Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:28])[C:12]3[S:19][CH:18]=[C:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.C([Li])CCC.C1C[O:54][CH2:53]C1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:28])[C:12]3[S:19][C:18]([CH:53]=[O:54])=[C:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:25])[CH3:27])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:29][CH:30]=1
Reactant: C1CCOC1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2scc(COCC[Si](C)(C)C)c21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(C=O)c(COCC[Si](C)(C)C)c21
Temperature: -78 °C

Procedure:
To a cold (−78° C.), stirred mixture of 2.03 g of N-(4-chlorobenzyl)-4-methyl-7-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide in 50 mL of dry TBF is added via cannula a solution of LDA, prepared as usual in 25 mL of dry THF from 2.5 mL of diisopropylamine and 5.3 mL of a 2.5 M solution of butyllithium in hexanes. The resulting deeply colored solution is stirred for 5 min at −78° C., then 1.7 mL of dry DMF is added, causing the mixture to solidify. The mixture is allowed to warm to 0° C. whereupon it becomes fluid, and is quenched with 50 mL of 1N HCl. Aqueous workup (CH2Cl2, dil. HCl) followed by flash chromatography on silica gel using 30-40% EtOAc in CH2Cl2 affords 1.56 g of the title compound as a yellow solid. Recrystallization from EtOAc provides pale yellow crystals.
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]([NH2:13])=[O:12]>C(O)=O>[CH:11]([NH:13][CH:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:9])=[O:12]
Reactant: NC=O
Reactant: CC(=O)Cc1ccccc1
Solvent: O=CO
Product: CC(Cc1ccccc1)NC=O
Yield: 60 %

Procedure:
Many methods of making amphetamine and related compounds are known in the prior art, including the commercially used Leukart-Wallach reaction for producing racemic amphetamine from phenylacetone. For example, in one commercial process, phenylacetone is reacted with formamide and formic acid to form (±)-N-formylamphetamine (racemic N-formylamphetamine). The racemic N-formylamphetamine is then hydrolyzed with sulfuric acid, the solution basified, and the resulting d,l-amphetamine ((±)-amphetamine; racemic amphetamine) is distilled with an overall yield of about 60%.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:11]([C:13](=[CH:19]OCC)[C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12]>C(O)(=O)C>[NH2:12][C:11]1[N:7]2[N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=[C:8]2[N:10]=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: CC(C)(C)c1cc(N)[nH]n1
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2cc(C(C)(C)C)nn2c1N

Procedure:
A solution of 3-tert-butyl-1H-pyrazol-5-amine (484 mg, 3.48 mmol, 1 eq.) and ethyl 2-cyano-3-ethoxyacrylate (590 mg, 3.49 mmol, 1.00 eq.) in acetic acid (10 mL) was stirred for 16 h at 100° C. under nitrogen. After cooling, the resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 8 with saturated aqueous NaHCO3 solution and extracted with ethyl acetate (100 mL×3). The organic layers were combined, dried and concentrated under reduced pressure. The residue was applied onto a silica gel column with CH2Cl2/MeOH (30:1) as an eluent to obtain the corresponding product as a white solid: LCMS (m/e) 263 (M+H); 1H NMR (300 MHz, DMSO-d6) δ ppm 8.56 (s, 1H), 8.40-8.38 (broad, d, J=6.0 Hz, 2H), 6.48 (s, 1H), 4.33 (q, J=7.2 Hz, 2H), 1.37-1.31 (m, 12H).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7]C=1.[NH2:19]C1C=CC=CC=1O.ClC1C2C(=CC=CC=2)N=CC=1.[H-].[Na+]>CS(C)=O>[NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:19]=1
Reactant: Nc1ccccc1O
Reactant: Nc1ccccc1Oc1ccnc2ccccc12
Agent: Clc1ccnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1ccccc1Oc1ncnc2ccccc12

Procedure:
Alternatively, the 4-(aminophenoxy)quinoline derivative can be produced by reacting an aminophenol derivative with the 4-chloroquinoline derivative in a suitable solvent, for example, dimethyl sulfoxide, in the presence of a base, for example, sodium hydride. Alternatively, the 4-(aminophenoxy)quinazoline derivative can also be produced by dissolving an aminophenol derivative in an aqueous sodium hydroxide solution and subjecting the solution to a two-phase reaction with a solution of the 4-chloroquinazoline derivative in a suitable organic solvent, for example, ethyl methyl ketone, in the presence of a phase transfer catalyst, for example, tetra-n-butylammonium chloride, or in the absence of a catalyst (Scheme 2).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([NH2:18])[CH:12]=1)(=[O:4])=[O:3].Cl.C(O[C:23](=N)[CH2:24][Br:25])C>C(O)C>[Br:25][CH2:24][C:23]1[NH:17][C:14]2[CH:15]=[CH:16][C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:2]([CH3:1])(=[O:3])=[O:4])=[CH:12][C:13]=2[N:18]=1
Reactant: CS(=O)(=O)c1ccccc1-c1ccc(N)c(N)c1
Reactant: CCOC(=N)CBr
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)c1ccccc1-c1ccc2[nH]c(CBr)nc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.1 %

Procedure:
A mixture of 2′-methanesulfonyl-biphenyl-3,4-diamine (8.09 g, 0.0308 mol) and 2-bromoacetimidic acid ethyl ester hydrochloride salt (11.82 g, 0.0370 mol) in anhydrous ethanol (200 proof, 120 mL) was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate and brine. The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to provide 2-bromomethyl-5-(2-methanesulfonyl-phenyl)-1H-benzoimidazole (10.36 g, 92%) as a yellow oil. To a solution of this material in CH2Cl2, was added Boc2O (7.39 g, 0.0339 mol), Et3N (12.9 mL, 0.0924 mol), and DMAP (0.19 g, 0.00154 mol). After stirring 1 h at room temperature, the reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography (silica, EtOAc: hexanes, 1:2) to afford the title compound as a yellow oil (10.17 g, 77%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:23])[CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][CH:10]=[C:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[CH2:25](O)[CH2:26][OH:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:25]1[CH2:26][O:27][C:12]([C:11]2[C@:15]3([CH3:24])[C@H:8]([C@H:7]4[C@H:18]([C:17](=[O:23])[CH2:16]3)[C@:19]3([CH3:22])[C@H:4]([CH2:3][C@@H:2]([OH:1])[CH2:21][CH2:20]3)[CH2:5][CH2:6]4)[CH2:9][CH:10]=2)([CH3:13])[O:14]1
Reactant: OCCO
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C2=CC[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4C(=O)C[C@]23C)OCCO1
Reaction time: 20 h

Procedure:
3β-Hydroxy-5α-pregn-16-ene-11,20-dione (3 g) was refluxed with ethylene glycol (8 ml) in benzene (150 ml) containing p-toluenesulphonic acid (150 mg) under a Dean Stark water separator for 20 hours. The mixture was diluted with ethyl acetate, washed with sodium hydrogen carbonate solution, and brine, and dried (sodium sulphate). Evaporation gave 20,20-ethylenedioxy-3β-hydroxy-5α-pregn-16-en-11-one (3.42 g) as a white foam. This foam was dissolved in ethanol (170 ml) and sodium borohydride (2.1 g) in water (21 ml) was added with stirring under reflux. After 1.25 hours, most of the ethanol was evaporated and the residue was partitioned between ethyl acetate and water. The ethyl acetate extract was washed, and evaporated to small volume. This solution was filtered through silica gel (100 g) in ethyl acetate. Evaporation of the eluate gave 20,20-ethylenedioxy-5α-pregn-16-ene-3β,11β-diol (2.45 g) as a white foam which was heated on a steam bath for 1 hour in acetic acid (24 ml) and water (25 ml). The mixture was concentrated and diluted with water. The solid was collected by filtration, washed, and dried. Recrystallisation from ethyl acetate-acetone gave title compound (97 mg), m.p. 214°-218°, [α]D +82.1°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].S(C1C=CC(C)=CC=1)(O[CH2:22][CH2:23][O:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)(=O)=O.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:22][CH2:23][O:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCOC2CCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc(OCCOC3CCCC3)cc2)cc1

Procedure:
A solution of 24 g (0.12 mol) of 4-benzyloxyphenol in 100 cc of DMF is added dropwise to a 50% suspension of 6.2 g (0.132 mol) of NaH in 50 cc of DMF. When the evolution of gas has ended, a solution of 36 g (0.127 mol) of 2-cyclopentyloxyethyl tosylate in 100 cc of DMF is then added. The mixture is stirred for half an hour. It is then heated for 2 hours at 55°-60° C. with stirring. The reaction mixture is poured into iced water. Extraction is carried out with diethyl ether. The ether phase is washed with dilute sodium hydroxide solution and then with water, dried and evaporated to dryness.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:8]=2[CH:26]=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][Mg]Br.[NH4+].[Cl-]>C1COCC1.C(OCC)C>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)(=[O:17])=[O:18])[C:8]=2[CH:26]([OH:27])[CH3:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(C=O)c(-c3ccccc3)c3ccccc32)cc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(C(C)O)c(-c3ccccc3)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-phenyl-1-(toluene-4-sulfonyl)-1H-indole-2-carbaldehyde (2.11 g, 5.62 mmol) in THF (30 mL) at −78° C. and under a nitrogen atmosphere, was added 3.0M methylmagnesium bromide in diethyl ether (2.6 mL). The mixture was stirred at 0° C. for 30 min then additional 3.0M methylmagnesium bromide in diethyl ether (0.3 mL) added. After 15 min, the reaction mixture was poured into a saturated solution of NH4Cl and extracted with EtOAc (×2). The combined organic fractions were washed with water, dried (Na2SO4) and concentrated in vacuo. The crude material was combined with a second portion of crude reaction mixture obtained following the same method (starting from 140 mg, 3.73 mmol of 3-phenyl-1-(toluene-4-sulfonyl)-1H-indole-2-carbaldehyde) and the combined batches were purified by column chromatography (Si—PCC, gradient 20-100% DCM in pentane) affording the title compound as a gum which solidified on standing (2.02 g, 86%). 1H NMR (CDCl3, 400 MHz): δ 8.07 (1H, d, J=8.35), 7.80-7.75 (2H, m), 7.51-7.38 (5H, m), 7.33-7.26 (2H, m), 7.20-7.14 (3H, m), 5.25-5.15 (1H, m), 4.06 (1H, d, J=11.01 Hz), 2.31 (3H, s), 1.70 (3H, d, J=6.88 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:7]=1[CH2:8]O.O=S(Cl)[Cl:19].C(N1C=CN=C1SC1C=NC=C(Cl)C=1CCl)CCC>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:7]=1[CH2:8][Cl:19]
Reactant: O=S(Cl)Cl
Reactant: OCc1c(Cl)cncc1Oc1ccccn1
Agent: CCCCn1ccnc1Sc1cncc(Cl)c1CCl
Product: ClCc1c(Cl)cncc1Oc1ccccn1

Procedure:
[3-Chloro-5-(pyridin-2-yloxy)-pyridin-4-yl]-methanol (4.24 mg, 0.018 mmol) was chlorinated with SOCl2 according to the synthesis of 3-(1-butyl-1H-imidazol-2-ylsulfanyl)-5-chloro-4-chloromethyl-pyridine to give the title compound. MS (m/z): 255.0 [M+H+].
Reaction SMILES: S([NH:11][C@H](C(O)=O)CC1N=CNC=1)(C1C=CC(C)=CC=1)(=O)=O.N[C@H:23]([C@@H:31]([OH:37])[CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[NH2:11][CH:24]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[CH2:23][C@@H:31]([OH:37])[CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35]
Reactant: CC(C)CC[C@H](O)[C@@H](N)CC1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]cn2)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)CC[C@H](O)CC(N)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.1 %

Procedure:
To a solution of Nα -t-butoxycarbonyl-Nα -methyl-Nim -tosyl-L-histidine (2.77 g) and 2(S)-amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (1.49 g) in dry methylene chloride (60 ml) which was cooled at 0° C., was added N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (1.25 g). The mixture was stirred at ambient temperature for 3 hours. After evaporation of the solvent, the residue was dissolved in ethyl acetate (200 ml) and the solution was washed with 0.5% hydrochloric acid, saturated sodium bicarbonate solution and water successively, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (1% methanol in chloroform as eluent) to give 2(S)-(Nα -t-butoxycarbonyl-Nα -methyl-Nim -tosyl-L-histidyl)amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (1.61 g) as an amorphous powder.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.ClCCl.CS(C)=O.[OH:14][CH2:15][C:16]1[N:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[CH:15]([C:16]1[N:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][CH:17]=1)=[O:14]
Reactant: COC(=O)c1cccc(CO)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)c1cccc(C=O)n1
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
To a solution of 2M oxalyl chloride/dichloromethane (236 mL, 462 mmol) in dichloromethane (800 mL) at −45° C. was slowly added dimethylsulfoxide (48.4 mL, 682 mmol) keeping temperature below −45° C. The mixture was stirred for 30 minutes at −45° C. after the addition, and a solution of the product of Example 50-1 (46 g, 276 mmol) in dichloromethane (160 mL) was added dropwise, stirred for 30 minutes at −45° C., treated with triethylamine (175 mL, 1256 mmol), stirred for 15 minutes at −45° C., removed dry ice bath, stirred at −40 to −50 C for 30 minutes, and quenched with pH 7 phosphate buffer solution (250 mL). The organic layer was separated and concentrated. This residue was heated to dissolve in ethyl acetate (100 mL), cooled to room temperature, stirred at room temperature for 1-2 hours and 1 hour at 0° C. The resulting precipitate was filtered and washed with cold ethyl acetate (100 mL) to give the title compound (30 g, 69%). 1H NMR (CDCl3) δ ppm 4.07 (s, 3 H), 8.05 (m, 1 H), 8.16 (m, 1 H), 8.36 (m, 1 H), 10.18 (d, 1 H).
Reaction SMILES: [SH:1][C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH3:14])[N:3]=1.C1COCC1.[OH-].[Na+].[F:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=2)=[O:28])=[CH:25][CH:24]=1>C(O)C.C(OCC)(=O)C>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH2:33][S:1][C:2]3[N:11]([CH3:12])[C:10](=[O:13])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][C:8]=4[CH3:14])[N:3]=3)=[CH:31][CH:30]=2)=[O:28])=[CH:37][CH:38]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Reactant: Cc1cccc2nc(S)n(C)c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(F)cc4)cc3)n(C)c(=O)c12
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 71.8 %

Procedure:
To a solution of 2-mercapto-3,5-dimethylquinazolin-4-one (0.492 g) as obtained in Reference Example 18-in ethanol (10.0 ml)-THF (10.0 ml) was added 1N-sodium hydroxide (2.50 ml). Then, 4-(4-fluorobenzoyl)benzyl bromide (0.700 g) was added and the mixture was stirred at 60° C. for 3.5 hours. This reaction mixture was diluted with ethyl acetate and washed with saturated aqueous NaCl solution and the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to provide the title compound as colorless needles (0.717 g, yield 72%). 1H-NMR (CDCl3) δ: 2.85(3H,s), 3.55(3H,s), 4.60(2H,s), 7.10-7.20(3H,m), 7.46-7.63(4H,m), 7.72-7.87(4H,m).
Reaction SMILES: [NH:1]1[CH:5]([C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])[CH2:4][CH2:3][C:2]1=[O:14].C(=O)([O-])[O-].[K+].[K+].[C:21](Cl)(=[O:25])[O:22][CH2:23][CH3:24]>C(#N)C>[CH2:23]([O:22][C:21]([N:11]1[CH2:10][CH2:9][N:8]([C:6]([CH:5]2[NH:1][C:2](=[O:14])[CH2:3][CH2:4]2)=[O:7])[CH2:13][CH2:12]1)=[O:25])[CH3:24]
Reactant: CCOC(=O)Cl
Reactant: O=C1CCC(C(=O)N2CCNCC2)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N1CCN(C(=O)C2CCC(=O)N2)CC1
Temperature: 0 °C
Yield: 84.3 %

Procedure:
A mixed solution of 2.1 g of 1-(2-pyrrolidone-5-carbonyl)piperazine, 2.5 g of anhydrous potassium carbonate and 120 ml of acetonitrile was cooled with ice water and 1.1 g of ethyl chlorocarbonate in 10 ml of acetonitrile was dropped therein with stirring. After dropping, the mixture was stirred overnight at room temperature. The solvent was evaporated from the reaction mixture in vacuo, methylene chloride was added to the residue, and insoluble matter was removed therefrom by filtration. The solvent was evaporated in vacuo from the filtrate to give 2.3 g of oily product. This was crystallized from ethyl acetate and further recrystallized to give 2.1 g of desired product, m.p. 147°-148.5° C.
Reaction SMILES: C1COCC1.Br[C:7]1[C:8]2[C:33]([CH3:40])([C:34]3[O:35][C:36]([CH3:39])=[N:37][N:38]=3)[C:32](=[O:41])[NH:31][C:9]=2[N:10]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH2:22][CH2:23][C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[N:14]=2)[N:12]=1.[CH3:42][NH2:43]>CO>[CH3:40][C:33]1([C:34]2[O:35][C:36]([CH3:39])=[N:37][N:38]=2)[C:8]2[C:7]([NH:43][CH3:42])=[N:12][C:11]([C:13]3[C:21]4[C:16](=[N:17][CH:18]=[CH:19][CH:20]=4)[N:15]([CH2:22][CH2:23][C:24]([F:29])([F:30])[C:25]([F:26])([F:28])[F:27])[N:14]=3)=[N:10][C:9]=2[NH:31][C:32]1=[O:41]
Reactant: Cc1nnc(C2(C)C(=O)Nc3nc(-c4nn(CCC(F)(F)C(F)(F)F)c5ncccc45)nc(Br)c32)o1
Reactant: CN
Solvent: CO
Solvent: C1CCOC1
Product: CNc1nc(-c2nn(CCC(F)(F)C(F)(F)F)c3ncccc23)nc2c1C(C)(c1nnc(C)o1)C(=O)N2

Procedure:
To a THF solution (9 mL) of the intermediate from Step A above (116 mg, 0.202 mmol) was added a 2 M methanol solution of methylamine (0.809 mL, 1.619 mmol) and the resultant mixture heated at 140° C. under microwave irradiation for 1 hour. Purification by silica gel column chromatography using DCM/MeOH (with 0.5% NH4OH) gradient provided the title compound. Chiral separation using SFC on a Chiralcel OD column provided both enantiomers of the title compound. 1H NMR (500 MHz, DMSO-d6): δ 11.52 (1H, s), 8.90-8.86 (1H, m), 8.66-8.64 (1H, m), 7.42 (1H, dd, J=8.08, 4.49 Hz), 6.77 (1H, d, J=5.11 Hz), 4.90 (2H, t, J=6.81 Hz), 3.05-2.92 (5H, m), 1.86 (3H, s). 1H NMR δ (ppm) (DMSO-d6 with added D2O): 8.86 (1H, d, J=8.14 Hz), 8.60 (1H, d, J=4.35 Hz), 7.40 (1H, dd, J=8.09, 4.54 Hz), 4.88 (2H, t, J=6.46 Hz), 2.99-2.85 (5H, m), 2.45 (3H, s), 1.81 (3H, s). m/z=524.1 (M+H).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([OH:14])=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH:2]=[CH:3][CH3:4].[CH2:16](Br)[CH3:17].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(C)=O.O>[CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:14][CH2:16][CH3:17])=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCC1Cc2ccc(O)cc2C1=O
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC=CCC1Cc2ccc(OCC)cc2C1=O
Yield: 98 %

Procedure:
A solution of 5.0 g of (RS)-2-(2-buten-1-yl)-6-hydroxy-1-indanone, 4.1 ml of ethyl bromide, 6.83 g of potassium carbonate and 10 ml of N,N-dimethyl-formamide in 70 ml of acetone was heated to 35° for 35 hours. After cooling, the solution was poured into 100 ml of water and extracted twice with 100 ml of ethyl acetate each time. The combined organic phases were washed once with 70 ml of water and once with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. 5.6 g (98%) of (RS)-2-(2-buten-1-yl)-6-ethoxy-1-indanone were obtained as a red-brown oil which was used directly in the next reaction.
Reaction SMILES: [CH3:1][C:2]1[S:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1F>>[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:11][CH:10]1[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]2[S:13][C:2]([CH3:1])=[CH:3][C:4]1=2
Reactant: Fc1ccccc1Br
Reactant: Cc1cc2c(s1)CN(C)CCC2O
Product: Cc1cc2c(s1)CN(C)CCC2Oc1ccccc1Br

Procedure:
The same method as in Example 1 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepin-4-ol (Reference Example 23) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2-bromo-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][C:10]1=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[Cl:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([S:33](Cl)(=[O:35])=[O:34])[CH:27]=[CH:26]2>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][N:9]1[CH2:14][CH2:13][N:12]([S:33]([C:28]2[CH:27]=[CH:26][C:25]3[C:30](=[CH:31][CH:32]=[C:23]([Cl:22])[CH:24]=3)[CH:29]=2)(=[O:34])=[O:35])[CH2:11][C:10]1=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NN1CCNCC1=O
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NN1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The resultant solution of 1-(tert-butoxycarbonylamino)-2-piperazinone in ethyl acetate (20 ml) and a 10% aqueous solution of sodium carbonate (20 ml) was treated at 0° C. with 6-chloronaphthalene-2-sulfonyl chloride (1.36 g) and stirred at room temperature for 30 minutes. The organic phase was separated, washed with brine, dried and concentrated. The residue thus obtained was purified by a column chromatography on a silica gel (hexane:ethyl acetate=1:2) to obtain 1-(tert-butoxycarbonylamino)-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (848 mg) as a colorless amorphous solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C(#N)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:14]2[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Yield: 54.1 %

Procedure:
A mixture of 2-bromo-5-nitropyridine (5.0 g, 24.6 mmol), tert-butyl piperazine-1-carboxylate (13.8 g, 74.2 mmol), acetonitrile (150 mL) was stirred at reflux for 2.5 h. After the reaction was completed, the solvent was removed under reduced pressure to afford 197a as a yellow solid (4.1 g, 54%). MS-ESI: [M+H]+ 309.