.33 g) was suspended in dimethylformamide (40 ml), and benzyl alcohol (3 g) was added under ice-cooilng with stirring. The mixture was stirred at room temperature for 1 hr. The mixture was again ice-cooled, and 1,5-dibromopentane (6.4 g) was added, which was followed by stirring at room temperature for 3 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure to give 7.2 g of 5-benzyloxypentyl bromide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:29](Cl)(Cl)=[O:30].C(N(CC)CC)C.[CH2:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)[CH3:41]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:10][N:9]2[C:29]([N:45]2[CH2:46][CH2:47][N:42]([CH2:40][CH3:41])[CH2:43][CH2:44]2)=[O:30])[CH:5]=[CH:6][CH:7]=1
Reactant: CCN1CCNCC1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CCN(C(=O)N2CC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)CC1
Yield: 36.6 %

Procedure:
In a manner similar to the method described in Example 4, rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol) was reacted with phosgene solution (Aldrich, 20% in toluene, 0.12 mL, 0.12 mmol), in the presence of triethylamine (TEA, 30.0 mg, 0.30 mmol) in CH2Cl2 (2 mL) followed by reacting with 1-ethyl-piperazine (17.2 mg, 0.15 mmol) at rt for 30 min to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-1-(4-ethyl-piperazine-1-carbonyl)-pyrrolidine-3-carbonitrile (20.6 mg, 30.4%, as TFA salt) as a white amorphous. HRMS (ES+) m/z Calcd for C29H34Cl2F2N4O+H [(M+H)+]: 563.2151, found: 563.2151.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[C:8](O)(=O)/[CH:9]=[CH:10]\[C:11](O)=O.[CH3:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=1[CH3:23]>>[C:4]1(=[O:5])[O:6][C:1](=[O:7])[C:2]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]12.[CH:21]1[C:22]2[C:17](=[CH:16][CH:1]=[CH:2][CH:23]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1ccccc1C
Reactant: O=C1C=CC(=O)O1
Reactant: O=C(O)/C=C\C(=O)O
Product: O=C1OC(=O)c2ccccc21
Product: c1ccc2ccccc2c1

Procedure:
Maleic anhydride has been generally prepared by concentration and dehydration of an aqueous solution of maleic acid, which is obtained by absorbing in water, in an apparatus such as a scrubber, a gas containing maleic anhydride, formed by catalytic oxidation of benzene, or gaseous by-products containing maleic anhydride, formed during the production of phthalic anhydride by catalytic oxidation of o-xylene or naphthalene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1.[CH3:28][N:29]1[CH:33]=[C:32]([S:34](Cl)(=[O:36])=[O:35])[N:31]=[CH:30]1>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:34]([C:32]2[N:31]=[CH:30][N:29]([CH3:28])[CH:33]=2)(=[O:36])=[O:35])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3ncccn3)cc2)c1
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3ncccn3)cc2)S(=O)(=O)c2cn(C)cn2)c1

Procedure:
The title compound of Step B was prepared following the method described in Step B of Example 1 from 3-{3-[(4-pyrimidin-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A, and 1-methyl-1 H-imidazole-4-sulfonyl chloride. 1H NMR (400 MHz, CDCl3) δ 8.81 (m, 2H), 8.30 (d, 2H), 7.52 (s, 1H), 7.39 (s, 1H), 7.28-7.20 (m, 3H), 7.14 (m, 1H), 7.04-6.63 (m, 3H), 4.46 (s, 2H), 4.43 (s, 2H), 3.72 (s, 3H), 3.65 (s, 3H), 2.83 (t, 2H), 2.52 (t, 2H); MS 506 (M+1).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[C:27]([O:30][CH2:31][CH2:32][O:33][C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:43]=1[N:42]=[C:41]([CH3:44])[CH:40]=[CH:39]2)(=[O:29])[CH3:28].C(O)C.C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[C:27]([O:30][CH2:31][CH2:32][O:33][C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:43]=1[N:42]=[C:41]([C:44]1[N:6]3[CH:5]=[C:4]([C@@H:3]([N:12]4[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:24])[CH2:13]4)[C:2]([F:25])([F:1])[F:26])[CH:9]=[CH:8][C:7]3=[N:10][N:11]=1)[CH:40]=[CH:39]2)(=[O:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Reactant: CC(=O)OCCOc1cccc2ccc(C)nc12
Agent: O=C([O-])O
Agent: O=Ic1ccccc1
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)OCCOc1cccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.7 %

Procedure:
A solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (0.48 g, 1.2 mmol) and 2-(2-methylquinolin-8-yloxy)ethyl acetate (0.30 g, 1.2 mmol) in ethanol (5.8 mL, 1.2 mmol) was allowed to stir at ambient temperature for 12 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (5.8 mL) and iodosobenzene diacetate (0.41 g, 1.3 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour. Ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL) were added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on a C18 column (0-100% acetonitrile/water) to give the title compound (0.47 g, 66%).
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[I-].[K+].[C:33](#N)C>>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH3:33])[CH2:15][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Reactant: CC#N
Reactant: ClCCc1ccccc1
Agent: [I-]
Agent: [K+]
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccccc1

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (0.28 g--see Preparation 3), phenethyl chloride (0.14 g) anhydrous potassium carbonate (0.58 g), anhydrous potassium iodide (0.3 g) and acetonitrile (10 ml) was heated under reflux for 16 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous sodium carbonate (30 ml), the layers separated and the aqueous layer extracted with dichloromethane (2×20 ml).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13](N)=[CH:12][CH:11]=1.[CH2:18]=O.[C:20]([BH3-])#[N:21].[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([N:21]([CH3:20])[CH3:18])=[CH:12][CH:11]=1
Reactant: COC(=O)CCCCCSc1ccc(N)cc1
Reactant: C=O
Reactant: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CO
Product: COC(=O)CCCCCSc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
To a solution of 6-(4-amino-phenylsulfanyl)-hexanoic acid methyl ester (2.5 g, 10 mmol) in methanol (20 mL) was added at 0° C. a 37% aqueous solution of formaldehyde (2.4 mL, 30 mmol) and a solution of sodium cyanoborohydride (2.5 g, 40 mmol) and zinc chloride (2.7 g, 20 mmol) in methanol (150 mL). The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was taken up in ethyl acetate (250 mL) and aqueous sodium hydroxide (100 mL, 2M). The organic layer was washed consecutively with aqueous sodium hydroxide (100 mL, 2M), distilled water (2×100 mL) and brine (2×100 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a yellow oil that was purified by flash chromatography (10:90:1 to 20:80:1 ethyl acetate:40-60° C. petroleum ether:triethylamine) to give the title compound (2.2 g, 79%) as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:12][CH2:11]3)=[CH:8][S:7][C:6]=2[CH:21]=1.C(N(CC)CC)C.[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:34](=[O:35])[C:33]4[CH:37]=[CH:38][C:30]([F:29])=[CH:31][CH:32]=4)[CH2:12][CH2:11]3)=[CH:8][S:7][C:6]=2[CH:21]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NCCCCN1CCN(c2csc3cc(F)ccc23)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCCN1CCN(c2csc3cc(F)ccc23)CC1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1.17 h
Yield: 64.8 %

Procedure:
To a 0° C. solution of 4-(6-fluorobenzo[b]thien-3-yl)-1-piperazine-butanamine (2.45 g, 7.97 mmol), triethylamine (1.23 g, 12.2 mmol), and dichloromethane (30 mL) under a nitrogen atmosphere was added 4-fluorobenzoyl chloride (1.61 g, 10.2 mmol) in one portion. The reaction was stirred at 0° C. for 70 minutes and then at room temperature for 3 hours. The reaction was diluted with dichloromethane (50 mL) and the mixture was washed successively with 5% aqueous NaOH (50 mL) and water (50 mL), dried (Na2SO4), and concentrated in vacuo to a tan solid. The crude product was chromatographed on silica gel with 10% ethanol/dichloromethane as eluent to afford an 2.22 g of an off-white solid. Recrystallization from ethyl acetate/heptane gave 1.60 g (46%) of the title compound as beige needles, m.p. 161°-163° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[C:12]([O:16][C:17](=O)[O:18]C(C)(C)C)([CH3:15])([CH3:14])[CH3:13]>>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:17](=[O:18])[O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][CH:4]=1
Reactant: CNc1ccc(CCN)cc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Product: CNc1ccc(CCNC(=O)OC(C)(C)C)cc1
Yield: 94.6 %

Procedure:
2.03 g of 2-(4-methylaminophenyl)ethylamine and 3.20 g of di-t-butylcarbonate were subjected to an acylation reaction to obtain 3.20 g of t-butyl 2-(4-methylaminophenyl)ethylcarbamate.
Reaction SMILES: [OH:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]([CH3:23])[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:33]1[S:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1>CN(C)C=O>[S:34]1[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=[C:33]1[O:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]([CH3:23])[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]2[C:16]([Cl:22])=[CH:17][CH:18]=[CH:19][C:20]=2[Cl:21])=[O:9])=[CH:4][CH:3]=1
Reactant: Clc1nc2ccccc2s1
Reactant: CC(Oc1ccc(O)cc1)C(=O)OCCOCc1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Oc2nc3ccccc3s2)cc1)C(=O)OCCOCc1c(Cl)cccc1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
38.5 g of 2-(2,6-dichlorobenzyloxy)ethyl 2-(4-hydroxyphenoxy)-propionate were dissolved in 200 ml of dimethylformamide and 15.2 g of potassium carbonate were added to the solution. The mixture was stirred at 80° C. for 1 hour. A solution of 18.6 g of 2-chlorobenzothiazole in 50 ml of dimethylformamide was added dropwise at this temperature to the resulting mixture. After the addition, the mixture was stirred at the same temperature for 2 hours to complete the reaction. The reaction mixture was poured onto ice water, and the separated oily product was extracted with toluene. The toluene layer was washed successively with a 1% aqueous solution of sodium hydroxide and water, and then toluene was evaporated under reduced pressure to give 43.5 g of 2-(2,6-dichlorobenzyloxy)ethyl 2-[4-(benzothiazol-2-yloxy)phenoxy]propionate as a viscous oily product represented by the formula above.