Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][S:3]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[O:20][C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:13][C:12](=[O:21])[C:11]=2[CH:22]=1)(=[O:5])=[O:4].Cl.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32]Cl)=[CH:27][N:26]=1.ClC1N=CC(CC(O)=O)=CC=1.S(Cl)(Cl)=O>>[CH3:2][S:3]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[O:20][C:14]3([CH2:15][CH2:16][N:17]([CH2:32][CH2:31][C:28]4[CH:29]=[CH:30][C:25]([Cl:24])=[N:26][CH:27]=4)[CH2:18][CH2:19]3)[CH2:13][C:12](=[O:21])[C:11]=2[CH:22]=1)(=[O:4])=[O:5]
Reactant: ClCCc1ccc(Cl)nc1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Agent: Cl
Agent: O=C(O)Cc1ccc(Cl)nc1
Solvent: O=S(Cl)Cl
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc(Cl)nc3)CC1)O2

Procedure:
The title compound was prepared from 3,4-dihydro-6-methanesulfonamidospiro[(2H)-1-benzopyran-2,4'-piperidine]-4-one hydrochloride and 2-chloro-5-chloroethylpyridine hydrochloride by a procedure analogous to that described in Example 92, Step B. [The 2-chloro-5-chloroethylpyridine hydrochloride used in this reaction was obtained by treating 6-chloropyrid-3-yl acetic acid (L. A. Carlson, Acta Pharm. Suecica, 9, 411 (1972)) with borane-tetrahydrofuran complex followed by reaction with thionyl chloride.] mp 213°-215° C.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][CH2:38][NH:39][C:40]1[CH:41]=[N:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:36][CH2:37][CH2:38][NH:39][C:40]2[CH:41]=[N:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=2)=[O:18])=[CH:19][CH:20]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: COc1ccc(NCCN)cn1
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(NCCNC(=O)c2ccc(OC/C=C(\C)CCC=C(C)C)cc2)cn1
Reaction time: 1 h
Yield: 25.9 %

Procedure:
4-geranyloxybenzoic acid(3.48 g) was dissolved in chloroform(50 ml) and triethylamine(3.52 ml), and then diphenylphosphinic chloride(2.42 ml) was added thereto while being cooled with ice. After being stirred for 1 hour, the mixture, with 3-(2-aminoethylamino)-6-methoxypyridine(2.12 g) added thereto, was stirred for 3 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 1.39 g of the aimed compound.
Reaction SMILES: [CH2:1]([NH:10][C:11](=O)[CH3:12])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:23]2)=CC=1>C1(C)C=CC=CC=1>[CH3:12][C:11]1[S:23][C:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:1][N:10]=1
Reactant: CC(=O)NCC(=O)c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1ncc(-c2ccccc2)s1
Yield: 31.4 %

Procedure:
A mixture of N-phenacylacetamide (0.70 g, 4 mmol), 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide (Lawesson's reagent) (0.80 g, 2 mmol) and toluene (10 ml) was heated for 1.5 h at reflux and then evaporated under reduced pressure. The residue was purified by chromatography (10 g silica, dichloromethane) to give 2-methyl-5-phenylthiazole as a yellowish solid (0.11 g, 16%) m.p. 72°-4° C.; δH (CDCl3) 7.85 (1H, S, CH), 7.3-7.7 (5H, m, C6H5), 2.7 (3H, S, CH3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:9][CH:8]=1)[NH2:5].[NH:25]1[CH2:30][CH2:29][O:28][CH:27]([CH2:31][CH2:32][C:33]2([C:38](O)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:26]1>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:11][CH:12]=1)[NH:5][C:38]([C:33]1([CH2:32][CH2:31][CH:27]2[O:28][CH2:29][CH2:30][NH:25][CH2:26]2)[CH2:34][CH2:35][CH2:36][CH2:37]1)=[O:39]
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Reactant: O=C(O)C1(CCC2CNCCO2)CCCC1
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)C1(CCC2CNCCO2)CCCC1
Yield: 62 %

Procedure:
4-[[(2,6-Dichlorophenyl)carbonyl]amino]-N-[[1-[(2-morpholinyl)ethyl]cyclopentyl]carbonyl]-L-phenylalanine methyl ester was prepared from 4-[[(2,6-Dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester and 1-[(2-morpholinyl)ethyl]cyclopentane carboxylic acid using the general coupling procedure described in example 46 to provide a 62% yield. HRMS (C29H35Cl2N3O5): Obs. mass, 576.2531. Calcd. mass, 576.2582, (M+H).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5]C[CH2:3][CH2:2]1.[CH:8](OC)([O:11][CH3:12])[O:9][CH3:10].C(O)C(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:10][O:9][C:8]1([O:11][CH3:12])[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1
Reactant: COC(OC)OC
Reactant: O=C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CO
Product: COC1(OC)CCCCC1

Procedure:
Cyclohexanone dimethyl ketal (CHMK) was prepared as described in Example 1 from 1 mol of cyclohexanone and trimethyl orthoformate. 370.6 g of isobutanol (2-methyl-1-propanol, 5.0 mols) were added, and the transketalization was then carried out under reflux while the sump temperature was gradually increased from 110° to 160° C. After a running time of 2 hours, another 0.4 g of p-toluenesulfonic acid was added. The low-boiling-point components, i.e. methyl formate, methanol and a small amount of isobutyl formate, were removed by distillation under reflux (ratio 1:5 to 1:2) over the course of 4 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[S:6][C:7]([S:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]4[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]4)=[CH:16][CH:15]=3)(=[O:12])=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:35]I>C1COCC1>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[S:6][C:7]([S:10]([N:13]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]4[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:23]4)=[CH:16][CH:15]=3)[CH3:35])(=[O:11])=[O:12])=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2)sc2ccc(Cl)cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(S(=O)(=O)N(C)c2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2)sc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
tert-Butyl 3-(4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonamido)phenyl)azetidine-1-carboxylate (216 mg, 0.44 mmol) was stirred in THF (5 ml) and NaH (25 mg, 0.53 mmol) was added. After stirring at r.t. for 15 min, methyl iodide (0.028 ml, 0.44 mmol) was added and stirring was continued for 116 h. The solution was concentrated in vacuo, dissolved in water (pH 11) and extracted with EtOAc. The organic extracts were dried (MgSO4), filtered and concentrated to give tert-butyl 3-(4-(5-chloro-N,3-dimethylbenzo[b]thiophene-2-sulfonamido)phenyl)azetidine-1-carboxylate (=starting compound methylated at the amido-N) (185 mg, 83%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]=O.C(OC(=O)C)(=O)C.[OH-].[Na+]>O>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:6]1[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=[C:2]1/[CH:1]=[CH:23]/[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=1
Reactant: O=Cc1ccccn1
Reactant: Cc1nc2ccccc2n1-c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccn1
Temperature: 80 °C
Yield: 25.2 %

Procedure:
A stirred mixture of 2-methyl-1-(2-pyridyl)-1H-benzimidazole (0.50 g, 2.39), pyridine-2-carboxaldehyde (0.50 g, 4.67 mmol) and acetic anhydride (5 ml) was heated to 80° C. for 1.5 h and then to reflux for about 6 h. After cooling, the mixture was diluted with water (15 ml), basified with a 10% aqueous solution of sodium hydroxide (100 ml) and extracted with dichloromethane (2×100 ml). The combined organic layers were washed with water (100 ml) and extracted with 2 N hydrochloric acid (3×50 ml). The combined aqueous extracts were basified with a 50% aqueous solution of sodium hydroxide (3×50 ml) and extracted with dichloromethane (4×50 ml). The combined organic extracts were washed consecutively with water (100 ml) and brine (100 ml), dried (magnesium sulfate) and concentrated to dryness. Column chromatography (silica gel, 125 g; ethyl acetate) gave 0.18 g of free base (E)-1-(2-pyridyl)-2-[2-(2-pyridyl)ethenyl]-1H-benzimidazole as a brown oil. This product was dissolved into methanol (5 ml), treated with a 10% methanol solution of hydrogen chloride (5 ml) and concentrated to dryness. Recrystallization from 2-propanol afforded 0.15 g (21%) of the titled compound.
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][CH2:9][N:10]([CH:18]([C:22]1[N:31]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30](=[O:39])[C:29]2[C:24](=[CH:25][C:26]([Cl:40])=[CH:27][CH:28]=2)[N:23]=1)[CH:19]([CH3:21])[CH3:20])[C:11](=[O:17])[C:12]([CH3:16])([CH3:15])CCl)(C)(C)C.C(OC(=O)NCCNC(C1N(CC2C=CC=CC=2)C(=O)C2C(=CC(Cl)=CC=2)N=1)C(C)C)(C)(C)C.ClCC(C)(C)C(Cl)=O.CCN(CC)CC>C(Cl)Cl>[CH2:32]([N:31]1[C:30](=[O:39])[C:29]2[C:24](=[CH:25][C:26]([Cl:40])=[CH:27][CH:28]=2)[N:23]=[C:22]1[CH:18]([N:10]1[C:11](=[O:17])[C:12]([CH3:16])([CH3:15])[CH2:6][NH:7][CH2:8][CH2:9]1)[CH:19]([CH3:20])[CH3:21])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N(CCNC(=O)OC(C)(C)C)C(=O)C(C)(C)CCl
Agent: CC(C)(CCl)C(=O)Cl
Agent: CC(C)C(NCCNC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N1CCNCC(C)(C)C1=O
Reaction time: 48 h

Procedure:
Preparation of {2-[[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-(3-chloro-2,2-dimethyl-propanoyl)-amino]-ethyl}-carbamic acid tert-butyl ester: {2-[1-(3-Benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propylamino]-ethyl}-carbamic tert-butyl ester (450 mg, 0.93 mmol) was treated with 3-chloropivaloyl chloride (360 μL, 2.80 mmol) and Et3N (388 μl, 2.80 mmol) in CH2Cl2 (10 mL) at room temperature. After 48 h, the mixture was diluted with CH2Cl2 (10 mL), washed with water, brine, dried and concentrated under vacuum. Purification by flash chromatography on silica gel (3–6% EtOAc in hexane) gave the title compound (413 mg) as a clear oil: MS (ES) m/e 603 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N+:7]([O-])[CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:13][CH2:14][C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[N:4]=1)#[N:2].O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:8]1[N:7]=[C:6]2[N:5]([CH2:13][CH2:14][C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[N:4]=[C:3]([C:1]#[N:2])[C:11]2=[CH:10][CH:9]=1
Reactant: N#Cc1nn(CCC(F)(F)C(F)(F)F)c2c1ccc[n+]2[O-]
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1nn(CCC(F)(F)C(F)(F)F)c2nc(Cl)ccc12
Temperature: 75 °C
Reaction time: 9 h

Procedure:
To the intermediate from Step A above (225 mg, 0.735 mmol) was added POCl3 (2.8 g, 18.3 mmol) and the mixture was stirred at 75° C. for 9 hours. The reaction mixture was then concentrated in vacuo to remove POCl3. To the residue was added hexane/ethyl acetate (2/1, 50 mL) and the pH adjusted to 7.5˜8.0 with aqueous K2CO3 at 0° C. The water layer was extracted with the hexane/ethyl acetate (2/1, 2×20 mL). The combined organic layer was dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using hexane/ethyl acetate eluent to give the product as a white solid. 1H NMR (500 MHz, CDCl3): δ 2.86 (m, 2H); 4.90 (t, J=8.4 Hz, 2H); 7.42 (d, J=8.4 Hz, 1H); 8.17 (d, J=8.4 Hz, 1H), m/z=325.04 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[CH2:13]O.S(Cl)([Cl:17])=O>C1COCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[Cl:17][CH2:13][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[CH:7][C:2]=1[F:1]
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(-n2cccn2)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cc(-n2cccn2)ccc1CCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2-fluoro-4-(1H-pyrazol-1-yl)phenyl)methanol (0.71 g) in THF (15.0 mL) was added thionyl chloride (0.40 mL) under ice-cooling, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, saturated aqueous sodium bicarbonate was added thereto, and the mixture was partitioned. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.50 g).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH2:24]([NH:28][CH2:29][C:30]1[CH:42]=[CH:41][C:33]([O:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:32]([CH3:43])[CH:31]=1)[CH2:25][CH2:26][CH3:27]>C(Cl)Cl>[CH2:24]([N:28]([CH2:29][C:30]1[CH:42]=[CH:41][C:33]([O:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:32]([CH3:43])[CH:31]=1)[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:3]=1)[CH2:25][CH2:26][CH3:27]
Reactant: Cc1ccc(-c2cncc(Br)n2)cc1
Reactant: CCCCNCc1ccc(OCC(=O)OCC)c(C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cncc(-c2ccc(C)cc2)n1
Temperature: 100 °C
Yield: 8.3 %

Procedure:
A mixture of 2-bromo-6-(4-methylphenyl)pyrazine (0.25 g, 1 mmol), N,N-diisopropylethylamine (0.35 mL, 2 mmol) and ethyl {4-[(butylamino)methyl]-2-methylphenoxy}acetate (0.42 g, 1.5 mmol) was heated at 100° C. in a sealed reactivial for 18 h. The reaction mixture was then allowed to come to room temperature and the residue dissolved in CH2Cl2 (30 mL), the organic extract was washed water (15 mL) and passed through a hydrophobic frit before concentrating in vacuo. Purification by Biotage™ chromatography (Silica, 40 g) eluting 1:19–1:4 EtOAc:cyclohexane afforded the title compound as a pale yellow oil (37 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:21][C:22]([C:24]2[CH:33]=[C:32](Cl)[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH:35][C@@H:36]1[CH2:41][CH2:40]C[NH:38][CH2:37]1.CCN(C(C)C)C(C)C.[OH-].[Li+]>CS(C)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:21][C:22]([C:24]2[CH:33]=[C:32]([N:38]3[CH2:40][CH2:41][CH:36]([OH:35])[CH2:37]3)[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC)NC(=O)c2cc(Cl)c3ccccc3n2)CC1
Reactant: O[C@@H]1CCCNC1
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)O)NC(=O)c2cc(N3CCC(O)C3)c3ccccc3n2)CC1
Temperature: 110 °C
Yield: 24.7 %

Procedure:
To a solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(methoxycarbonyl)propyl]aminocarbonyl-4-chloroquinoline (150 mg, 0.315 mmol) in DMSO (3.0 mL) was added (R)-3-hydroxypiperidine (68 mg, 0.5 mmol) and DIEA (65 mg, 0.5 mL). The mixture was heated at 110° C. for 18 hours. The crude reaction mixture was treated with lithium hydroxide (3.0 mL 0.25 M) for 4 hours. The reaction was purified by preparative HPLC to afford 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-hydroxypyrrolidin-1-yl)quinoline (41.0 mg); NMR (DMSO-d6) 1.2 (t, 3), 2.00-2.20 (m, 4), 2.45 (m, 2), 3.30-3.75 (m, 8), 4.05 (q, 2), 4.60 (s, 1), 5.11 (m, 1), 7.39 (s, 1), 7.65 (m, 1), 7.95 (m, 1), 8.28 (m, 1), 8.58 (br s, 1), 9.75 (m, 1) ppm.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2]1.C(N(CC)CC)C.[C:15](Cl)(=[O:19])[C:16]([CH3:18])=[CH2:17].[OH-].[Na+]>O1CCCC1>[C:15]([O:7][CH:3]1[CH2:4][CH2:5][CH2:6][S:1][CH2:2]1)(=[O:19])[C:16]([CH3:18])=[CH2:17]
Reactant: C=C(C)C(=O)Cl
Reactant: OC1CCCSC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1CCCSC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
Freshly distilled tetrahydrothiapyran-3-ol (8.97 g, 75.3 mmol) and triethylamine (10.6 mL, 75.5 mmol) were dissolved in anhydrous tetrahydrofuran (THF) (40 mL) and cooled to 0° C. Methacryloyl chloride (8.1 mL, 83.2 mmol) was then added slowly, dropwise. The reaction then was warmed slowly to room temperature. After stirring overnight, 30 mL DIW were added and the mixture was made basic with 5 M NaOH. The THF then was removed by rotary evaporation and the product was extracted with diethyl ether (3×40 mL). The ether extracts were combined and washed with 0.1 M NaOH, followed by DIW before being dried over sodium sulfate and filtered. The product was then concentrated by rotary evaporation and dried in vacuo to afford tetrahydro-2H-thiopyran-3-yl methacrylate as a light orange liquid (7.63 g, 54%). 1H NMR (600 MHz, CDCl3, ppm) δ 6.08 (s, 1H), 5.54 (s, 1H), 4.94 (m, 1H), 2.78 (m, 1H), 2.62 (m, 1H), 2.49 (m, 1H), 2.47 (m, 1H), 2.14 (m, 1H), 1.99 (m, 1H), 1.91 (s, 3H), 1.85 (m, 1H), 1.49 (m, 1H). 13C NMR (150 MHz, CDCl3, ppm) δ 166.61, 136.69, 125.62, 71.21, 32.26, 31.82, 28.10, 27.43, 18.43.
Reaction SMILES: CO[C:3](=[O:19])[C:4]1[C:9]([NH:10][C:11]([CH:13]2[CH2:15][CH2:14]2)=[O:12])=[CH:8][CH:7]=[C:6]([F:16])[C:5]=1[CH2:17]Br.CCN(CC)CC.[CH2:27]([O:29][C:30]1[CH:31]=[C:32]([C@H:38]([NH2:44])[CH2:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH3:28]>CN(C=O)C>[CH2:27]([O:29][C:30]1[CH:31]=[C:32]([C@H:38]([N:44]2[C:3](=[O:19])[C:4]3[C:5](=[C:6]([F:16])[CH:7]=[CH:8][C:9]=3[NH:10][C:11]([CH:13]3[CH2:14][CH2:15]3)=[O:12])[CH2:17]2)[CH2:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH3:28]
Reactant: CCOc1cc([C@H](N)CS(C)(=O)=O)ccc1OC
Reactant: COC(=O)c1c(NC(=O)C2CC2)ccc(F)c1CBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3c(F)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Temperature: 90 °C
Yield: 54.4 %

Procedure:
To a solution of 2-bromomethyl-6-(cyclopropanecarbonyl-amino)-3-fluoro-benzoic acid methyl ester (1 g, 3 mmol) and Et3N (1.25 ml, 9 mmol) in DMF (10 ml) was added (1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (870 mg, 3.2 mmol). The mixture was heated at 90° C. for 20 hrs. The reaction mixture was cooled to room temperature and extracted with water (50 ml) and EtOAc (50 ml). The organic layer was washed with water (50 ml), brine (25 ml), dried over Na2SO4 and concentrated. The resulted oil was purified by chromatography to give (1S)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-7-fluoro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (800 mg, 55% yield): mp, 176–178° C.; 1H NMR (CDCl3) δ 0.88–0.92 (m, 2H, c-propylCH2), 1.09–1.12 (m, 2H, c-propylCH2), 1.47 (t, J=7.0 Hz, 3H, OCH2CH3), 1.64–1.68 (m, 1H, c-propylCH), 2.98 (s, 3H, CH3), 3.63–3.73 (m, 1H, CHHSO2), 3.87 (s, 3H, CH3), 4.05–4.28 (m, 4H, CHHSO2+CNHH+OCH2CH3), 4.49 (d, J=18 Hz, 1H, CHHN), 6.85–6.92 (m, 1H, NCH), 6.86–6.93 (m, 3H, Ar), 7.04 (t, J=8 Hz, 1H, Ar), 8.45–8.55 (m, 1H, Ar), 10.32 (s, 1H, NHCO); 13C NMR (CDCl3) δ 8.26, 8.27, 14.67, 16.04, 41.50, 44.67, 51.30, 55.39, 55.96, 64.65, 111.63, 112.21, 118.95, 119.26, 119.68, 119.92, 126.43, 126.74, 128.99, 134.48, 134.53, 148.98, 149.88, 150.31, 154.22, 168.89, 172.39. Anal Calcd for C24H27FN2O6S: C, 58.76; H, 5.55; N, 5.71. Found: C, 58.60; H, 5.33; N, 5.65.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]2[C:18]([O:19][CH3:20])=[N:17][C:16]3[C:11]2=[N:12][C:13]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[N:14][C:15]=3[NH2:21])[CH2:4][CH2:3][CH2:2]1.[CH2:27](OC1N=C2C(N=C(OC)N2CCCCCCl)=C(N)N=1)[CH2:28][CH2:29]C.N1CCCCCC1>>[CH2:23]([O:22][C:13]1[N:12]=[C:11]2[C:16]([N:17]=[C:18]([O:19][CH3:20])[N:10]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][N:1]2[CH2:2][CH2:3][CH2:29][CH2:28][CH2:27][CH2:4]2)=[C:15]([NH2:21])[N:14]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCN3CCC3)c2n1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Agent: C1CCCNCC1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCN3CCCCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 27 from 2-(butyloxy)-9-(5-chloropentyl)-8-(methyloxy)-9H-purin-6-amine and hexahydro-1H-azepine but with sequential purifications by MDAPs using Method A followed by Method E.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C:22]([N+:30]([O-:32])=[O:31])([CH3:29])[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C([C@H]1CC[C@H](OC2C=CC3C(=CC=C(C([N+]([O-])=O)C)C=3)C=2[C:59]([F:62])([F:61])[F:60])CC1)(C)(C)C>>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[C:13]([C:59]([F:62])([F:61])[F:60])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C:22]([N+:30]([O-:32])=[O:31])([CH3:29])[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)[N+](=O)[O-]
Reactant: COC(=O)CCC(C)(c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)[N+](=O)[O-]
Product: COC(=O)CCC(C)(c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)[N+](=O)[O-]

Procedure:
Methyl 4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)-4-nitropentanoate was synthesized as per methyl 4-(6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)-4-nitropentanoate (Example 205) in 62% yield using 2-(trans-4-tert-butylcyclohexyloxy)-6-(1-nitroethyl)-1-(trifluoromethyl)naphthalene as starting material.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=2)[C:4](=[O:5])[NH:3]1.ClC1C=C(N2C(=O)NNC2=O)C=C(Cl)C=1.CBr.[C:34](Cl)(=[O:36])[CH3:35]>CN(C)C=O.C(N(CC)CC)C>[CH3:1][N:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([Cl:16])[CH:12]=[C:13]([Cl:15])[CH:14]=2)[C:4](=[O:5])[N:3]1[C:34](=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: Cn1[nH]c(=O)n(-c2cc(Cl)cc(Cl)c2)c1=O
Agent: CBr
Agent: O=c1[nH][nH]c(=O)n1-c1cc(Cl)cc(Cl)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)n1c(=O)n(-c2cc(Cl)cc(Cl)c2)c(=O)n1C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To a solution of 2.6 g of 1-methyl-4-(3',5'-dichlorophenyl) urazole, which had been prepared by reacting 4-(3',5'-dichlorophenyl) urazole and methyl bromide in an equimolar proportion, and 1.0 g of triethylamine in 10 ml of N,N-dimethylformamide was added 0.8 g of acetyl chloride in small increments at room temperature with agitation. After completing the addition, the reaction was carried out on a water bath for 2 hours with continued agitation. The solvent was removed by distillation into vacuo and the mass was poured in water to precipitate crystals which were recrystallized from ethanol to obtain 2.3 g of 1-methyl-2-acetyl-4-(3',5'-dichlorophenyl) urazole in a yield of 76%.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1)#N.O.C(Cl)Cl.N([O-])=O.[Na+].[C:19]([OH:22])(=[O:21])[CH3:20]>>[C:19]([O:22][CH2:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)(=[O:21])[CH3:20]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CC(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)OCc1ccc(C#N)cc1
Yield: 84 %

Procedure:
p-Cyanobenzylamine (13.2 g), water (18 g), and methylene chloride (18 g) were mixed, and the mixture was stirred with cooling with ice. Acetic acid (18 g) was added to the mixture. Subsequently, a 20 wt % aqueous solution (51.8 g) of sodium nitrite was added dropwise to the mixture over a one hour period. The mixture was stirred at the same temperature for four hours. The reaction mixture was subjected to extraction with methylene chloride, and the organic solvent was concentrated. Water was added to the concentrated solution, and the residual organic solvent was removed through distillation, to thereby obtain 14.7 g of p-cyanobenzyl acetate (yield 84%). The purity of the product was 98%.