Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 93.4 %

Procedure:
To a solution of 355 mg of t-butyl 4-(2-ethoxy-2-oxoethylidene)tetrahydropyridine-1(2H)-carboxylate in 10 ml of methanol, 50 mg of 10% palladium-on-carbon catalyst was added and stirred for 13 hours in 3 atmospheres' hydrogen pressure. Filtering the catalyst off, the solvent was distilled off under reduced pressure to provide 334 mg of the title compound.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].N1C=CC=CC=1.[C:14]([NH:18][C:19]([C:21]1[N:22]([C:27](=[O:29])[CH3:28])[CH2:23][CH2:24][NH:25][CH:26]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15].[OH-].[Na+]>O>[C:14]([NH:18][C:19]([C:21]1[N:22]([C:27](=[O:29])[CH3:28])[CH2:23][CH2:24][N:25]([C:1](=[O:3])[CH3:2])[CH:26]=1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)N1CCNC=C1C(=O)NC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N1C=C(C(=O)NC(C)(C)C)N(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
16.7 g (163 mmol) of acetic anhydride and 12.4 g (157 mmol) of pyridine were added to 20.00 g (88.8 mmol) of 1-acetyl-1,4,5,6-tetrahydropyrazine-2-carboxylic acid tert-butylamide and the mixture was stirred for 4 hours at 25° C. 100 ml of water was then added and the pH was adjusted to 6 with 30 ml of sodium hydroxide solution (20%). Extraction was then carried out by shaking with three times 100 ml of methyl ethyl ketone. The combined organic extracts were dried over magnesium sulfate, toluene was added and the mixture was concentrated. The vigorously foaming crude product crystallized and 11.40 g (48%) of the title compound was isolated in the form of a light brown solid. The melting point of the title compound was: 138.0° to 139.2° C. Other data concerning the title compound was:
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]([O:24]CC)=[O:23])[N:13]=2)=[CH:8][CH:7]=1.[OH-].[Na+]>>[CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]([OH:24])=[O:23])[N:13]=2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)Cn1nc(-c2ccc(NCCN(C)C)cc2)c2cccnc21
Agent: [Na+]
Agent: [OH-]
Product: CN(C)CCNc1ccc(-c2nn(CC(=O)O)c3ncccc23)cc1

Procedure:
By conducting reactions and treatments in the same manner as in Example 66 (3), using 4.6 g of ethyl 3-[4-(2dimethylaminoethylamino)phenyl]-1H-pyrazolo[3,4-b]pyridin-1-ylacetate and 0.65 g of sodium hydroxide and recrystallizing from hydrous methanol, there was obtained 3-[4-(2-dimethylaminoethylamino)phenyl]-1H-pyrazolo[3,4-b]pyridin-1-ylacetic acid, m.p. 240°-242° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=[C:6]([OH:29])[CH:5]=1.[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:5]=[C:6]([O:29][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:7]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:9]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(C(=O)OC)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Yield: 75.5 %

Procedure:
A mixture of 50.9 g (0.12 mol) of 3-hydroxy-5-(octadecyloxy)benzoic acid methyl ester, 21.6 ml (0.18 mol) of benzyl bromide and 50 g (0.36 mol) of potassium carbonate in 750 ml of DMF was stirred and heated at 85° for 65 hours. The reaction mixture was filtered and the filtrate was concentrated at reduced pressure. The residue was recrystallized from methylene chloride-methanol to give 46.3 g (75% yield, mp 61°-63°) of 3-(octadecyloxy)-5-(phenylmethoxy)benzoic acid methyl ester. The structure was confirmed by the nmr spectrum.
Reaction SMILES: [OH-].[NH4+:2].[C:3]([NH:6][C@H:7]([C:10]([OH:12])=[O:11])[CH2:8][SH:9])(=[O:5])[CH3:4]>O>[C:3]([NH:6][C@H:7]([C:10]([O-:12])=[O:11])[CH2:8][SH:9])(=[O:5])[CH3:4].[NH4+:2]
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N[C@@H](CS)C(=O)[O-]

Procedure:
N-acetyl-L-cysteine ammonium salt can also be obtained by modification of the above procedure as follows. About 6.5 ml. of concentrated ammonium hydroxide is added slowly to a stirred mixture of N-acetyl-L-cysteine (16.3 g., 0.1 mole) in 100 ml. of water. The pH of the mixture should be 7 at the end of the addition. The solvent is allowed to evaporate and the white residue thus obtained when dried to constant weight at 45°C. in vacuo over phosphorous pentoxide provides a quantitative yield (18 g.,) of analytically pure ammonium N-acetyl-L-cysteinate, M.P. 148°- 150°C. (dec.), [ α ]D25 + 20.3°(c 5,H2O).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[NH2:8][C:9]([CH3:13])([CH3:12])[C:10]#[N:11]>C(Cl)Cl>[C:10]([C:9]([NH:8][S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])([CH3:13])[CH3:12])#[N:11]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)(N)C#N
Solvent: ClCCl
Product: C=CS(=O)(=O)NC(C)(C)C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.8 %

Procedure:
To a stirred solution of 39.3 g (0.241 mole) 2-chloroethylsulfonyl chloride in 250 ml methylene chloride at 0° C. under N2, 63.09 g (0.75 moles) 2-amino-2-methyl-propionitrile was added dropwise over several hours. The solution was allowed to come to room temperature overnight and then was heated to reflux for one hour, was cooled to room temperature and filtered. The filtrate was evaporated to give 44 g of a yellow oil. One half, 22 g, of the oil was chromatographed to give 21 g of the above-identified product.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([Cl:12])[N:6]=[CH:7]2.[C:13](Cl)(Cl)=[O:14]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[Cl:12][C:5]1[N:6]=[CH:7][C:8]2[C:3]([CH:4]=1)=[C:2]([N:1]=[C:13]=[O:14])[CH:11]=[CH:10][CH:9]=2
Reactant: O=C(Cl)Cl
Reactant: Nc1cccc2cnc(Cl)cc12
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C=Nc1cccc2cnc(Cl)cc12

Procedure:
5-Amino-3-chloroisoquinoline (740 mg, 4.15 mmol) was suspended in toluene (20 mL) and treated with 20% w/v phosgene solution in toluene (9 mL) and triethylamine (5 mL). The mixture was refluxed overnight and was then concentrated in vacuo and used in the next step without further purification.
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][C:4](=[O:6])[OH:5].O[N:25]1[C:29](=[O:30])[CH2:28][CH2:27][C:26]1=[O:31].C1(N=C=NC2CCCCC2)CCCCC1>CCOC(C)=O>[O:31]=[C:26]1[CH2:27][CH2:28][C:29](=[O:30])[N:25]1[O:6][C:4](=[O:5])[CH2:3][CH:2]([NH:1][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(CC(=O)ON1C(=O)CCC1=O)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of BOC-Asp-OBzl (1.49 g, 4.61 mmol) and N-Hydroxy succinimide (584 mg, 5.07 mmol) in EtOAc (20 ml) was cooled to 0° C. 1,3-Dicyclohexylcarbodiimide (1.05 g, 5.07 mmol) was added portionwise. White precipitate began forming. The resulting mixture was stirred at 0° C. for 10 min. and then allowed to warm to rt. After stirring for 6 h. at rt the mixture was filtered and concentrated in vacuo to give 2-tert-butoxycarbonylamino-succinic acid 1-benzyl ester 4-(2,5-dioxo-pyrrolidin-1-yl) ester as a clear, colorless oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][CH2:11][NH2:12].C(N(C(C)C)CC)(C)C.CS(O[CH:27]([C:34]1[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:41])[CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)(=O)=O>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][CH2:11][NH:12][CH:27]([C:34]1[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:41])[CH2:28][N:29]1[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: Cc1cccc(C)c1C(CN1CCCC1)OS(C)(=O)=O
Reactant: NCCCc1c(F)cccc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C)c1C(CN1CCCC1)NCCCc1c(F)cccc1F
Temperature: 80 °C
Reaction time: 6 h

Procedure:
140 mg (0.81 mmol) of 3-(2,6-difluorophenyl)propylamine (Example 34.1) and 2 ml of diisopropylethylamine are added to a solution of 190 mg (0.63 mmol) of 1-(2,6-dimethylphenyl)-2-pyrrolidin-1-ylethyl methanesulfonate (Example 34.3) in 2 ml of acetonitrile. The mixture is stirred for 6 hours at 80° C., evaporated down and the residue is purified by flash chromatography. Yield: 13 mg of yellow oil, MS: m/z 373 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5].[Cl:21][S:22](O)(=[O:24])=[O:23]>>[CH3:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:10]=[C:9]([S:22]([Cl:21])(=[O:24])=[O:23])[CH:8]=1)=[O:5]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccccc1C(=O)Nc1cccc2c1CCCC2
Product: Cc1ccccc1C(=O)Nc1cc(S(=O)(=O)Cl)cc2c1CCCC2
Temperature: 25 °C

Procedure:
To neat amide (58), at 0° C., was added chlorosulfonic acid (5 eq) dropwise. The temperature was allowed to warm to 25° C. and then heated at 70° C. for 45 minutes. After cooling to 25° C., the reaction mixture was poured into ice water, and the resultant precipitate was collected by filtration to give the title compound as a solid. The product (mixture of regioisomers) was used without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8](O)[C:7]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][N:5]=1.P(Cl)(Cl)([Cl:19])=O>>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][C:7]1[C:8]([Cl:19])=[N:9][C:4]([CH2:3][O:2][CH3:1])=[N:5][CH:6]=1)[CH3:16]
Reactant: CCOC(=O)Cc1cnc(COC)nc1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cc1cnc(COC)nc1Cl
Yield: 78 %

Procedure:
A mixture of the product of Step 1, above (0.01 mol) and phosphorous oxychloride (7 ml) was refluxed for 20 minutes. The excess phosphorous oxychloride was removed, the residue was quenched with ice water (15 ml) and the mixture was extracted with ethyl acetate (2×20 ml). The ethyl acetate layer was collected and washed with water (2×10 ml). The organic extract was collected, dried over MgSO4 and the dried portion was evaporated to obtain the title compound as an oil (78% yield).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[O:15]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:25]3[CH2:26][CH2:27][CH:22]([O:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:23][CH2:24]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1ccc(OC2CCNCC2)cc1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(Oc2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(phenoxy)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 69% overall yield. FDMS m/e=366 (M+ of free base). α[D]589 =-14.29(c=0.5, methanol).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=O)[N:6]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[N:33]1([C:39]2[CH:40]=[C:41]3[C:46](=[CH:47][CH:48]=2)[NH:45][C:44](=[O:49])[CH:43]=[CH:42]3)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>C(N(CC)CC)C.CN(C)C=O>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([N:36]2[CH2:37][CH2:38][N:33]([C:39]3[CH:40]=[C:41]4[C:46](=[CH:47][CH:48]=3)[NH:45][C:44](=[O:49])[CH:43]=[CH:42]4)[CH2:34][CH2:35]2)=[O:10])[N:6]=1
Reactant: O=c1ccc2cc(N3CCNCC3)ccc2[nH]1
Reactant: Cc1nc(CC(=O)O)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(CC(=O)N2CCN(c3ccc4[nH]c(=O)ccc4c3)CC2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
A mixture of 2-(2-methyl-4-thiazolyl)acetic acid (628 mg), 1-hydroxybenzotriazole (648 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (917 mg) and N,N-dimethylformamide (25 ml) was stirred for 1 hour at ambient temperature. 6-(1-Piperazinyl)-2(1H)-quinolinone (687 mg) and triethylamine (1 ml) were added thereto, and the mixture was stirred for 3 hours at the same temperature. After the reaction mixture was concentrated in vacuo, to the residue were added ethyl acetate (10 ml) and water (10 ml) and the mixture was stirred. The resulting oil was separated by decantation and dissolved in tetrahydrofuran. The solution was washed with brine, dried over magnesium sulfate and concentrated. The residue was subjected to a column chromatography on silica gel (80 g) and eluted with 3% solution of methanol in chloroform. The fractions containing the desired compound were collected and concentrated to give a residue, which was crystallized from ethyl acetate-diethyl ether to give 6-[4-{2-(2-methyl- 4-thiazolyl)acetyl}-1-piperazinyl]-2(1H)-quinolinone (0.74 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.[CH2:11]1[CH2:17][S:14](=[O:16])(=[O:15])[O:13][CH2:12]1.CC(=O)OCC>C(#N)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH:8][CH2:12][CH2:11][CH2:17][S:14]([OH:16])(=[O:15])=[O:13])=[CH:4][CH:3]=1
Reactant: NCCc1ccc(Br)cc1
Reactant: O=S1(=O)CCCO1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=S(=O)(O)CCCNCCc1ccc(Br)cc1
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture of 4-Bromophenethylamine (4 g, 20 mmol) and 1,3-propane sultone (2.56 g, 21 mmol) in acetonitrile (30 mL) was heated at reflux for 2.5 hours. The mixture was cooled to room temperature. The solid was collected by filtration, rinsed with acetonitrile (2×5 mL) air-dried for 15 minutes (9.57 g), and further dried for 15 minutes in vacuo (8.02 g). The solid was suspended in ethanol (40 mL) and the suspension was heated at reflux for 1 hour. The mixture was then cooled to room temperature. The solid was collected by suction filtration, rinsed with ethanol (2×5 mL), air-dried for 15 minutes, and further dried in a vacuum oven at 60° C. for 18 hours. Compound EA was obtained as a white solid (6.04 g, 18.8 mmol, 94% yield). 1H NMR (500 MHz, DMSO) δ 1.95 (t, J=6.3 Hz, 3H), 2.63 (t, J=6.1 Hz, 2H), 2.88 (t, J=7.6 Hz, 2H), 3.09 (t, J=6.3 Hz, 2H), 3.15 (t, J=7.8 Hz, 2H), 7.25 (2, J=7.8 Hz, 2H), 7.53 (2, J=7.8 Hz, 2H), 8.63 (br s, 2H). 13C NMR (125 MHz, DMSO) δ 21.8, 31.0, 46.7, 47.2, 48.8, 119.9, 131.0, 131.4, 136.5. ES-MS 324 (M+1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[N:16]3[C:17]([CH3:20])=[N:18][N:19]=[C:15]3[C@H:14]([CH2:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])[N:13]=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:11]=2[CH:34]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH:43]([C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1)=[O:44].C(O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:12]2[C:11]3[CH:34]=[C:7]([C:49]4[CH:48]=[CH:47][CH:46]=[C:45]([CH:43]=[O:44])[CH:50]=4)[CH:8]=[CH:9][C:10]=3[N:16]3[C:17]([CH3:20])=[N:18][N:19]=[C:15]3[C@H:14]([CH2:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])[N:13]=2)=[CH:32][CH:31]=1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2-n2c(C)nnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3cccc(C=O)c3)ccc2-n2c(C)nnc21
Temperature: 120 °C

Procedure:
(S)-6-(4-Chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl trifluoromethanesulfonate (for a preparation see Intermediate 3) (500 mg) potassium carbonate (638 mg), 3-formylphenylboronic acid (166 mg) and bis(triphenylphosphine)palladium(II) chloride (64.8 mg) were added to a 20 ml microwave vial. Ethanol (9 ml) and toluene (9 ml) were added to the vial and the reaction mixture was heated at 120° C. for 20 min (microwave). The reaction mixture was filtered through Celite™ and the filter bed was washed with ethanol. The solvent was evaporated and the residue was chromatographed (0-10% methanol:DCM) to give (S)-2-(6-(4-chlorophenyl)-8-(3-formylphenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide as a light brown solid (287 mg). LCMS (formate): MH+ 498/500, RT 0.99 min
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([CH3:19])=[CH:14][C:13]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:13]3[CH:14]=[C:15]([CH3:19])[C:16]([CH3:18])=[CH:17][C:12]=3[CH3:11])[CH2:21][CH2:22]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: Cc1cc(C)c(N2CCNCC2)cc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)nc3)CC2)cc1C
Yield: 101 %

Procedure:
Using 6-bromonicotinic acid (412 mg) and 1-(2,4,5-trimethylphenyl)piperazine (440 mg) and by the reaction and treatment in the same manner as in Preparation Example 118, the title compound (800 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[Cl-].[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:14]=1[CH2:15][Zn+]>O1CCCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Br:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([CH2:15][C:14]2[C:13]([Cl:12])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:21])[CH:7]=1
Reactant: N#Cc1ncc(Br)cc1Br
Reactant: Clc1cccc(Cl)c1C[Zn+]
Agent: [Pd]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ncc(Cc2c(Cl)cccc2Cl)cc1Br
Temperature: 85 °C

Procedure:
A solution of the product of EXAMPLE 1A (4.52 g, 15.34 mmol) in tetrahydrofuran (75 mL) was treated with palladium tetrakis(triphenylphosphine) (0.887 g, 0767 mmol) and 2,6-dichlorobenzyl zinc chloride (46 mL, 0.5M in tetrahydrofuran). The mixture was heated at 85° C. for 1 hour. After cooling to ambient temperature, the mixture was diluted with water and extracted with ethyl acetate. The organics were washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. Purification by silica gel chromatography (0-100% ethyl acetate in hexanes) provided the title compound. MS (LC-MS) m/z 342 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[CH2:10][CH:9]1[C:29](O)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32]([O:34][C:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:36])[CH3:33]>>[CH2:32]([O:34][C:35]([N:37]1[CH2:38][CH2:39][N:40]([C:29]([C@@H:9]2[CH2:10][C@H:11]([NH:13][CH2:14][C:15]3[CH:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=3)[CH2:12][N:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:30])[CH2:41][CH2:42]1)=[O:36])[CH3:33]
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=C(O)C1CC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1Cc1ccccc1
Product: CCOC(=O)N1CCN(C(=O)[C@@H]2C[C@H](NCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CN2Cc2ccccc2)CC1
Yield: 7.5 %

Procedure:
As described for Example 56d, 1-benzyl-4-(3,5-bis-trifluoromethyl-benzylamino)-pyrrolidine-2-carboxylic acid (65 mg, 0.146 mmol) was converted, using piperazine-1-carboxylic acid ethyl ester instead of 1-(3-trifluoromethyl-phenyl)-piperazine, to the title compound (6.8 mg, 7.5%) as light yellow oil. MS m/e=587.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=1)[C:10]([CH3:26])([CH3:25])[CH2:9]2)=[O:5])[CH3:2]>C(O)C.Cl.[Fe]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[C:10]([CH3:25])([CH3:26])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc([N+](=O)[O-])c1)N2
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N)c1)N2
Temperature: 95 °C
Reaction time: 4 h
Yield: 95.8 %

Procedure:
To a mixture of 3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (10 g, 28 mmol) in ethanol 95% (150 mL) and 10% hydrochloric acid (20 mL) was added iron (4.74 g, 85 mmol). The reaction mixture was stirred at 95° C. for 4 h. Then the insoluble solid was filtered off and the filtrate was concentrated in vacuo. The residue was extracted with ethyl acetate (2×200 mL), washed with 30% sodium hydroxide in water (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (8.7 g, 95%) as a light yellow solid: LC/MS m/e calcd for C20H24N2O2 (M+H)+: 325.43, observed: 325.2.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH2:23])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>CC#N>[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH:23][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(Nc2cc(F)ccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
A mixture of 2,4-difluoro-1-nitrobenzene (3.69 g, 23.2 mmol), 3-aminoazetidine-1-carboxylic acid tert-butyl ester (4.0 g, 23.2 mmol) and DIPEA (3.97 mL, 23.2 mmol) in CH3CN (37 mL) was stirred at RT for 18 h under an argon atmosphere. The volatiles were removed in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-40% EtOAc in cyclohexane) to afford the title compound as a yellow solid (4.84 g, 67%). LCMS (Method B): RT 3.80 min [M+H]+ 312.1.