Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:9]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[C:17]([O:23]C)[CH:16]=1)[CH2:10][CH2:11][CH3:12])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>Br>[CH2:1]([N:9]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([OH:23])[CH:16]=1)[CH2:10][CH2:11][CH3:12])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCN(CCc1ccccc1)CCc1ccc(OC)c(OC)c1
Agent: Br
Product: CCCN(CCc1ccccc1)CCc1ccc(O)c(O)c1
Yield: 94.5 %

Procedure:
A solution of 9.37 g of the product of Step B in 90 ml of 48% hydrobromic acid was refluxed for 3 hours under a nitrogen atmosphere and was then evaporated to dryness. The residue was taken up in 50 ml of ammonium hydroxide solution and the solution was extracted with methylene chloride. The organic extracts were washed with water, dried over magnesium sulfate, filtered and evaporated to dryness to obtain 8.1 g of N-phenethyl-N-propyl-3,4-dihydroxyphenethylamine in the form of a reddish oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][C:6]=2[CH:13]=1.S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH2:19][CH3:20])=[O:11])=[CH:7][C:6]=2[CH:13]=1
Reactant: O=C(O)c1cc2cc(Br)ccc2o1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc2cc(Br)ccc2o1
Reaction time: 2 h
Yield: 93 %

Procedure:
A solution of 5-bromo-2-benzofurancarboxylic acid (5.01 g, 20.8 mmol) in absolute ethanol (150 ml) was added with concentrated sulfuric acid (15 ml) and the mixture was refluxed under stirring for 2 h. After this time, the volatiles were evaporated off under reduced pressure and the resulting residue was neutralized with a sodium bicarbonate saturated solution and extracted with ethyl ether (4×100 ml). The mixture was dried and the solvent was evaporated off under reduced pressure, to obtain 5.19 g of the title compound as a white solid with melting point 58-60° C. (93% yield).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[C:13]1([C:19](=O)[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][N:10]=[C:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]
Reactant: NNc1ccccc1C(F)(F)F
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Product: O=C(C(=NNc1ccccc1C(F)(F)F)c1ccccc1)c1ccccc1

Procedure:
1,2-Diphenylethane-1,2-dione [2-(trifluoromethyl)phenyl]hydrazone was prepared from 2-trifluoromethylphenyl hydrazine and 1,2-diphenyl-ethane-1,2-dione according to the procedure of Step 1 Example 2. MS (ESI) m/z 369; MS (ESI) m/z 367;
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F

Procedure:
Compound M1 was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (J5) (262 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (K1) (223 mg, 0.75 mmol) according to the general procedure M.
Reaction SMILES: [NH2:1][OH:2].C([O:5][C:6](=O)[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17](=[O:37])[C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)C>CO>[OH:2][NH:1][C:6]([CH:7]=[CH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH:16][C:17](=[O:37])[C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)=[CH:13][CH:14]=1)=[O:5]
Reactant: NO
Reactant: CCOC(=O)C=Cc1ccc(CNC(=O)c2ccc(N3CCN(Cc4cccnc4)CC3)cc2)cc1
Solvent: CO
Product: O=C(C=Cc1ccc(CNC(=O)c2ccc(N3CCN(Cc4cccnc4)CC3)cc2)cc1)NO
Temperature: 25 °C
Reaction time: 24 h
Yield: 46 %

Procedure:
To a solution of 1.76 M NH2OH in MeOH (1.23 mL) was added the compound (150 mg, 0.31 mmol) from the process (1-2), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated, and the residue was dissolved in 1 N HCl aqueous solution (pH 5). The solid precipitated was collected by filtration, dried under vacuum, and crystallized from MeOH/CH2Cl2/ether to afford the titled compound (67 mg, 46%) as a pale brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1.CC(C1C=CC(Br)=CC=1)=O.BrC1C=CC([C@H](O)C)=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(O)c1ccc(Br)cc1
Agent: CC(=O)c1ccc(Br)cc1
Agent: C[C@@H](O)c1ccc(Br)cc1
Product: C[C@H](O)c1ccc(Br)cc1
Reaction time: 192 h
Yield: 57 %

Procedure:
As shown here, the biochemical conversion reaction of immobilized green pea protein for the substrate (±)-1-(4-bromophenyl)ethanol (200 mg) requires 8 days by going through bioconversion to 4-bromoacetophenone accompanying sterically selective oxidation of (R)-1-(4-bromophenyl)ethanol to obtain 114 mg of (S)-1-(4-bromophenyl)ethanol at a yield of 57%. Optical purity was obtained at 88% e.e. The reaction course and time at completion of reaction were determined by GC using the Hitachi Model G-3500 gas chromatograph under conditions consisting of carrier gas: He at 0.48 ml/min, split ratio: 1/55, oven temperature: 150° C., inlet temperature: 250° C., outlet temperature: 250° C., pressure: 136, flow rate value: 42, analytical column: TC-5HT 0.25 mm I.D.×30M df (GL Science).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:16][C:17]#[N:18])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[Ni].N>[NH2:18][CH2:17][CH2:16][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:2]([CH:3]=1)[NH2:1]
Reactant: N#CCc1ccc(OCc2ccccc2)c(N)c1
Agent: [Ni]
Agent: N
Product: NCCc1ccc(OCc2ccccc2)c(N)c1
Yield: 70.6 %

Procedure:
In the presence of Raney nickel, 9.5 g of (3-amino-4-benzyloxyphenyl)acetonitrile is hydrogenated in 60 ml of ammonia-saturated methanol at 100° C. and under a pressure of 5,000 kPa. The hydrogenation product is chromatographed on silica gel with methylene chloride/methanol (7:3), thus obtaining 6.82 g of 5-(2-aminoethyl)-2-benzyloxyaniline as an oil, converted by treatment with 2N HCl in methanol and evaporation into the hydrochloride.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)=[CH:2][CH3:3].Cl.C1(S([O-])=O)C=CC=CC=1.[Na+].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH:1](/[C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:11][CH2:12][C@H:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=3)[CH2:14][CH2:15]2)[CH2:6][CH2:5]1)=[CH:2]\[CH3:3]
Reactant: CC=C[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(F)c(F)c3)CC2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: O=S([O-])c1ccccc1
Solvent: Cc1ccccc1
Product: C/C=C/[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(F)c(F)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.303 g of the obtained 1-[trans-4-(trans-4-propenylcyclohexyl)cyclohexyl]-3, 4-difluorobenzene, 5 ml of toluene, 0.31 ml of 3N hydrochloric acid and 45 mg of sodium benzenesulfinate was stirred at 60°-65° C. for 3 hours. Subsequently, the reaction mixture was cooled to room temperature, poured on to 20 ml of 10% sodium hydrogencarbonate solution, and extracted with diethyl ether. The organic phases were washed with water, dried over sodium sulfate, and concentrated. Chromatographic purification of the crude product (0.314 g with an E/Z ratio of 83:16) with hexane/ethyl acetate (vol. 98:2) on silica gel treated with silver nitrate, and subsequent recrystallization from diethyl ether/methanol yielded 0.126 g of 1-[trans-4-(trans-4-(1E-propenyl)cyclohexyl]-cyclohexyl]-3,4-difluorbenzene as colorless crystals with m.p. (C-S ) 49.0° C., S -N 65.6° C., cl.p. (N-I) 159.7° C.; Δε (149° C)=3.22.
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=O)[C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[CH3:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[NH:43]N>>[CH3:1][CH:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:39]4[C:38](=[C:37]([CH3:36])[CH:42]=[CH:41][CH:40]=4)[NH:43][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: Cc1ccccc1NN
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(C(F)(F)F)cc3)CC2)c1
Agent: Cl
Product: Cc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3ccc(C(F)(F)F)cc3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-[3-(1-{5-oxo-5-[4-(trifluoromethyl)phenyl]pentyl}-4-piperidinyl)phenyl]propanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 562.2(M+H)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([Br:7])[N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCCC1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CCOC(C)=O.O>[Br:7][C:5]1[N:6]=[C:2]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[S:3][C:4]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1sc(Br)nc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(N2CCOCC2)nc1Br
Temperature: 90 °C
Reaction time: 4 h
Yield: 81.1 %

Procedure:
In a sealable reaction vessel, to a suspension of ethyl 2,4-dibromo-1,3-thiazole-5-carboxylate (2.90 g, 9.21 mmol, prepared as in WO 2005026149) and cesium carbonate (9.00 g, 27.6 mmol) in tetrahydrofuran (24.3 mL, 299 mmol) was added morpholine (0.883 mL, 10.1 mmol), at which point the vessel was sealed and the mixture was heated with stirring at 90° C. for 4 hours. Reaction mixture was diluted with EtOAc and water and transferred to a separatory funnel. Layers were separated, and the organic layer was washed with water, dried over Na2SO4, filtered, and concentrated in vacuo. Residue was subjected to column chromatography (gradient elution, 0 to 50% EA in hexanes) to afford ethyl 4-bromo-2-morpholin-4-yl-1,3-thiazole-5-carboxylate (2.4 g, yield 81%) as a white solid. LC/MS: (FA) ES+ 321, 323; 1H NMR (300 MHz, CDCl3) δ 4.30 (dd, J=7.1, 7.1, 2H), 3.82-3.75 (m, 4H), 3.58-3.50 (m, 4H), 1.34 (dd, J=7.1, 7.1, 3H).
Reaction SMILES: C[NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][C:4]=1[CH2:18][C:19]([O:21][CH3:22])=[O:20].[Br:23][C:24]1[CH:25]=[C:26]2[CH2:38][CH2:37][C@@H:36]([CH2:39][C:40]([OH:42])=O)[N:28]3[C:29](=[O:35])[C:30](=[O:34])[NH:31][C:32]([CH:33]=1)=[C:27]23>>[Br:23][C:24]1[CH:25]=[C:26]2[CH2:38][CH2:37][C@@H:36]([CH2:39][C:40](=[O:42])[NH:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][C:4]=3[CH2:18][C:19]([O:21][CH3:22])=[O:20])[N:28]3[C:29](=[O:35])[C:30](=[O:34])[NH:31][C:32]([CH:33]=1)=[C:27]23
Reactant: CNc1ccc(CNC(=O)OC(C)(C)C)cc1CC(=O)OC
Reactant: O=C(O)C[C@@H]1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: COC(=O)Cc1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 60.8 %

Procedure:
A procedure similar to that described in Example 9-7) was performed with methyl 4-tert-butoxycarbonylaminomethyl-2-methoxycarbonylmethylaniline (7.63 g, 22.51 mmol) and (S)-9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (6.03 g, 21.43 mmol) to give 8.02 g of the title compound (61%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=CC=1.[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20]CC)=[O:19])[CH2:14][CH2:13]1.C1(=O)CCCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C1COCC1.CCO.C(O)(=O)C>[CH:4]1([N:12]2[CH2:13][CH2:14][CH:15]([C:18]([OH:20])=[O:19])[CH2:16][CH2:17]2)[CH2:5][CH2:6][CH2:1][CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(=O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1CCN(C2CCCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Catalytic quantities of p-toluenesulphonic acid (750 mg) and 12.5 ml of glacial acetic acid are added to a solution of ethyl piperidine-4-carboxylate (22.9 g, 145 mmol) and cyclopentanone (13.5 g, 160 mmol) in 400 ml of THF. After stirring at RT for 30 min, sodium triacetoxyborohydride (42 g, 190 mmol) is added in portions. The reaction mixture is stirred at RT for 15 h and, after evaporating, the residue is extracted by shaking with sodium carbonate solution and dichloromethane. The organic phase is dried, filtered and evaporated. Yield: 32 g of ethyl 1-cyclopentylpiperidine-4-carboxylate. The intermediate compound (1 g, 4.4 mmol) is then hydrolysed, in 10 ml of EtOH, at 80° C. for 15 h with 10 ml of NaOH (5 N). After having been cooled down, the reaction mixture is acidified and the resulting precipitate is filtered off.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][C:7]([C:10]2([OH:17])[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:8][N:9]=1)[CH3:3].[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[CH3:1][N:2]([CH2:4][C:5]1[S:6][C:7]([C:10]2([OH:17])[CH2:15][CH2:14][CH:13]([N:18]3[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=4)=[O:24])[CH2:19]3)[CH2:12][CH2:11]2)=[CH:8][N:9]=1)[CH3:3]
Reactant: CN(C)Cc1ncc(C2(O)CCC(=O)CC2)s1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: CN(C)Cc1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-(2-dimethylaminomethyl-thiazol-5-yl)-4-hydroxy-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]2[CH2:11][CH:12]([CH2:14]OS(C3C=CC(C)=CC=3)(=O)=O)[O:13][C:9]=2[CH:8]=[C:7]([C:26](=[O:34])[NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH3:33])[N:29]=2)[CH:6]=1)([CH3:3])[CH3:2].Cl.[CH3:36][NH:37][CH3:38].C(N(CC)CC)C>C1COCC1>[CH3:33][N:30]1[CH:31]=[CH:32][C:28]([NH:27][C:26]([C:7]2[CH:6]=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[C:10]3[CH2:11][CH:12]([CH2:14][N:37]([CH3:38])[CH3:36])[O:13][C:9]=3[CH:8]=2)=[O:34])=[N:29]1
Reactant: CNC
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(OC(C)C)cc(C(=O)Nc4ccn(C)n4)cc3O2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)Oc1cc(C(=O)Nc2ccn(C)n2)cc2c1CC(CN(C)C)O2
Temperature: 50 °C
Yield: 9.8 %

Procedure:
To a solution of toluene-4-sulfonic acid 4-isopropoxy-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-2-ylmethyl ester (216a) (84 mg, 0.17 mmol) in THF (2 mL) was added dimethyl amine hydrochloride (190 mg) and triethylamine (0.4 mL). The mixture was heated at 50° C. for 2 days, then concentrated, and purified by reverse phase HPLC to give a white solid (6 mg, 10% yield). 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 1 H) 7.25-7.32 (m, 1 H) 7.04 (s, 1 H) 6.90 (d, J=1.01 Hz, 1 H) 6.84 (d, J=2.27 Hz, 1 H) 5.03-5.14 (m, 1 H) 4.61-4.71 (m, 1 H) 3.81 (s, 3 H) 3.29 (dd, J=16.42, 9.35 Hz, 1 H) 2.75-2.92 (m, 2 H) 2.60-2.70 (m, 1 H) 2.47 (s, 6 H) 1.34 (d, J=6.06 Hz, 6 H); LCMS for C19H26N4O3 m/z 359.20 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:21]=[C:20]([O:22]CC3C=CC=CC=3)[C:13]3[CH2:14][CH:15]([CH2:17][O:18][CH3:19])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1>CCOC(C)=O.[Pd]>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:21]=[C:20]([OH:22])[C:13]3[CH2:14][CH:15]([CH2:17][O:18][CH3:19])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1
Reactant: COCC1Cc2c(OCc3ccccc3)cc(C(=O)Nc3ccn(C)n3)cc2O1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCC1Cc2c(O)cc(C(=O)Nc3ccn(C)n3)cc2O1
Reaction time: 8 h
Yield: 102.8 %

Procedure:
10% Pd on Carbon (100 mg) was added to a solution of 4-benzyloxy-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (204c) (640 mg, 1.63 mmol) in EtOAc (15 mL). The reaction mixture was stirred under H2 balloon overnight. The mixture was filtered through Celite, washed with EtOAc and concentrated to give a white solid (508 mg, 100% yield). 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1 H) 7.96 (s, 1 H) 7.28 (d, J=2.27 Hz, 1 H) 6.98 (s, 1 H) 6.82 (s, 1 H) 6.78 (d, J=2.27 Hz, 1 H) 4.98-5.07 (m, 1 H) 3.76 (s, 3 H) 3.56-3.65 (m, 2 H) 3.44 (s, 3 H) 3.25 (dd, J=15.92, 9.60 Hz, 1 H) 2.97 (dd, J=16.04, 7.20 Hz, 1 H); LCMS for C15H17N3O4 m/z 304.00 (M+H)+.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH2:31][C@@H:30]([CH3:32])[N:12]2[C:13]3[CH:14]=[CH:15][C:16]([O:20][CH:21]4[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]4)=[CH:17][C:18]=3[CH:19]=[C:11]2[C:10]1=[O:33])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>ClCCl>[OH:6][CH2:7][CH2:8][N:9]1[CH2:31][C@@H:30]([CH3:32])[N:12]2[C:13]3[CH:14]=[CH:15][C:16]([O:20][CH:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:25][CH2:26]4)=[CH:17][C:18]=3[CH:19]=[C:11]2[C:10]1=[O:33]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CN(CCO[Si](C)(C)C(C)(C)C)C2=O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CN(CCO)C2=O)CC1
Reaction time: 1 h
Yield: 86 %

Procedure:
To the solution of 0.14 g (0.28 mmol) (R)-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 98 μL (0.89 g, 0.34 mmol) tetra-n-butylammonium fluoride solution (1M in tetrahydrofuran) was added. After 1 h, the reaction was diluted with dichloromethane and was poured on 1M aqueous sodium hydroxide solution. The organic phase was separated, washed with brine and dried over magnesium sulfate. After filtration the volatile components were removed at a rotary evaporator to give the desired product as a colorless oil (86%).
Reaction SMILES: Cl[CH2:2][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH3:10])[C:5](=[O:11])[C:4]1=[O:12].[C:13]([O-:16])(=[S:15])[CH3:14].[K+]>>[C:13]([S:15][CH2:2][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH3:10])[C:5](=[O:11])[C:4]1=[O:12])(=[O:16])[CH3:14]
Reactant: CC([O-])=S
Reactant: CCN1CCN(CCl)C(=O)C1=O
Agent: [K+]
Product: CCN1CCN(CSC(C)=O)C(=O)C1=O
Temperature: 0 °C
Yield: 44 %

Procedure:
To a solution of crude 1-(chloromethyl)-4-ethyl-piperazine-2,3-dione (170 mg, 0.9 mmol) in CDCl3 (1 ml) solid potassium thioacetate (123 mg, 1.08 mmol) was added with stirring at 0° C. The reaction mixxture was allowed to stir at room temperature overnight. The mixture was centifuged and the supernatant solution collected. The residual solid (KCl) was washed with CDCl3 (2 ml) and the organic solutions combined and the solvent removed in vacuo. The residue was chromatographed on silica gel (6 g, 63-200 μm) using chloroform-methanol (19:1) to give 1-(acetylthiomethyl)-4- ethyl-piperazine-2,3-dione as a white solid (overall yield 44%). NMR-specrum in CDCl3: 1.22 (t, 3H, J=7 Hz), 2.44 (s, 3H), 3.48 (q, 2H, J=7 Hz), 3.4-3.7 (m, 4H), 4.95 (s, 2H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[Li]CCCC.[O:14]1[CH2:17][C:16](=[O:18])[CH2:15]1>CCCCC.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2([OH:18])[CH2:17][O:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: O=C1COC1
Reactant: Brc1ccc(I)cc1
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: OC1(c2ccc(Br)cc2)COC1
Reaction time: 1 h
Yield: 63.2 %

Procedure:
1-Bromo-4-iodobenzene (0.65 g, 2.3 mmol, Lancaster) was stirred in pentane (7 mL) and then n-BuLi (1.6 M in hexane, 1.4 mL, 2.3 mmol) was added dropwise at rt. The mixture was and the stirred for 1 h. A white precipitate formed and the precipitate was allowed to settled. The pentane was removed by pipette. The mixture was diluted with pentane (7 mL) back up to the original volume. The mixture was then added to a solution of 3-oxetanone (0.315 g, 4.37 mmol) in THF (7 mL) that was cooled in an ice bath. The mixture was then allowed to come to rt and stirred for about 2 h. The mixture was quenched by the addition of saturated NH4Cl (10 mL) and allowed to stir overnight. EtOAc (15 mL) was added and the layers separated. The aqueous layer was then extracted with EtOAc (5 mL). The combined organic layers were washed with brine (5 mL), dried over MgSO4, filtered, and concentrated in vacuo. The solid was purified by flash column chromatography (40 g Silicycle™ column) eluting with 20-50% EtOAc/heptane. The solid was recrystallized by dissolving in a mixture of heptane and DCM and concentrating under reduced pressure until a precipitate had formed. The solid was collected by filtration and washed with heptane (10 mL) to provide 3-(4-bromophenyl)oxetan-3-ol (0.333 g, 63%): 1H NMR (400 MHz, DMSO) δ 7.65-7.43 (m, 4H), 6.42 (s, 1H), 4.68 (dd, J=50.6, 6.8, 4H).
Reaction SMILES: Br.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][CH:17]=1)[C:10]1[N:11]=[C:12]([NH2:14])[S:13][C:9]=1[CH2:8][CH2:7]2.[Br:18][C:19]1[CH:23]=[C:22]([Cl:24])[S:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26]>>[Br:18][C:19]1[CH:23]=[C:22]([Cl:24])[S:21][C:20]=1[S:25]([NH:14][C:12]1[S:13][C:9]2[CH2:8][CH2:7][C:6]3[C:15](=[CH:16][CH:17]=[C:4]([O:3][CH3:2])[CH:5]=3)[C:10]=2[N:11]=1)(=[O:27])=[O:26]
Reactant: COc1ccc2c(c1)CCc1sc(N)nc1-2
Reactant: O=S(=O)(Cl)c1sc(Cl)cc1Br
Agent: Br
Product: COc1ccc2c(c1)CCc1sc(NS(=O)(=O)c3sc(Cl)cc3Br)nc1-2

Procedure:
The title compound was prepared 7-methoxy-4,5-dihydronaphtho(1,2-D)(1,3)thiazol-2-amine hydrobromide (85 mg) and 3-bromo-5-chlorothiophene-2-sulfonyl chloride (80 mg) as described in the synthetic METHOD B to give a white solid (17.8 mg) with purity >80%: MS (pos) m/z 491.3, 493.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][CH2:20][C:21]([OH:23])=O)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][CH2:20][C:21]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:23])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccccc2CCC(=O)O)=C(C)C1=O
Reactant: C1COCCN1
Product: COC1=C(OC)C(=O)C(Cc2ccccc2CCC(=O)N2CCOCC2)=C(C)C1=O
Yield: 34.3 %

Procedure:
3-(2-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (25 mg, 0.070 mmol) obtained in Example 69 and morpholine (0.009 ml, 0.11 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (10 mg, 0.024 mmol, yield 34%).