Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[Cl:33])=[N:10][C:11]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)=[C:12]([CH:16]=2)[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.Cl.[CH2:35]([NH2:37])[CH3:36].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[Cl:33])=[N:10][C:11]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)=[C:12]([CH:16]=2)[C:13]([NH:37][CH2:35][CH3:36])=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Oc1ccc(F)c(F)c1
Reactant: CCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Oc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude acid chloride from Step A was dissolved in methylene chloride (1 mL) and treated with ethylamine hydrochloride (0.018 g; 0.217 mmol) and triethylamine (0.06 mL; 0.434 mmol) then stirred at room temperature for 1 h. The volatiles were removed in vacuo and purified by MPLC (silica gel; 0-50% ethyl acetate:hexane gradient) to afford the desired product: m/e=534 (M+2); Rt=4.57 min on LCMS.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:39])[C:11]([NH:13][C@H:14]([C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C@H:21]1[C:26]([NH:28][C@H:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)=[O:27])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH:40](=O)[CH:41]([CH3:43])[CH3:42].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH2:40]([N:23]1[CH2:24][CH2:25][N:20]([C:18]([C@@H:14]([NH:13][C:11](=[O:12])[C@@H:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:7])([CH3:8])[CH3:6])[CH3:39])[CH:15]([CH3:17])[CH3:16])=[O:19])[C@H:21]([C:26]([NH:28][C@H:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][CH2:31][CH2:30]2)=[O:27])[CH2:22]1)[CH:41]([CH3:43])[CH3:42]
Reactant: CC(C)C=O
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCNC[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)CN1CCN(C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C)[C@H](C(=O)N[C@@H]2CCCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Intermediate 7 (250 mg, 0.46 mmol) is dissolved in 1,2-dichloroethane (4 mL), to which is added iso-butyraldehyde (63 μL, 0.69 mmol) and NaBH(OAc)3 (146 mg, 0.69 mmol). This mixture is stirred under N2 at RT overnight. LCMS at this point shows a small amount of unreacted starting material so further quantities of iso-butyraldehyde (63 μL, 0.69 mmol) and NaBH(OAc)3 (146 mg, 0.69 mmol) are added. After a further 4 h. of stirring at RT the reaction mixture is diluted with CH2Cl2 (50 mL) and then washed with water (50 mL), brine (50 mL) and dried (Na2SO4). After filtration, the solvent is removed under reduced pressure to afford an oil which is purified by flash chromatography on silica gel (10-50% Et2O/CH2Cl2). The title compound is isolated as a white foam (255 mg, 92% yield): 1H NMR δ (CDCl3) 6.72-7.27 (m, 5H), 4.37-5.24 br m, 5H), 3.26-3.90 (br m, 2H), 2.67-2.96 (br m, 6H), 1.62-2.19 (m, 1H), 1.48 (s, 9H), 1.23-1.34 (m, 3H), 0.69-0.99 (m, 12H); LCMS (APCl+) 601.3 (MH+, 100%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Br:26])[CH:19]=2)[C:14]([OH:17])([CH3:16])[CH3:15])(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].C[N:32]([CH:34]=[O:35])C>CCOC(C)=O.CCCCCC.O>[Br:26][C:20]1[CH:19]=[C:18]([C@@H:13]2[C:14]([CH3:15])([CH3:16])[O:17][C:34](=[O:35])[NH:32][CH2:12]2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: COc1ccc([C@@H](COS(=O)(=O)c2ccc(C)cc2)C(C)(C)O)cc1Br
Reactant: CN(C)C=O
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: COc1ccc([C@H]2CNC(=O)OC2(C)C)cc1Br
Temperature: 60 °C

Procedure:
To a solution of (S)-2-(3-bromo-4-methoxyphenyl)-3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (58 mg, 0.13 mmol) in 2 mL DMF was added NaN3 (34 mg, 0.52 mmol). The resulting reaction mixture was heated at 60° C. overnight and was then diluted with 10 mL EtOAc/hexane (1:1) and 10 mL water. The layers were separated. The organics were dried over sodium sulfate, filtered and concentrated. Crude product was purified on Combiflash prepacked silica gel column, eluted with hexane to 40% EtOAc in hexane to give 38 mg desired product. 1H NMR (500 MHz, CDCl3): δ 7.49 (d, J=1.9 Hz, 1H), 7.22 (dd, J=2.1, 8.5 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 3.93 (s, 3H), 3.9 (m, 1H), 3.71 (m, 1H), 2.82 (m, 1H), 1.28 (s, 3H), 1.17 (s, 3H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH:6]1([CH:12]=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl:14]CCl>[Cl-].[Zn+2].[Cl-]>[C:1]([O:13][CH:12]([Cl:14])[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: ClCCl
Reactant: O=CC1CCCCC1
Agent: [Cl-]
Agent: [Zn+2]
Product: CCC(=O)OC(Cl)C1CCCCC1
Temperature: -5 °C
Reaction time: 8 h

Procedure:
A stirred solution of 73 ml (0.84 mole) of propionyl chloride in 250 ml of dichloromethane was cooled to 0° C. (salt-ice bath) and treated portionwise with 94.2 g (0.84 mole) of freshly distilled cyclohexanecarboxaldehyde. After further cooling to -5° C., approximately 0.5 g of zinc chloride was added. The temperature rose gradually to 7° C. as a solid separated. The cooling bath was removed and while stirring was continued the reaction mixture was allowed to warm to room temperature (the solid gradually went into solution). After about 1 hour some additional zinc chloride was added; there was no further reaction. The solution was kept overnight at room temperature.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[C:13]([SH:15])[CH:12]=[CH:11][C:10]=1[OH:16].Br[CH2:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.O>O1CCOCC1>[Cl:8][C:9]1[CH:14]=[C:13]([S:15][CH2:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=2)[CH:12]=[CH:11][C:10]=1[OH:16]
Reactant: O=Cc1ccc(CBr)cc1
Reactant: Oc1ccc(S)cc1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: O=Cc1ccc(CSc2ccc(O)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84 %

Procedure:
Triethylamine (5.0 mL, 35.9 mmol) was added dropwise to a solution of 2-chloro-4-mercaptophenol (3.60 g, 22.4 mmol) and 4-bromomethyl benzaldehyde (3.93 g, 19.7 mmol) in dioxane (150 mL) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 20 hours. Water (100 mL) was added to the reaction mixture and it was then partitioned with ethyl acetate and brine (200 mL each). The aqueous layer was re-extracted with ethyl acetate (100 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo affording a yellow solid. This was purified by trituration with acetonitrile (5 mL/g) for 30 minutes. After filtration this afforded a light yellow solid as the pure product, 84% yield, 5.27 g.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH:12]=O)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH2:12][N:28]2[CH2:29][CH2:30][N:25]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:18]=3[CH3:17])[CH2:26][CH2:27]2)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1cc(CCC=O)n(C(C)(C)C)n1
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3cccc(C)c3C)CC2)n(C(C)(C)C)n1

Procedure:
158 mg (81%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.450 mmol), 1-(2,3-dimethylphenyl)piperazine (86 mg, 0.450 mmol), DIPEA (0.118 mL, 0.675 mmol) and NaBH(OAc)3 (286 mg, 1.350 mmol).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)([O:12][CH2:13][CH3:14])[PH2:10]=[O:11])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].O.O.Cl[Sn]Cl>CCO>[CH2:1]([O:3][P:4]([C:9]([C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=1)([O:12][CH2:13][CH3:14])[PH2:10]=[O:11])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOC([PH2]=O)(c1ccc([N+](=O)[O-])cc1)P(=O)(OCC)OCC
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CCOC([PH2]=O)(c1ccc(N)cc1)P(=O)(OCC)OCC
Temperature: 70 °C
Reaction time: 0.73 h
Yield: 76.2 %

Procedure:
A mixture of [(4-nitro-phenyl)-ethoxy-phosphinoylmethyl]-phosphonic acid diethyl ester (940 mg, 2.57 mmol) and SnCl2.2H2O (2.9 g, 12.9 mmol) in EtOH (˜10 mL) was stirred at 70° C. for 44 min and then concentrated at ambient temperature. The residue was taken up in CH2Cl2 and washed with half saturated aq NaHCO3 (40 mL), H2O (40 mL) and brine (40 mL). The aqueous washes were reextracted once with CH2Cl2, and the combined extracts were dried over K2CO3 and concentrated. The crude material was purified by flash chromatography on silica gel. Elution with 20:1 CHCl3-MeOH followed by 15:1 CHCl3-MeOH afforded 657 mg of product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl.[Cl:34][CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.Cl>CC(C)=O>[ClH:34].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:35][CH2:36][N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:24][CH:25]=2)[CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1
Reactant: ClCCN1CCCC1
Reactant: COc1ccc(C(c2ccc(O)cc2)C2CCCc3ccccc32)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(c2ccc(OCCN3CCCC3)cc2)C2CCCc3ccccc32)cc1

Procedure:
A mixture of (4-methoxyphenyl)-(4-hydroxyphenyl)-1,2,3,4-tetrahydronaphth-1-yl-methane (400 mg, 0.001 mol), anhydrous K2CO3 (2.0 gm, 0.14 mol), 1-(2-chloroethyl)pyrrolidine hydrochloride (400 mg, 0.002) and dry acetone (25.0 ml) was refluxed for 10 hrs. K2CO3 was filtered off, acetone was distilled off and the residue was diluted with water. The reaction mixture was extracted with ethyl acetate, washed with water, dried over sodium sulphate and concentrated to give an oil which was filtered through basic alumina column using benzene as the eluent, and concentrated to give an oil. The oil thus obtained was treated with ethanolic HCl. The solvent was evaporated and the compound was crystallized with absolute alcohol and dry ether, filtered under anhydrous conditions, and dried to give the title compound of formula I. Yield 350 mg. (68.35%).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH2:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:17]([NH:23][C:8](=[O:9])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CCCCCCN
Product: CCCCCCNC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, off-white solid, m.p. 100° C. and MS: m/e=296.4 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and hexylamine.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([OH:3])=O.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C(O)(=O)C>[CH2:17]([N:24]1[C:1](=[O:3])[CH2:4][C:5]2[C:6](=[CH:10][CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=2)[C:7]1=[O:9])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)Cc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: NCc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: O=C1Cc2cc([N+](=O)[O-])ccc2C(=O)N1Cc1ccccc1
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of the diacid (9) (55 g, 0.244 mole) in acetic acid (550 mL) was added benzylamine (28.91 g, 0.27 mole). The reaction was heated to 115° C. for 18 hrs., cooled to 25° C., water was added (450 mL), the contents stirred for 2 hrs., and the product filtered off as a white solid. The product was washed with water (400 mL) and vacuum dried to give 59.51 g (82%).
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.N1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C[OH:17]>>[C:12]([C:13]1[S:8][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[N:9][C:14]=1[CH3:15])(=[O:17])[CH3:11]
Reactant: NC(=S)c1cccnc1
Reactant: c1ccncc1
Reactant: CO
Product: CC(=O)c1sc(-c2cccnc2)nc1C
Temperature: 72.5 °C

Procedure:
A mixture of 5-chloro-pentadione (5.12 g, 38 mmol) and thionicotinamide (5.25 g, 38 mmol) in MeOH (10 mL) was treated with pyridine (3 mL). The reaction mixture was heated at 70-75° C. for 5 h. The solvent was evaporated. The resulting solid was filtered and washed with EtOAc/MeOH to afford 4.33 g 5-acetyl-4-methyl-2-(3-pyridyl)-thiazol as a yellow solid, which was subjected to the next reaction without further purification. A mixture of this material (2.0 g) and N,N-dimethylformamide dimethyl acetal (4 mL) was heated at 80° C. for 22 h. The reaction mixture was concentrated and then triturated with EtOAc/PE. The precipitates were collected and washed with EtOAc/PE to afford the title compound (2.05 g, 75%) as a grey solid.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:32][S:33]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)(=[O:35])=[O:34].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:39]3[CH:40]=[CH:41][C:36]([S:33]([CH3:32])(=[O:35])=[O:34])=[CH:37][CH:38]=3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCC5)CC4)ccc32)cc1
Yield: 12 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 4-(methanesulphonyl)benzeneboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown solid (12%).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:10]1[N:11]=[CH:12][C:13]([C:16]([NH:18][C:19]2[NH:20][N:21]=[C:22]([CH2:24][CH2:25][C:26]3[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=3)[CH:23]=2)=[O:17])=[N:14][CH:15]=1>CS(C)=O.CO>[CH3:35][O:34][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][C:22]2[CH:23]=[C:19]([NH:18][C:16]([C:13]3[CH:12]=[N:11][C:10]([N:5]4[CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:15][N:14]=3)=[O:17])[NH:20][N:21]=2)[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=1
Reactant: CN1CCCNCC1
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Solvent: CO
Solvent: CS(C)=O
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCCN(C)CC4)cn3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
1-methyl-1,4-diazepane (0.20 ml, 1.60 mmol) was added to 5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (310 mg, 0.80 mmol) in DMSO (4.00 ml) at 25° C. The resulting solution was stirred at room temperature for 1 h. The reaction mixture was diluted with MeOH (5 ml) and the crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford crude product as an orange dry film. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (296 mg, 79%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:17](=[O:18])[CH2:16][C:15]2[N:11]([C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:13][N:14]=2)[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]1=2)([CH3:4])([CH3:3])[CH3:2].[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[CH:31]1.N1CCCCC1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:17](=[O:18])[C:16](=[CH:39][C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[NH:30][CH:31]=2)[C:15]2[N:11]([C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:13][N:14]=2)[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]1=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2ccccc21
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CN1C(=O)C(=Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21
Temperature: 110 °C
Reaction time: 24 h
Yield: 133.4 %

Procedure:
To a solution of (5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-acetic acid tert-butyl ester (Preparation 13(B)) (3.66 g, 9.37 mmol) in toluene (94 mL) was added 1H-indole-3-carbaldehyde (1.63 g, 11.2 mmol) and piperidine (2.78 mL, 28.1 mmol). The reaction was heated to 110° C. in a Soxhlet for 10 hours and was stirred at room temperature for 24 hours. The precipitate was filtered and was washed with toluene to provide 6.47 g of [4-(1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-acetic acid tert-butyl ester. MS 518.5 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:18][OH:19])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][NH:5]1.C=O.Cl.[C:23](O)(=O)C>C1C=CC=CC=1.CO>[OH:1][CH2:2][CH:3]1[CH:4]2[C:13]3[C:8]([CH2:7][CH2:6][N:5]2[CH2:23][O:19][CH2:18]1)=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=3
Reactant: CC(=O)O
Reactant: COc1cc2c(cc1OC)C(C(CO)CO)NCC2
Agent: C=O
Agent: Cl
Solvent: c1ccccc1
Solvent: CO
Product: COc1cc2c(cc1OC)C1C(CO)COCN1CC2
Yield: 89 %

Procedure:
A suspension of 6 mmoles (1.6 g) of 1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline in 50 ml of absolute benzene is admixed with a suspension of 7 mmoles (0.02 g) of paraformaldehyde in 10 ml of absolute methanol. The reaction mixture is refluxed for two hours in the presence of a catalytic amount of hydrochloric acid or acetic acid, whereupon the obtained pale-yellow solution is evaporated in vacuo. The residual oily product is triturated with a small amount of acetone to yield the aimed compound in crystalline form in a yield of 89%.
Reaction SMILES: [NH2:1][C:2]1[C:20]([Br:21])=[CH:19][C:5]([CH2:6][C@H:7]([C:16]([OH:18])=O)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[Br:22].[N:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:25][CH:24]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:1][C:2]1[C:3]([Br:22])=[CH:4][C:5]([CH2:6][C@H:7]([C:16]([N:32]2[CH2:33][CH2:34][N:29]([C:26]3[CH:27]=[CH:28][N:23]=[CH:24][N:25]=3)[CH2:30][CH2:31]2)=[O:18])[NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[CH:19][C:20]=1[Br:21]
Reactant: c1cc(N2CCNCC2)ncn1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cc(Br)c(N)c(Br)c1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: CC(C)(C)OC(=O)N[C@H](Cc1cc(Br)c(N)c(Br)c1)C(=O)N1CCN(c2ccncn2)CC1
Yield: 92 %

Procedure:
Prepared analogously to Example A15a) from 4-amino-3,5-dibromo-N-(1,1-dimethylethoxycarbonyl)-D-phenylalanine and 1-(4-pyrimidinyl)piperazine in the presence of TBTU in a yield of 92% of theory. Colourless, amorphous substance, Rf=0.42 (FM4; Macherey-Nagel POLYGRAM® SIL G/UV254, ready-made films for TLC).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:5]([NH:7][C@@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=2)[CH2:11][CH2:10][C@H:9]1[OH:21])=[O:6].[C:26](OC(=O)C)(=[O:28])[CH3:27]>C1COCC1.C(N(CC)CC)C.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:5]([NH:7][C@@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=2)[CH2:11][CH2:10][C@H:9]1[O:21][C:26](=[O:28])[CH3:27])=[O:6]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(N[C@@H]1c2cc([N+](=O)[O-])ccc2CC[C@H]1O)c1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H]1CCc2ccc([N+](=O)[O-])cc2[C@H]1NC(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 2 h

Procedure:
A mixture of 113 (1.9 g, 0.005 mol) in THF (200 mL), triethylamine (1.3 mL), and a catalystic amount of 4-dimethylaminopyridine was treated with acetic anhydride (0.9 mL). After stirring over night, the solvent was evaporated and the residue treated with H2O. After 2 h, the mixture was extracted with EtOAc. The extracts were washed with 1 N H2SO4, brine, aqueous NaHCO3 and brine, then the solvent was dried and evaporated to give a floculant white solid (1.94 g) that had the appropriate nmr for the desired material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][O:8][C:9](=[O:29])[C@@H:10]2[CH2:14][C@@H:13]([OH:15])[CH2:12][N:11]2[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:17])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9](=[O:29])[C@@H:10]2[CH2:14][C@@H:13]([O:15][C:39](=[O:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:12][N:11]2[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:17])=[CH:30][CH:31]=1
Reactant: COc1ccc(COC(=O)[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)[C@@H]2C[C@@H](OC(=O)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C

Procedure:
Trans-1-(p-Nitrobenzyloxycarbonyl)-4-hydroxy-L-proline p-methoxybenzyl ester (49 g) was dissolved in 300 ml of dry tetrahydrofuran, and 33 ml of triethylamine, 9.59 g of 4-dimethylaminopyridine and 33.2 g of benzoyl chloride were added thereto, followed by stirring under reflux for 5 hours. The reaction mixture was cooled down to room temperature and distilled to remove the solvent. The residue was diluted with ethyl acetate, washed successively with water, dilute hydrochloric acid, water, a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and distilled to remove the solvent. Recrystallization of the residue from diethyl ether gave trans-1-(p-nitrobenzyloxycarbonyl)-4-benzoyloxy-L-proline p-methoxybenzyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([NH:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O>>[CH2:17]([O:16][C:11](=[O:15])[C:12](=[N:9][NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:10])[CH3:14])[CH3:18]
Reactant: CCOC(=O)C(C)=O
Reactant: NNc1cccc(Cl)c1F
Product: CCOC(=O)C(C)=NNc1cccc(Cl)c1F

Procedure:
The title compound, EI-MS: m/e=258.1 (M+), was prepared in accordance with the general method of example 25b) from (3-Chloro-2-fluoro-phenyl)-hydrazine and ethyl pyruvate.