Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]([F:43])([F:42])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[S:35][CH:36]=[C:37]([C:39](O)=[O:40])[N:38]=1>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:39]([C:37]2[N:38]=[C:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[C:27]([F:43])([F:26])[F:42])[S:35][CH:36]=2)=[O:40])[CH2:6][CH2:7]1
Reactant: O=C(O)c1csc(-c2ccccc2C(F)(F)F)n1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2csc(-c3ccccc3C(F)(F)F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 2-(2-(trifluoromethyl)phenyl)thiazole-4-carboxylic acid (Intermediate 124) gave 311. 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.58 (s, 1H), 7.97-7.93 (m, 1H), 7.89-7.75 (m, 4H), 4.78 (dd, J=10.9, 3.7 Hz, 1H), 4.37-4.19 (m, 1H), 4.14-4.02 (m, 1H), 4.02-3.84 (m, 1H), 3.78 (s, 3H), 3.20-3.08 (m, 1H), 2.08-1.99 (m, 1H), 1.88-1.76 (m, 1H), 1.71-1.59 (m, 3H). LCMS (ES+) m/z 484 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>CCO>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCCN(CCCNCc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCCN(CCCNCc1ccc(N)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
A mixture of the compound obtained in step d) (0.183 g, 0.382 mmol) in EtOH (20 cm3) and of FeO(OH) as catalyst (20 mg) was heated to 60° C. under N2 atmosphere. Then hydrazine hydrate (19.5 mg, 0.60 mmol) was added and the resulting mixture was stirred 18 h at RT. After filtration through celite the solvent was removed at the rotary evaporator to yield a yellow oil which was dried under reduced pressure. (0.112 g, 0.248 mmol, yield 65.0%).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.C(O)(=O)C.[NH3:21]>>[Cl:11][C:9]1[CH:10]=[C:2]([NH2:21])[C:3](=[CH:7][C:8]=1[S:12]([CH3:15])(=[O:14])=[O:13])[C:4]([OH:6])=[O:5]
Reactant: N
Reactant: CS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1Cl
Agent: Cl
Solvent: CC(=O)O
Product: CS(=O)(=O)c1cc(C(=O)O)c(N)cc1Cl
Temperature: 0 °C
Yield: 64 %

Procedure:
A solution of 2,4-dichloro-5-methylsulfonylbenzoic acid (Example 1, Step B) (60 g.; 0.267 mole) in aqueous ammonia (28%, 900 ml.) is heated in an autoclave at 180° C. for 12 hours. The cooled reaction mixture is poured into ice (3 kg.) and concentrated hydrochloric acid (1.3 liters) which causes the product to precipitate 42 g. (64% yield) of 4-chloro-5-methylsulfonylanthranilic acid, m.p. 286.5°-288.5° C. after recrystallization from acetic acid.
Reaction SMILES: [CH2:1]([S:13][C:14]1[N:15]=[N:16][N:17]([CH:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]([OH:22])=O)[N:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1N=NN(CC(O)=O)N=1)CCCCCCCCC.[CH3:48][O:49][C:50]1[CH:56]=[C:55]([O:57][CH3:58])[CH:54]=[C:53]([O:59][CH3:60])[C:51]=1[NH2:52].C(C1C=CC=C(C(C)C)C=1N)(C)C>>[CH2:1]([S:13][C:14]1[N:15]=[N:16][N:17]([CH:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]([NH:52][C:51]2[C:53]([O:59][CH3:60])=[CH:54][C:55]([O:57][CH3:58])=[CH:56][C:50]=2[O:49][CH3:48])=[O:22])[N:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: COc1cc(OC)c(N)c(OC)c1
Reactant: CCCCCCCCCCCCSc1nnn(C(C(=O)O)c2ccccc2)n1
Agent: CC(C)c1cccc(C(C)C)c1N
Agent: CCCCCCCCCCc1nnn(CC(=O)O)n1
Product: CCCCCCCCCCCCSc1nnn(C(C(=O)Nc2c(OC)cc(OC)cc2OC)c2ccccc2)n1

Procedure:
When in the general procedure of Example 88 an appropriate amount of (±)-5-(dodecylthio)-α-phenyl-2H-tetrazole-2-acetic acid was substituted for 5-decyl-2H-tetrazole-2-acetic acid and 2,4,6-trimethoxyaniline was substituted for 2,6-diisopropylaniline, the title compound was obtained, mp 141°-143° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Tl+3].[Br:23]Br>C(O)(=O)C>[Br:23][C:7]1[C:6]([CH3:8])=[CH:5][N+:4]([O-:9])=[CH:3][C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1cc(C)c[n+]([O-])c1
Agent: CC(=O)[O-]
Agent: [Tl+3]
Solvent: CC(=O)O
Product: Cc1c[n+]([O-])cc(C)c1Br
Temperature: 60 °C
Yield: 53.5 %

Procedure:
To a solution of 3,5-dimethylpyridine 1-oxide (6.1 g, 50 mmol) in acetic acid (30 mL) was added thallium(III) triacetate (5.0 g, 13 mmol) and bromine (2.6 mL, 50 mmol). The resulting solution was heated at 60° C. overnight. The reaction was concentrated in vacuo, diluted with water and ethyl acetate. The organic layer was concentrated and residue was purified by silica gel chromatography to afford the desired product (5.40 g, 54%). 1H NMR (400 MHz, CDCl3): δ 7.96 (s, 2 H), 2.38 (s, 6 H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH:22]=[CH:23]N(C)C)=[CH:17][C:16]=1[N:28]([CH3:32])[C:29](=[O:31])[CH3:30].C(OCC)(=O)C>C(O)(=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:23][CH:22]=2)=[CH:17][C:16]=1[N:28]([CH3:32])[C:29](=[O:31])[CH3:30]
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Reactant: CC(=O)N(C)c1cc(C(=O)C=CN(C)C)ccc1Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N(C)c1cc(-c2ccnc3c(C(=O)c4cccs4)cnn23)ccc1Cl
Yield: 78.7 %

Procedure:
A mixture of 0.083 g (0.43 mmol) of (5-amino-1H-pyrazol-4-yl)-thiophene-2-yl-methanone and 0.12 g (0.43 mmol) of N-[2-chloro-5-(3-dimethylamino-acryloyl)-phenyl]-N-methyl-acetamide in 12 ml of glacial acetic acid was refluxed for 1.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 ml of dichloromethane and 10 ml of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 139 mg of N-{2-chloro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide as a solid (yield 79%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:14][N:15]=2)=[O:9])[N:6]=1.[CH2:19]([C:21](I)(CC)[C:22]([O-])=[O:23])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH:16]([C:13]1[S:12][C:11]([NH:10][C:8](=[O:9])[CH2:7][C:5]2[N:6]=[C:2]([N:1]3[CH2:20][CH2:19][CH2:21][C:22]3=[O:23])[S:3][CH:4]=2)=[N:15][CH:14]=1)([CH3:18])[CH3:17]
Reactant: CC(C)c1cnc(NC(=O)Cc2csc(N)n2)s1
Reactant: CCC(I)(CC)C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)c1cnc(NC(=O)Cc2csc(N3CCCC3=O)n2)s1
Yield: 30 %

Procedure:
A mixture of 2.8 g (0.01 mol) of 2-(2-amino-1,3-thiazol-4-yl)-N-(5-isopropyl-1,3-thiazol-2-yl)acetamide, 4.84 g (0.02 mol) of ethyl-iodobutyrate and 2.76 g (0.02 mol) of potassium carbonate in 50 ml of absolute ethanol was stirred under reflux for 5 hours. The mixture was cooled and filtered, and the salts were washed with two 20 ml portions of ethanol. The ethanol was removed at reduced pressure and the residue was dissolved in 100 ml of CH2Cl2. The solution was washed with 30 ml of water, dried, and the solvent was evaporated. The residue was purified by chromatography on silica gel, using CH2Cl2:MeOH 95:5 as eluent, to give the title compound in 30% yield (1.05 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10].[CH:21]([S:23]([C:26]1[CH:27]=[CH:28][C:29]([O:36][CH3:37])=[C:30]([S:32](Cl)(=[O:34])=[O:33])[CH:31]=1)(=[O:25])=[O:24])=[CH2:22]>C(Cl)Cl.N1C=CC=CC=1>[CH:21]([S:23]([C:26]1[CH:27]=[CH:28][C:29]([O:36][CH3:37])=[C:30]([S:32]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH:13]=2)(=[O:11])=[O:10])(=[O:33])=[O:34])[CH:31]=1)(=[O:24])=[O:25])=[CH2:22]
Reactant: C=CS(=O)(=O)c1ccc(OC)c(S(=O)(=O)Cl)c1
Reactant: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CS(=O)(=O)c1ccc(OC)c(S(=O)(=O)Nc2ccccc2NS(=O)(=O)c2cc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid (2-aminophenyl)-amide (10 mmol, prepared as in Example 1) in DCM (20 mL) and pyridine (20 mL), 5-ethenesulfonyl-2-methoxybenzenesulfonyl chloride (11 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (100 mL). The organic phase was washed with 10% aqueous HCl (100 mL), water (100 mL) and brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to obtain benzo[b]thiophene-2-sulfonic acid [2-(5-ethenesulfonyl-2-methoxybenzenesulfonylamino)phenyl] amide (2.8 g). LC: Tr 1.15 min; MS: 565.9 (M+1)+. 1H NMR (CDCl3, 400 MHz): δ 4.17 (s, 3H), 6.03 (d, 1H), 6.42 (d, 1H), 6.56 (dd, 1H), 6.81 (dd, 1H), 6.97 (t, 1H), 7.13 (t, 1H), 7.18 (d, 1H), 7.32 (d, 1H), 7.42-7.52 (m, 2H), 7.62 (s, 1H), 7.80 (d, 1H), 7.83 (d, 1H), 8.04 (dd, 1H), 8.19 (d, 1H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][NH2:13])=[CH:7][CH:6]=2.Br[C:15]1[C:16]([NH2:22])=[N:17][CH:18]=[C:19]([Br:21])[N:20]=1.CCN(C(C)C)C(C)C>C(O)C>[Br:21][C:19]1[N:20]=[C:15]([NH:13][CH2:12][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]=[CH:3][C:2]([Br:1])=[CH:11]3)[C:16]([NH2:22])=[N:17][CH:18]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: NCc1ccc2ncc(Br)cc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1ncc(Br)nc1NCc1ccc2ncc(Br)cc2c1
Temperature: 120 °C

Procedure:
A microwave tube was charged with (3-bromoquinolin-6-yl)methanamine (237 mg, 1.0 mmol), 3,5-dibromopyrazin-2-amine (253 mg, 1.0 mmol), DIPEA (0.6 mL) and 5 mL of ethanol. The tube was heated at 120° C. under microwave irradiation for 15 h. After cooling, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with DCM/methanol gradient to afford the title compound. LCMS (method E): [MH]+=406/408/410, tR=5.803 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][O-].[K+].S(=O)(=O)(O)O>C(O)C>[Br:1][C:2]1[C:3]2[N:4]([C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:9]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1ncc(Cl)cc1Br
Reactant: CCOC(=O)C(Cl)=C[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cnc2c(Br)cc(Cl)cn12
Yield: 57.4 %

Procedure:
A mixture of 3-bromo-5-chloropyridin-2-amine (1.0 g), potassium 2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (2.27 g), sulfuric acid (0.334 mL) and ethanol (20 mL) was heated with reflux overnight. The solvent was evaporated under reduced pressure, the residue was neutralized with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and 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), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (0.84 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:39]=[C:38]([CH3:40])[C:32]3[N:33]([CH3:37])[C:34](=[O:36])[O:35][C:31]=3[CH:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:37][N:33]1[C:32]2[C:38]([CH3:40])=[CH:39][C:29]([O:28][C:24]3[N:25]=[CH:26][N:27]=[C:22]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:23]=3)=[CH:30][C:31]=2[O:35][C:34]1=[O:36]
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5c(c4)oc(=O)n5C)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
95 mg (0.35 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.10 g (0.34 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-3,4-dimethyl-3H-benzoxazol-2-one and 0.15 mL (0.86 mmol) DIPEA were combined in 1.8 mL DMF and stirred overnight at RT. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined, the acetonitrile was evaporated down, the precipitate was suction filtered and dried i. vac.
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:31]1([C:37]2[NH:41][N:40]=[C:39]([C:42]([NH:44][CH2:45][C:46]([OH:48])=O)=[O:43])[CH:38]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl.[F:50][C:51]1[CH:52]=[C:53]([CH:59]=[C:60]([C:62]([F:65])([F:64])[F:63])[CH:61]=1)[O:54][CH:55]1[CH2:58][NH:57][CH2:56]1>CN(C=O)C>[F:50][C:51]1[CH:52]=[C:53]([CH:59]=[C:60]([C:62]([F:64])([F:63])[F:65])[CH:61]=1)[O:54][CH:55]1[CH2:58][N:57]([C:46](=[O:48])[CH2:45][NH:44][C:42]([C:39]2[CH:38]=[C:37]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:41][N:40]=2)=[O:43])[CH2:56]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Fc1cc(OC2CNC2)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CC(Oc2cc(F)cc(C(F)(F)F)c2)C1)c1cc(-c2ccccc2)[nH]n1
Yield: 24.4 %

Procedure:
DIPEA (143 mg, 1.1 mmol) followed by HOBt (39 mg, 0.29 mmol) and EDCI (56 mg, 0.29 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (68 mg, 0.27 mmol) in DMF (2 mL) After 2 minutes of stirring, 3-(3-fluoro-5-trifluoromethyl-phenoxy)-azetidine hydrochloride (prepared by the method used for the synthesis of Intermediate 71) (75 mg, 0.27 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between cold water and ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification by preparative HPLC afforded 31 mg (24.4% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[3-(3-fluoro-5-trifluoromethyl-phenoxy)-azetidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 463, 81.67%. 1H NMR (300 MHz, DMSO-d6): δ 13.75 (s, 1H), 7.8 (d, 2H), 7.42 (t, 2H), 7.26 (m, 2H), 7.1 (d, 1H), 7.04 (s, 1H), 5.2 (m, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 4.2 (m, 2H), 3.7 (m, 2H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:26]2[N:25]3[CH2:33][CH2:34][N:35]=[C:36]([CH:37]([CH3:39])[CH3:38])[C:24]3=[CH:23][C:22]=2[CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[Si:1]([O:18][CH2:19][C:20]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:26]2[N:25]3[CH2:33][CH2:34][NH:35][CH:36]([CH:37]([CH3:39])[CH3:38])[C:24]3=[CH:23][C:22]=2[CH:21]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)C1=NCCn2c1cc1cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(S(C)(=O)=O)cc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)C1NCCn2c1cc1cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(S(C)(=O)=O)cc12

Procedure:
A solution of 8-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indole (140 mg, 0.25 mmol), 10% palladium on charcoal (37 mg, 0.025 mmol), and methanol (5 mL) was stirred at rt under 1 atmosphere of hydrogen for 3 h. The mixture was filtered through Celite and the Celite was washed thoroughly with methanol. Combined solvent was removed under reduced pressure to afford 8-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole. It was used directly without further purification. A small portion of product was purified by chromatography for characterization. LC-MS m/z 561 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 8.00 (s, 1H), 7.73-7.70 (m, 5H), 7.47-7.40 (m, 6H), 6.36 (s, 1H), 5.20 (d, J=2.0 Hz, 2H), 4.24-4.19 (m, 1H), 4.11-4.00 (m, 2H), 3.52-3.47 (m, 1H), 3.20-3.13 (m, 1H), 3.03 (s, 3H), 2.47-2.39 (m, 1H), 1.18 (d, J=6.8 Hz, 3H), 1.09 (s, 9H), 0.96 (d, J=6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 143.06, 135.68, 134.04, 133.31, 131.52, 130.26, 129.79, 129.51, 127.77, 121.39, 111.22, 97.14, 63.76, 59.28, 45.00, 42.94, 42.47, 31.55, 26.94, 19.72, 19.31, 16.49.
Reaction SMILES: P([O-])([O-])([O-])=O.C([NH:9][CH:10]([C:15]([OH:17])=[O:16])[CH2:11][CH2:12][S:13][CH3:14])(=O)C>[Co](Cl)Cl>[NH2:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH2:12][S:13][CH3:14]
Reactant: CSCCC(NC(C)=O)C(=O)O
Agent: Cl[Co]Cl
Agent: O=P([O-])([O-])[O-]
Product: CSCC[C@H](N)C(=O)O
Temperature: 30 °C
Reaction time: 8 h

Procedure:
While maintaining the above column at 30° C., a 20 mM phosphate buffer containing 0.5% N-acetyl-DL-methionine and 1 mM cobalt chloride was flowed through the column at a flow rate of 30 ml per hour. 3 l of the effluent was collected and passed through IR 120 cation exchange resin, after which it was concentrated under reduced pressure until it was dry and solid. The obtained residue, after being washed twice with 10 ml of cool absolute alcohol, was dissolved in about 100 ml of hot water, and the crystal which separated during cooling was collected by filtration. Furthermore, alcohol was added drop-by-drop to the filtrate, and this mixture was kept standing overnight. The crystal which separated was collected and dried to obtain 9.6 g of L-methionine. The melting point was 280° to 281° C., [α]D25 -8.2°(c=1%). This product showed entirely the same behaviors as those of a standard sample of L-methionine in high performance liquid chromatography and thin layer chromatography. In addition, this product, when melted together with a standard sample, exhibited no drop of melting point.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[NH:4][N:3]=1.[H-].[Na+].[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[N:4]([C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1ccc2[nH]nc(Br)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h
Yield: 97.8 %

Procedure:
To a suspension of ethyl 3-bromo-1H-indazole-5-carboxylate (1032 g, 0.04 mol) in 160 mL of THF was added NaH (2.8 g, 0.068 mol) portion wise at 5-10 C under ice/water bath. The solution was stirred for 15 minutes further until no more bubling. Tritylchloride (14 g, 0.05 mol) was added in several portions. After the addition, the cooling bath was removed and the orange suspension was stirred at room temperature for overnight. The reaction mixture was poured slowly into 100 mL of saturated NH4Cl with stirring and 100 mL EtOAc. The layers were separated and the aqueous phase extracted with Ethyl acetate (2 Lx2). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na2SO4, filter and concentrated. The solid was triturated with hexane (100 mL), filtered and washed with hexane and dried under vacuum to give 20 gram product as light yellow solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[Br:13][CH2:14][C:15](Cl)=[O:16]>ClCCl>[Br:13][CH2:14][C:15]([NH:6][C:3]1[CH:4]=[CH:5][O:1][N:2]=1)=[O:16]
Reactant: Nc1ccon1
Reactant: O=C(Cl)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(CBr)Nc1ccon1

Procedure:
Isoxazol-3-ylamine (1.14 g) was dissolved in dichloromethane (50 mL) and potassium carbonate (3.74 g) was added. Bromoacetyl chloride (1.12 mL) was added slowly with stirring and the suspension was stirred overnight. The reaction mixture was washed with water (2×50 mL), dried and evaporated. The product was recrystallised from dichloromethane/isohexane to afford the sub-titled compound (2.3 g).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>C(O)(C)C.Cl>[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:25][CH2:26][N:27]([C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:10]=4)[N:5]=[CH:4][CH:3]=3)[CH2:28][CH2:29]2)=[CH:20][CH:19]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: COC(=O)COc1ccc2nccc(Br)c2c1
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)COc1ccc2nccc(N3CCN(c4ccncc4)CC3)c2c1
Yield: 34.3 %

Procedure:
To a solution of methyl 4-bromoquinolin-6-yloxyacetate (169 mg) in isopropanol(10 ml) was added 1-(4-pyridyl)piperazine (93 mg) followed by 2 drops of saturated ethereal HCl. The resulting mixture was refluxed for 18 hours. The mixture was filtered and concentrated. Purification by flash column chromatography on silica, eluting with methanol/dichloromethane (10% to 15% v/v in 1% increments) gave methyl 4-[4-(4-pyridyl)piperazin-1-yl]quinolin-6-yloxyacetate (74 mg) as a solid: NMR(d6DMSO) δ 3.2-3.4(m,4H), 3.6-3.7(m,4H), 3.75(s, 3H), 5.0(s,2H), 6.95(d,2H), 7.05(d,1H), 7.25(d,1H), 7.45(dd,1H), 7.9(d,1H), 8.25(d,2H), 8.6(d,1H); m/e 379(M+H)+.
Reaction SMILES: [NH:1]([C:20]([O:22]C(C)(C)C)=O)[C@H:2]([C:13]([NH:15][CH2:16][C:17]([NH2:19])=[O:18])=[O:14])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+:9]([O-:11])=[O:10].Cl.CCOC(C)=O.[N:34]1([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:48][CH2:47][CH2:46][C@H:35]1C(ON1C(=O)CCC1=O)=O>CCN(CC)CC>[N:34]1([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:48][CH2:47][CH2:46][C@H:35]1[C:20]([NH:1][C@H:2]([C:13]([NH:15][CH2:16][C:17]([NH2:19])=[O:18])=[O:14])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+:9]([O-:11])=[O:10])=[O:22]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)NCC(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)NCC(N)=O

Procedure:
The desired compound was prepared from 6.0 g of Boc-Arg(NO2)-Gly-NH2, 40 ml of 4 N HCl-AcOEt, 3.4 ml of Et3N and 5.1 g of Boc-Pro-OSu in the same manner as in Example 26-(4).