Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])[NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][Si](C)(C)C.[CH2:30]([N:32]([CH2:46][CH3:47])[C:33](=[O:45])[NH:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1)[CH3:31]>CCOC(C)=O.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:41]([C:38]1[CH:37]=[CH:36][C:35]([NH:34][C:33]([N:32]([CH2:46][CH3:47])[CH2:30][CH3:31])=[O:45])=[CH:40][CH:39]=1)(=[O:43])=[O:42])[C:6](=[O:11])[C:5]2([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])[NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18]
Reactant: C[Si](C)(C)OCCOCCNC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(NCCOCCO)(c3ccccc3Cl)c3cc(Cl)ccc32)cc1
Yield: 47.6 %

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 114 from 1.5 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-[[2-[2-(trimethylsilyloxy)ethoxy]ethyl]amino]indol-2-one and 1.03 g of 4-(N',N'-diethylureido)benzenesulfonyl chloride. Chromatography on silica using a DCM/AcOEt mixture (50/50; v/v) as the eluent gives 1 g of the expected product after crystallization from a DCM/iso ether mixture. M.p.=114°-118° C.
Reaction SMILES: F[C:2]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:3]=1[O:4][CH2:5][CH2:6][O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1.[O:21]1[CH2:24][CH:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[N+:18]([C:15]1[CH:16]=[CH:17][C:2]([N:28]2[CH2:29][CH2:30][N:25]([CH:23]3[CH2:24][O:21][CH2:22]3)[CH2:26][CH2:27]2)=[C:3]([O:4][CH2:5][CH2:6][O:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[CH:14]=1)([O-:20])=[O:19]
Reactant: C1CN(C2COC2)CCN1
Reactant: O=[N+]([O-])c1ccc(F)c(OCCOC2CCCCO2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(N2CCN(C3COC3)CC2)c(OCCOC2CCCCO2)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(2-(2-fluoro-5- nitrophenoxy)ethoxy)tetrahydro-2H-pyran XXII (1550 mg, 5.43 mmol), 1-(oxetan-3-yl)piperazine (772 mg, 5.43 mmol) and potassium carbonate (1126.41 mg, 8.15 mmol) in NMP (6 mL) was stirred at 100° C. for 8 h. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts were washed with H2O (5× to remove NMP) and brine and dried over sodium sulfate. The resulting residue was purified by column chromatography ISCO Rf (24 g column) eluting with a gradient of 100% DCM—60:35:5 DCM:Et2O:MeOH to provide 1-(4-nitro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-4-(oxetan-3-yl)piperazine XXIII.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:24])[CH2:5][S:6][C:7]=1[CH:8]1[CH:13]=[CH:12][N:11](C(OCC(Cl)(Cl)Cl)=O)[CH:10]=[C:9]1[CH:22]=[O:23].[S]>C(Cl)(Cl)Cl.CO>[CH3:1][C:2]1[NH:3][C:4](=[O:24])[CH2:5][S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[CH:22]=[O:23]
Reactant: CC1=C(C2C=CN(C(=O)OCC(Cl)(Cl)Cl)C=C2C=O)SCC(=O)N1
Agent: [S]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC1=C(c2ccncc2C=O)SCC(=O)N1
Temperature: 160 °C
Reaction time: 3 h
Yield: 10.5 %

Procedure:
A mixture of 5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-3-formyl-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one (0.5 g) and sulfur (2.5 g) was stirred at 160° C. for 3 hours. After cooling, the solid was ground and was extracted with methanol using Soxhlet extractor. Methanol was removed under reduced pressure. The residue was extracted with 40 ml of 2N hydrochloric acid. The insoluble matter was removed by filtration and the filtrate was washed with ether and the water phase was adjusted to pH 7.5 by 2N aqueous sodium hydroxide. The resulting precipitates were extracted with chloroform and were dried. Chloroform was removed under reduced pressure and the residue was purified by the preparative thin layer chromatography [TLC silica gel plate 60F254 (supplied by Merck & Co. Inc., U.S.A.), 20×20 cm, thickness 1 mm, chloroform-methanol=40:1] to give the titled compound (0.03 g, yield 10.6%) as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:27]3[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=3[O:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17].[CH3:33][C:34]1[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=1[NH2:36]>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:36][C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[CH3:33])=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][C:21]4([C:27]5[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=5[O:25][CH2:24]4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CC3)COc3ccc(F)cc34)cnc12
Reactant: Cc1ccccc1N
Product: CCOC(=O)c1cnn2c(Nc3ccccc3C)c(C(=O)N3CCC4(CC3)COc3ccc(F)cc34)cnc12
Yield: 50.1 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(5-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.260 g, 0.569 mmol) obtained in step 2 and 2-methylaniline (0.091 mL, 0.853 mmol), the title compound (0.151 g, 50%) was obtained.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:27][S:26][C@@H:9]2[C@H:10]([NH:13][C:14](/[C:16](/[C:20]3[N:24]=[C:23]([NH2:25])[S:22][CH:21]=3)=[N:17]\[O:18][CH3:19])=[O:15])[C:11](=[O:12])[N:8]2[C:7]=1[C:28]([OH:30])=[O:29])=O.[N-:31]=[N+:32]=[N-:33].[Na+].[I-].[Na+]>P([O-])([O-])([O-])=O>[N:31]([CH2:5][C:6]1[CH2:27][S:26][C@@H:9]2[CH:10]([NH:13][C:14](=[O:15])/[C:16](/[C:20]3[N:24]=[C:23]([NH2:25])[S:22][CH:21]=3)=[N:17]\[O:18][CH3:19])[C:11](=[O:12])[N:8]2[C:7]=1[C:28]([OH:30])=[O:29])=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Agent: [Na+]
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]12)c1csc(N)n1
Reaction time: 4.5 h

Procedure:
To a solution of cefotaxime (5.24 g.) in phosphate buffer (pH 6.4, 440 ml.) was added sodium azide (2.86 g.) and sodium iodide (1.65 g.) and the mixture was immersed in a 70° bath with stirring for 4.5 hours. The solvent was evaporated to the point of precipitation and then the pH adjusted to 2.5 with 2N aqueous HCl. The resulting precipitate was collected, washed with water, acetone and ether and dried over P2O5 to give 3-azidomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-methoxyimino)acetamido]ceph-3-em-4-carboxylic acid in quantative yield, having the following n.m.r. in solvent A: 3.4 (d, 1H); 3.7 (d, 1H); 3.86 (s, 3H); 3.95 (d, 1H); 4.4 (d, 1H); 5.15 (d, 1H); 5.78 (d, 1H); 6.75 (s, 1H).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[C:10]([N:12]3[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]3)=[N:9][CH:8]=[N:7][C:6]=2[NH:5][CH:4]=1.CCN(C(C)C)C(C)C.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34]>C(Cl)Cl>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33]([NH:18][CH:15]1[CH2:16][CH2:17][N:12]([C:10]2[N:9]=[CH:8][NH:7][C:6]3=[N:5][CH:4]=[C:3]([CH3:2])[C:11]=23)[CH2:13][CH2:14]1)=[O:34]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Cc1c[nH]c2ncnc(N3CCC(N)CC3)c12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(C(=O)NC2CCN(c3nc[nH]c4ncc(C)c3-4)CC2)c1
Reaction time: 18 h

Procedure:
To a mixture of 1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine hydrochloride D11 (70 mg) and DIPEA (0.159 mL, 0.908 mmol) in DCM (1 mL) was added 3-(methyloxy)benzoyl chloride (56.8 mg, 0.333 mmol) and the reaction stirred for 18 hours. The mixture was partitioned between DCM (4 mL) and aqueous sodium bicarbonate (4 mL). The organic phase was then washed with 2M HCl (4 mL) before it was dried (phase separator) and concentrated. The crude product was purified by MDAP but the product was not clean, so it was then purified by silica chromatography eluting 2-10% MeOH in DCM to give E24 (17 mg) as a white solid, 1H NMR (d6-DMSO) δ 11.53 (1H, s), 8.33 (1H, d), 8.22 (1H, s), 7.45 (1H, d), 7.41 (1H, s), 7.37 (1H, t), 7.08 (1H, d), 7.07 (1H, s), 4.12-3.99 (3H, m), 3.81 (3H, s), 3.04 (2H, t), 2.37 (3H, s), 1.94 (2H, d), 1.74 (2H, ddd), MS(ES+) 366 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][CH2:14][CH2:15][N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)OCC[O:9]2)=[CH:4][CH:3]=1.Cl>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:9])[CH2:13][CH2:14][CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2(CCCN3CCc4ccccc4C3)OCCO2)cc1
Agent: Cl
Solvent: CO
Product: O=C(CCCN1CCc2ccccc2C1)c1ccc(F)cc1
Yield: 106.5 %

Procedure:
Dioxolane 4A (2.75 g, 6.0 mmol) and 1 M HCl (15 mL) were stirred in MeOH (50 mL) at RT for 3 days. After concentration in vacuo the residue was extracted with EtOAc (400 mL) and 1 M NaOH (100 mL), then H20 (2×50 mL), and brine (25 mL). The solution was dried (Na2SO4), filtered, and concentrated to yield ketone 11A (1.9 g, quant.) as a yellow solid. 13C NMR(300 MHz, CDCl3, δ): 198.60, 165.59 (d, J=254 Hz), 134.85, 134.38, 133.56, 131.65 (d, J=9 Hz), 128.61, 126.56, 126.08, 125.56, 115.52 (d, J=22 Hz), 57.36, 56.08, 50.87, 36.14, 29.12, 21.79.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([CH3:25])[C:12]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=1)([OH:17])[C:13]([F:16])([F:15])[F:14])[C:5](O)=[O:6].[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[N:30]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:26][O:27][C:28]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([CH:11]([CH3:25])[C:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)([OH:17])[C:13]([F:16])([F:14])[F:15])=[C:2]([Cl:1])[CH:3]=2)[N:30]=1)=[O:36]
Reactant: COC(=O)c1cccc(N)n1
Reactant: CC(c1ccc(C(=O)O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)c1cccc(NC(=O)c2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)n1

Procedure:
In analogy to Example 26, step 4, 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzoic acid (Example 26, step 3), was reacted with 6-aminopicolinic acid methyl ester and HBTU at 80° C. 17 h to give the title compound as a white solid. MS (m/e)=528.3 [M+H+].
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[NH2:12][C:13]1[CH:14]=[C:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:9]([C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][NH:12][C:13]1[CH:14]=[C:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH:16]=[CH:17][CH:18]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(NCc2cccc([N+](=O)[O-])c2)c1
Yield: 96.2 %

Procedure:
To a solution of 1-(bromomethyl)-3-nitro-benzene (4.50 g, 0.021 mol) and tert-butyl (3-aminophenyl)carbamate (4.34 g, 0.021 mol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (4.32 g, 0.03 mol). The resultant mixture was stirred at room temperature overnight and the reaction was complete. The reaction mixture was filtered first to remove K2CO3, and then quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and then dried (Na2SO4), filtered and concentrated to give the desired product as a light brown gel (6.94 g, 97%). LCMS for C18H22N3O4 (M+H)+: m/z=344.1.
Reaction SMILES: [CH3:1][C:2]1[CH:43]=[CH:42][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:15][N:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]4[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=4)[N:17]=3)[CH2:13][CH2:12][N:11]2C(OC(C)(C)C)=O)=[O:9])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:15][N:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]4[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=4)[N:17]=3)[CH2:13][CH2:12][NH:11]2)=[O:9])=[CH:42][CH:43]=1
Reactant: COc1cc(Nc2nccc(N3CCN(C(=O)OC(C)(C)C)C(C(=O)NCc4ccc(C)cc4)C3)n2)cc(OC)c1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Nc2nccc(N3CCNC(C(=O)NCc4ccc(C)cc4)C3)n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
To a solution of 2.4 (43 mg, 0.073 mmol) in DCM was added TFA (10.8 μL, 0.145 mmol). The resulting solution was stirred at room temperature. After 18 hours, additional TFA (0.145 mmol) was introduced. After 30 hours, the reaction was concentrated. The material was brought up in MeOH (2 mL) and filtered through a Si-carbonate cartridge to give 2 in 89% yield. 1H NMR (300 MHz, CDCl3) δ ppm 1.86 (br. s., 1H) 2.31 (s, 3H) 2.79-3.07 (m, 2H) 3.25-3.37 (m, 1H) 3.40-3.54 (m, 2H) 3.75-3.97 (m, 10H) 4.09-4.22 (m, 1H) 4.39 (d, J=5.41 Hz, 2H) 6.10 (d, J=6.14 Hz, 1H) 6.87 (s, 2H) 7.11 (s, 4H) 7.26-7.34 (m, 1H) 8.00 (d, J=5.99 Hz, 1H); M+H 493.25580.
Reaction SMILES: C(OC([N:8]1[CH2:22][CH2:21][C:11]2[NH:12][C:13](=[O:20])[N:14]([CH2:17][C:18]#[CH:19])[C:15](=[O:16])[C:10]=2[CH2:9]1)=O)(C)(C)C.[ClH:23]>C(OCC)(=O)C.C(O)C>[ClH:23].[CH2:17]([N:14]1[C:15](=[O:16])[C:10]2[CH2:9][NH:8][CH2:22][CH2:21][C:11]=2[NH:12][C:13]1=[O:20])[C:18]#[CH:19]
Reactant: C#CCn1c(=O)[nH]c2c(c1=O)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: C#CCn1c(=O)[nH]c2c(c1=O)CNCC2

Procedure:
6-(tert-Butoxycarbonyl)-3 propargyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-dione (1.0 g) was suspended in 4 N hydrochloric acid in ethyl acetate (10 ml) and the resultant mixture was stirred at room temperature for 3 hours. A precipitate was obtained by filtration and dissolved in ethanol and the solvent was distilled away under reduced pressure. This was repeated three times to obtain the titled compound (790 mg) as a colorless amorphous substance. The resultant compound was subjected to a next reaction without further purifying.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=[O:8].[H-].[Na+].O.[CH3:13]N(C)C=O>>[CH3:13][O:8][C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)=[O:9]
Reactant: CN(C)C=O
Reactant: Cn1cccc1C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cccn1C
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: The solution of 28 g of 1-methylpyrrole-2-carboxylic acid in 20 ml of dimethylformamide is added to the suspension prepared from 12 g of 50% sodium hydride in mineral oil, washed with petroleum ether and suspended in 50 ml of dimethylformamide, while stirring and cooling. Thereupon 30 ml of methyl iodide are added and stirring is continued at ambient temperature. Another 10 ml of methyl iodide are added after the initial exothermic reaction has subsided. After standing overnight, the mixture is treated with water, extracted with diethyl ether, the extract washed with aqueous sodium carbonate and water, dried and evaporated, to yield the 1-methylpyrrole-2-carboxylic acid methyl ester as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:20][CH3:21])[C:18]=1[Br:19])[C:12]([O:14]C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:20][CH3:21])[C:18]=1[Br:19])[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(OC)c(Br)c(OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)cc(OCc2ccccc2)c1Br
Yield: 95.5 %

Procedure:
To a solution of methyl 3-(benzyloxy)-4-bromo-5-methoxybenzoate (3.72 g, 10.59 mmol) in 1:1 MeOH/THF (50 mL) was added aqueous sodium hydroxide (1 M, 53.0 mL, 53.0 mmol). After 10 minutes the volatiles were removed under reduced pressure and the solution acidified to pH 1 by addition of concentrated hydrochloric acid resulting in formation of a thick white precipitate. The mixture was extracted with ethyl acetate (2×), and DCM (3×). The combined extracts were washed with brine, dried over magnesium sulfate and concentrated to provide 3-(benzyloxy)-4-bromo-5-methoxybenzoic acid as a white solid (3.41 g). MS (M−1)=335.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.21-7.49 (m, 7H), 5.16 (s, 2H), 3.91 (s, 3H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([CH2:15][CH2:16][OH:17])[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][OH:14])[CH:7]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:17][CH2:16][CH2:15][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][OH:14])[CH:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1cccc(CCO)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cccc(CCO)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.67 mL) in DCM (2 mL) was added dropwise to a stirred solution at 0° C. of 2,2′-(1,3-phenylene)diethanol (1.30 g) and triethylamine (1.36 mL) in DCM (30 mL). The reaction mixture was stirred for 1 hour at 0° C. and then washed with water. The aqueous layer was re-extracted with DCM and the combined organic phases were dried, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 3% methanol in dichloromethane as solvent. Fractions containing the product were evaporated to dryness to afford the titled compound. Yield 0.52 g.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[CH:15][C:14]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:13][CH:12]=3)=[O:5])[CH3:2].[CH:30](O)(C)C>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[CH:15][C:14]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[CH:13][CH:12]=3)=[O:5])([CH3:30])[CH3:2]
Reactant: CC(C)O
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(OCc4ccccc4)cc3c2c1COC
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Yield: 80 %

Procedure:
1.4 g (3.6 mmol) of 6-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester is boiled under reflux for 2 hours in 100 ml of isopropanol with 0.7 ml (2.2 mmol) of titanium tetraisopropoxide. After concentration, the mixture is taken up in 80 ml of 1N hydrochloric acid and extracted by shaking with 250 ml of ethyl acetate. The ethyl acetate phase is washed with a small amount of water, dried, filtered, and concentrated. After chromatography over silica gel with methylene chloride:acetone=4:1 as the eluent, the 6-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester, mp 150°-151° C., is obtained in an 80% yield.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:13]1([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:15][CH2:14]1.[Cl-].[NH4+]>C(O)CCC>[CH:13]1([N:16]2[CH2:21][CH2:20][N:19]([C:2]3[S:3][C:4]4[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:5]=4[N:6]=3)[CH2:18][CH2:17]2)[CH2:15][CH2:14]1
Reactant: N#Cc1ccc2nc(Cl)sc2c1
Reactant: C1CN(C2CC2)CCN1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCO
Product: N#Cc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Yield: 43 %

Procedure:
A suspension of 2-chlorobenzothiazole-6-carbonitrile (3.5 g, 18 mmol), 1-cyclopropyl-piperazine (3.63 g, 28.8 mmol) and ammonium chloride (0.96 g, 18 mmol) in butan-1-ol (112 mL) was heated at reflux for 48 h. The solvent was removed under reduced pressure and the residue was diluted with water (30 mL). The mixture was made alkaline with potassium carbonate and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were concentrated to give a residue which was purified by column chromatography on silica gel (20% ethyl acetate in petroleum ether) to give 2.2 g (43 5) of 2-(4-cyclopropylpiperazin-1-yl)-benzothiazole-6-carbonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[OH:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:28]([C:25]3[CH:24]=[CH:23][C:22]([OH:21])=[CH:27][N:26]=3)=[O:29])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: O=C(O)c1ccc(O)cn1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1ccc(O)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 5-hydroxy-2-pyridinecarboxylic acid (CAN 15069-92-8) as starting materials; LC-MS (UV peak area/ESI) 96.3%, 422.0523 (M−H)−.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][CH3:22])=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][N:21]([CH3:22])[C:2](=[O:3])[O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:17][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNCCc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCc1ccc(Br)cc1)C(=O)OCc1ccccc1
Yield: 64.8 %

Procedure:
Benzyl chloroformate (0.97 mL, 6.7 mmol) was added dropwise to a solution of 23B (1.1 g, 5.1 mmol)in CH2Cl2 (26 mL) and triethylamine (1 mL, 7.5 mmol). The reaction mixture washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography (0% to 50% EtOAc in hexanes) afforded 28C (1.15 g, 65%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 2.70-2.94 (m, 5 H) 3.47 (m, 2 H) 5.08 (m, 2 H) 6.90-7.12 (m, 2 H) 7.26-7.44 (m, 7 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C@@H:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>ClCCl>[CH3:20][O:19][C:17](=[O:18])[CH:13]([NH:12][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:14]([CH3:16])[CH3:15]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: COC(=O)[C@H](N)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(NS(=O)(=O)c1ccc(Br)cc1)C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
Step 1A [Intermediate 1] To a dry round-bottom flask was added 4-Bromo-benzenesulfonyl chloride (12.2 g, 47.7 mmol, 1 equiv.), anhydrous methylene chloride (170 mL), and H-D-Val-OMe (8.0 g, 47.7 mmol, 1 equiv.). The mixture was cooled to 0° C. in an ice bath followed by the addition of Hunig base (19.11 mL, 109.7 mmol, 2.3 equiv.). The reaction mixture was allowed to warm to room temperature and was stirred overnight. Reaction was complete as determined by TLC. The reaction mixture was then diluted with dichloromethane (100 mL) and washed with brine. The organic layer was dried over anhydrous MgSO4, solvent evaporated to yield 2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid methyl ester in 96% yield (16.0 g). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.87 (d, J=6.82 Hz, 3 H) 0.96 (d, J=6.82 Hz, 3 H) 2.04 (m, 1 H) 3.49 (s, 3 H) 3.74 (d, J=14.40 Hz, 1 H) 5.10 (d, J=9.85 Hz, 1 H) 7.66 (m, 4 H
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:12][C:11]([NH2:21])=[N:10]1.[C:22](OC(=O)C)(=[O:24])C>C(O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[CH:12][C:11]([NH:21][CH:22]=[O:24])=[N:10]1
Reactant: Nc1cc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)n1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNc1cc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)n1
Reaction time: 0.5 h

Procedure:
0.50 g of 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazol-3-ylamine, obtained in the previous Example, is added in small portions to a mixture of 4 ml of formic acid and 0.5 ml of acetic anhydride, cooled in an ice bath. After stirring for 30 min, the solvents are evaporated off under vacuum and the residue is taken up in isopropyl ether. The white solid obtained is filtered off, washed with isopropyl ether and dried under vacuum to give 0.49 g of the expected formamide.