Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[N:2]1.C(N(C(C)C)CC)(C)C.[CH3:39][N:40]1[CH:44]=[C:43]([S:45](Cl)(=[O:47])=[O:46])[N:42]=[C:41]1[CH3:49]>C(Cl)Cl>[S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[S:45]([C:43]2[N:42]=[C:41]([CH3:49])[N:40]([CH3:39])[CH:44]=2)(=[O:47])=[O:46])=[N:2]1
Reactant: COc1ccc(-c2ccc(CNCCCNc3nsc4ncccc34)cc2)cc1
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2ccc(CN(CCCNc3nsc4ncccc34)S(=O)(=O)c3cn(C)c(C)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
N1-(Isothiazolo[5,4-b]pyridin-3-yl)-N3-((4′-methoxybiphenyl-4-yl)methyl)propane-1,3-diamine (100 mg, 0.25 mmol) was dissolved in anhydrous methylene chloride with diisopropylethylamine (0.11 mL, 0.63 mmol). The mixture was cooled in an ice-bath under nitrogen and a solution of 1,2-dimethylimidazole-4-sulfonyl chloride (58.4 mg, 0.30 mmol) in methylene chloride (5 mL) was added dropwise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride and then washed successively with saturated sodium bicarbonate solution and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-scale reverse phase high performance liquid chromatography to yield N-(3-(isothiazolo[5,4-b]pyridin-3-ylamino)propyl)-N-((4′-methoxybiphenyl-4-yl)methyl)-1,2-dimethyl-1H-imidazole-4-sulfonamide (45 mg). 1H NMR (300 MHz, DMSO-d6): 8.64-8.66 (d, 1H), 8.45-8.50 (d, 1H), 7.52-7.75 (m, 8H), 7.28 (s, 1H), 6.95 (s, 1H), 6.82 (s, 1H), 3.99 (s, 2H), 3.89 (s, 3H), 3.55-3.65 (m, 5H), 2.88-2.90 (t, 2H), 2.50 (s, 3H), 1.99-2.10 ppm (t, 2H). MW=563 confirmed by LC-MS, tr=4.31 min (Method E) MH+=564.
Reaction SMILES: B([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(O)O.Br[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.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>[N:17]1[CH:18]=[CH:19][C:14]([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=2)=[CH:15][CH:16]=1
Reactant: Brc1ccncc1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1ccc(-c2ccncc2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 90.4 %

Procedure:
To a solution of 4-boronobenzoic acid (1.66 g, 10 mmol) and 4-bromopyridine (1.72 g, 11 mmol) in acetonitrile (40 mL) and water (40 mL), potassium carbonate (5.5 g, 40 mmol), Bis(triphenylphosphine)palladium(II) chloride (400 mg, 0.37 mmol) was added. The mixture was degassed and purged withed nitrogen. The mixture was stirred at 100° C. for 24 h. Then the hot suspension was filtered and concentrated to half of the original volume and washed with dichloromethane. The aquatic phase was adjusted to pH=3 with hydrochloric acid (1 M) and filtrated, washed with water. The residue was dried in vacuum to obtain 1.8 g of white solid of 4-(pyridin-4-yl)benzoic acid. Yield: 90%. LC-MS (ESI) m/z: 200 (M+1)+.
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8](=[O:37])[N:9]=[C:10]([S:35][CH3:36])[C:11]([C:25]1[CH:30]=[C:29]([OH:31])[CH:28]=[C:27]([O:32][CH2:33][CH3:34])[CH:26]=1)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][CH2:46][O:47][CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][O:49]1>O>[CH3:6][O:7][C:8](=[O:37])[N:9]=[C:10]([S:35][CH3:36])[C:11]([C:25]1[CH:30]=[C:29]([O:31][CH2:45][CH2:46][O:47][CH:48]2[CH2:53][CH2:52][CH2:51][CH2:50][O:49]2)[CH:28]=[C:27]([O:32][CH2:33][CH3:34])[CH:26]=1)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: BrCCOC1CCCCO1
Reactant: CCOc1cc(O)cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(OCCOC2CCCCO2)cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1 ml of a DMF solution containing 80 mg of {2-(3-ethoxy-5-hydroxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (78a)), 200 mg of potassium carbonate and 0.1 ml of 2-(2-bromoethoxy)tetrahydro-2H-pyran were added. The resulting mixture was stirred at room temperature overnight, and then water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give {2-{3-ethoxy-5-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (76 mg) as a yellow oil.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.Cl.[CH2:21]([O:23][C:24](=[O:31])[C@H:25]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH2:26])[CH3:22].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:21]([O:23][C:24](=[O:31])[CH:25]([NH:26][C:16]([C@@H:11]1[CH2:12][S:13][CH2:14][CH2:15][N:10]1[S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=1)(=[O:8])=[O:9])=[O:18])[CH2:27][CH:28]([CH3:29])[CH3:30])[CH3:22]
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C(CC(C)C)NC(=O)[C@@H]1CSCCN1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.3 %

Procedure:
0.301 g (1 mmol) of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.215 g (1.1 mmol) of L-leucine ethyl ester hydrochlorid, 0.227 g (1.2 mmol) of DCC and 0.122 g (1 mmol) of DMAP were dissolved in 30 mL of CH2Cl2, 0.2 ml (1.4 mmol) of TEA was added. The mixture was stirred for 24 h at room temperature. The solid was filtrated and the solvent was evaporated. The residual was dissolved in a suitable amount of ethyl acetate (20 ml) and then the mixture was filtered to remove insoluble substance. The ethyl acetate was added to 60 ml and then the liquid was washed with 10% NaHCO3 solution, saturated NaCl solution and dried over Na2SO4. After the drying agent was removed and part of ethyl acetate was evaporated, the crude product was purified by flash column chromatography (eluent: CH2Cl2:CH3Cl=1:1) to obtain the product as a oil (0.36 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:19]([OH:21])=[O:20])[CH:7]([C:15]([F:18])([F:17])[F:16])[O:8]2.[Cl:22]Cl>C(O)(=O)C.[Zn]>[Cl:22][C:12]1[C:3]([O:2][CH3:1])=[C:4]2[C:9](=[CH:10][C:11]=1[O:13][CH3:14])[O:8][CH:7]([C:15]([F:16])([F:17])[F:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2
Reactant: COc1cc(OC)c2c(c1)OC(C(F)(F)F)C(C(=O)O)=C2
Reactant: ClCl
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1cc2c(c(OC)c1Cl)C=C(C(=O)O)C(C(F)(F)F)O2
Reaction time: 2 h
Yield: 17.2 %

Procedure:
The solution of the 5,7-dimethoxy-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid from Example 34 (WO 00/23433) (150 mg, 0.49 mmole) in acetic acid (1.0 mL) was stirred at 10° C. The pre-prepared solution of Cl2 (gas) in acetic acid (1.1 mL, 0.64 mmol) was added to above solution. The mixture was stirred for 2 hours. After Cl2 (gas) was blown away, Zn powder (5 eq) was added to the mixture and the mixture was stirred for 30 min. Zn salts were removed by filtration and the filtrate was evaporated to dryness. The residue was purified by RPHPLC and eluted with 30 to 85% ACN in water with 0.05% TFA. The Ist peak fractions were combined to give the desired compound 28.6 mg (17.2%) as mono-chloro compound: LCMS m/z 339.05 (M+H) at 5.474 min. ESHRMS m/z 337.0112 (M−H, C13H9O5F3Cl, Calc'd 337.0085). 1H NMR (CDCl3/400 MHz) 7.90 (s, 1H), 6.67 (s, 1H), 5.82 (q, 1H, J=6.8 Hz), 3.97 (s, 3H), 3.94 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=O)[CH:8]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:39][CH2:40][CH:41]([OH:53])[CH2:42][N:43]1[CH2:52][CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1>C(Cl)Cl>[CH2:44]1[C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:51][CH2:52][N:43]1[CH2:42][CH:41]([OH:53])[CH2:40][NH:39][C:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2)=[O:14]
Reactant: Cc1ccc2cc(C(=O)O)ccc2n1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2cc(C(=O)NCC(O)CN3CCc4ccccc4C3)ccc2n1
Temperature: 15 °C
Reaction time: 16 h
Yield: 52.9 %

Procedure:
To a solution of 2-methylquinoline-6-carboxylic acid (100 mg, 0.535 mmol) in DCM (20 mL) was added HATU (244 mg, 0.642 mmol) and TEA (162 mg, 1.604 mmol). The mixture was stirred at 15° C. for 30 minutes before 1-amino-3-(3,4-dihydro isoquinolin-2(1H)-yl)propan-2-ol (110 mg, 0.535 mmol) was added. The resulting mixture was stirred for another 16 h at 15° C., at which point LCMS showed the completion of the reaction. The mixture was concentrated and the residue was purified by Preparation HPLC to give the desired title compound (106.2 mg, 53%). 1H NMR (400 MHz, METHANOL-d4) δ=8.32 (d, J=1.9 Hz, 1H), 8.14 (d, J=8.4 Hz, 1H), 8.09 (dd, J=2.1, 8.8 Hz, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.16-7.08 (m, 3H), 7.08-7.03 (m, 1H), 4.18 (quin, J=6.1 Hz, 1H), 3.79 (s, 2H), 3.59 (d, J=5.8 Hz, 2H), 2.94-2.88 (m, 4H), 2.79-2.68 (m, 5H). LCMS (m/z): 376.0 (M+1).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[C:6]([O:10][C:11](=[O:20])[NH:12][CH2:13][C:14](=[O:19])N(OC)C)([CH3:9])([CH3:8])[CH3:7].C(OCC)(=O)C>O1CCCC1>[C:6]([O:10][C:11](=[O:20])[NH:12][CH2:13][C:14]([CH:1]1[CH2:3][CH2:2]1)=[O:19])([CH3:7])([CH3:8])[CH3:9]
Reactant: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC(=O)C1CC1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To 22 ml of a 0.5M solution of cyclopropylmagnesium bromide in tetrahydrofuran was added 2.2 g [(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester at −10° C. (acetone/ice) and the mixture was stirred at −10° C. for 30 min and then at ambient temperature for 30 min. (tic shows little conversion heptanes:ethyl acetate=1:1) To the resulting colorless solution was added another 22 ml of a 0.5M solution of cyclopropylmagnesium bromide in tetrahydrofuran and the mixture was stirred at ambient temperature for 18 h. The reaction mixture was quenched by addition of 10% citric acid. The phases were separated and the organic phase was purified by chromatography on silica gel with a gradient of heptane:ethyl acetate=9:1 to 1:1 to yield 1.300 g of the title compound as colorless oil. MS (EI): 199 (M+).
Reaction SMILES: N(C(N1CCNCC1)=O)=NC(N1CCNCC1)=O.[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]([CH:29]=[N:30][O:31][CH2:32][CH2:33][OH:34])[CH:20]=1.O[C:36]1[CH:68]=[CH:67][C:39]([CH2:40][CH:41]2[S:45][C:44](=[O:46])[N:43]([C:47]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:42]2=[O:66])=[CH:38][CH:37]=1.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.O1CCCC1>[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]([CH:29]=[N:30][O:31][CH2:32][CH2:33][O:34][C:36]2[CH:68]=[CH:67][C:39]([CH2:40][CH:41]3[S:45][C:44](=[O:46])[N:43]([C:47]([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)[C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:42]3=[O:66])=[CH:38][CH:37]=2)[CH:20]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCON=Cc1cnc2ccccc2c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCNCC1)N1CCNCC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1SC(Cc2ccc(OCCON=Cc3cnc4ccccc4c3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 16 h
Yield: 92.5 %

Procedure:
A solution of 0.73 g of 1,1'-(azodicarbonyl)dipiperazine in 10 ml of toluene was added dropwise at room temperature to a suspension of 0.60 g of 2-(3-quinolylmethyleneaminooxy)ethanol (prepared as described in Preparation 3), 1.10 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione and 0.72 ml of tributylphosphine in 30 ml of tetrahydrofuran, and the resulting mixture was stirred for 16 hours. At the end of this time, the reaction product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.45 g of the title compound as a crystalline powder, melting at 127-130° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1.[C:29]([O:33][C:34]([N:36]1[CH2:40][CH2:39][N:38]=[C:37]1SC)=[O:35])([CH3:32])([CH3:31])[CH3:30]>CO.C(Cl)(Cl)Cl>[C:29]([O:33][C:34]([N:36]1[CH2:40][CH2:39][N:38]=[C:37]1[NH:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CSC1=NCCN1C(=O)OC(C)(C)C
Reactant: Cc1c(N)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1c(NC2=NCCN2C(=O)OC(C)(C)C)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Temperature: 70 °C
Reaction time: 8 h
Yield: 33.6 %

Procedure:
A mixture of 6-amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile hydrochloride (Example 11) (49 mg, 0.125 mmol) and 2-methylsulfanyl-4,5-dihydro-imidazole-1-carboxylic acid tert-butyl ester (25.5 mg, 0.125 mmol) in MeOH (2 ml) was heated at 70° C. for 3 h, then cooled to rt and stirred overnight. The reaction mixture was diluted with CHCl3 (25 ml), washed with saturated NaHCO3 (10 ml) dried with Na2SO4. Concentrated in vacuo and purified by prep. TLC to give 424A (22 mg, 97%) as pale yellow flakes (5% MeOH—CHCl3). It has a retention time of 6.82 min (standard LC1 method, 8 min run). MS Found: (M+M)+=523.9
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]([OH:36])[CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35]>CCOC(C)=O>[CH2:14]([O:36][S:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)(=[O:11])=[O:12])[CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCOCCOCCOCCOCCOCCOCCO
Solvent: CCOC(C)=O
Product: COCCOCCOCCOCCOCCOCCOCCOS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 78.3 %

Procedure:
6.7 g (60 mmol) of TEA are dropwise added, in 10 min, to a solution of 13.3 g (60 mmol) of 4-nitrobenzenesulfonyl chloride (marketed product) and of 20.4 g (60 mmol) of 3,6,9,12,15,18,21-heptaoxadocosan-1-ol (according to Liebigs Ann. Chem. 1980, 858-862) in 60 mL of AcOEt. After 2 h at the temperature of 20° C., the precipitated TEA hydrochloride is filtered off, washing with 10 mL of AcOEt for three times. The filtrates are collected, washed with 30 mL of H2O, 20 mL of 2N HCl and then with H2O to reach a neutral pH. The organic phase is evaporated to dryness, to give a thick oil which is directly used in the successive step without a further purification. 25 g (47 mmol) of the desired product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[F:12].C(NCC)C.[CH:18]1([NH2:21])[CH2:20][CH2:19]1>O>[Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:7]=1)[NH:21][CH:18]1[CH2:20][CH2:19]1
Reactant: O=[N+]([O-])c1cc(F)c(Cl)cc1F
Reactant: NC1CC1
Solvent: CCNCC
Solvent: O
Product: O=[N+]([O-])c1cc(F)c(Cl)cc1NC1CC1
Reaction time: 16 h
Yield: 79.9 %

Procedure:
1-Chloro-2,5-difluoro-4-nitrobenzene (3.69 g, 19 mmol) is treated at 0° with diethylamine (2.3 g, 23 mmol) and cyclopropylamine (1.3 g, 23 mmol). After 1 hour at 0° the suspension obtained is stirred at 25° for 16 hours. The reaction mixture is taken up in water (150 ml) and extracted with ethyl acetate. The organic phase is washed with 10 percent sodium chloride solution and dried over magnesium sulfate. After distillation of the solvent the residue is recrystallized from ethanol (50 ml). There are obtained 3.5 g (79%) of 5-chloro-N-cyclopropyl-4-fluoro-2-nitroaniline with a m.p. of 73.5°-75.5°.
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH2:12])=[C:10]([NH:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:18](OC(OCC)OCC)C>C(O)C>[Cl:1][C:2]1[C:11]2[N:12]=[CH:18][N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CC(C)CNc1c(N)c(Cl)nc2ccccc12
Reactant: CCOC(OCC)OCC
Solvent: CCO
Product: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21
Temperature: 25 °C
Yield: 92 %

Procedure:
A suspension of 2-chloro-N4 -(2-methylpropyl)-3,4-quinolinediamine (35 g) and triethylorthoformate (52.3 g, 2.5 eq) was heated at 145° C. for 10 h, during which time ethanol was removed by distillation. The resulting mixture was cooled to room temperature and the solid was removed by filtration. The solid was dissolved in hydrochloric acid (100 mL, 4N). The resulting solution was added to a solution of sodium hydroxide. The precipitate was filtered and washed with water to afford the product 4-chloro-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline in 92% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([S:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[CH:3]=1.O.[OH-].[Na+]>C(O)(=O)C.[Fe]>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([S:12][C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:18][CH:17]=1
Reactant: O=C(O)Cc1ccc(F)cc1Sc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(Sc2cc(F)ccc2CC(=O)O)cc1
Reaction time: 8 h
Yield: 55.4 %

Procedure:
A solution of 19 g [4-fluoro-2-(4-nitrophenylthio)phenyl] acetic acid in 60 ml of acetic acid was slowly added dropwise into a boiling mixture of 300 ml water and 30 g iron powder. The mixture was then stirred and refluxed for 6 hours. After cooling, 200 ml of a 20% sodium hydroxide solution were added, the solution filtered and the filtrate acidified with acetic acid. After standing overnight, the separated product was filtered, washed with a small quantity of water and dried in vacuo. There were obtained 9.5 g of crude [2-(4-aminophenylthio)-4-fluorophenyl]acetic acid melting at 151°-155° C. After a single crystallization from a mixture of benzene and petroleum ether, the product was pure and melted at 154°-156° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[F:20][C:21]([F:32])([F:31])[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>CCO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])/[CH:12]=[CH:27]/[C:26]2[CH:29]=[CH:30][C:23]([O:22][C:21]([F:20])([F:31])[F:32])=[CH:24][CH:25]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(/C=C/C(C)=O)cc1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(/C=C/C(=O)/C=C/c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 11.9 %

Procedure:
A suspension of (E)-4-(4-methoxyphenyl)-but-3-en-2-one (615 mg, 3.5 mmol) in EtOH (10 mL) was stirred for 5 min at 0° C. A solution of K2CO3 (965 mg, 7.0 mmol) in H2O (5 mL) was added and the reaction mixture was stirred for further 10 min at 0° C. After the dropwise addition of 4-(trifluoromethoxy)-benzaldehyde (528 μl, 3.7 mmol), the pale yellow suspension was stirred for further 4 h at 0° C. The resulting yellow precipitate was filtered and dried in vacuo to obtain NW350 as a pale yellow solid (145 mg, 12%). mp: 105-107° C.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10](Br)=[CH:9][N:8]=1.[F:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:17]=1[CH:18]=[O:19].[Cl-].[NH4+]>C(OCC)C.CCCCCC>[Br:6][C:7]1[N:8]=[CH:9][C:10]([CH:18]([C:17]2[C:20]([F:25])=[CH:21][CH:22]=[C:23]([F:24])[C:16]=2[F:15])[OH:19])=[C:11]([CH3:13])[CH:12]=1
Reactant: Cc1cc(Br)ncc1Br
Reactant: O=Cc1c(F)ccc(F)c1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1cc(Br)ncc1C(O)c1c(F)ccc(F)c1F
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
A hexane solution of n-butyllithium (1.54 M, 12.2 ml, 18.7 mmol) was added to a solution of 2,5-dibromo-4-methylpyridine (4.27 g, 17.0 mmol) in diethyl ether (200 ml) in an argon atmosphere at −78° C. After stirring the reaction mixture for 30 minutes, 2,3,6-trifluorobenzaldehyde (1.99 ml, 17.0 mmol) was added thereto. After stirring for 30 minutes at the same temperature, saturated aqueous ammonium chloride was added to the mixture at room temperature. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=4:1 was concentrated under reduced pressure to obtain the title compound (4.60 g, 13.9 mmol, 81%) as a pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[N:18]=[C:17]([O:33][CH2:34][CH2:35][C:36]([OH:38])=O)[C:16]=2[O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[O:46][CH3:47])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:48]([C:51]1[CH:57]=[CH:56][CH:55]=[CH:54][C:52]=1[NH2:53])([CH3:50])[CH3:49]>>[CH:48]([C:51]1[CH:57]=[CH:56][CH:55]=[CH:54][C:52]=1[NH:53][C:36](=[O:38])[CH2:35][CH2:34][O:33][C:17]1[C:16]([O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[O:46][CH3:47])=[C:15]([NH:14][S:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:10][CH:9]=2)(=[O:13])=[O:12])[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:23][CH2:22]2)[N:18]=1)([CH3:50])[CH3:49]
Reactant: CC(C)c1ccccc1N
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCN(c3ccccc3)CC2)nc1OCCC(=O)O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCN(c3ccccc3)CC2)nc1OCCC(=O)Nc1ccccc1C(C)C

Procedure:
The procedure described in Example 2 was repeated by use of 3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(4-phenylpiperazinyl)-4-pyrimidinyloxy]propionic acid and 2-isopropylaniline, to thereby obtain the title compound as a pale yellow oil.