Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1.C(C1C=CC=CC=1CO)CC1C=CC=CC=1.[NH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C([O-])([O-])=O.[K+].[K+]>>[C:18]1([CH2:17][CH2:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([N:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[N:3]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C1CNCCN1
Reactant: Clc1cncc(OCc2ccccc2CCc2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: OCc1ccccc1CCc1ccccc1
Agent: [K+]
Product: c1ccc(CCc2ccccc2COc2cncc(N3CCNCC3)n2)cc1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-{[2-(2-phenylethyl)benzyl]oxy}pyrazine (1.72 g, 5.30 mmol; obtained according to the procedure of example 50, step 1, starting from 2-phenethylbenzyl alcohol), piperazine (1.37 g, 16.0 mmol) and K2CO3 (0.73 g, 5.3 mmol). The yield of the title compound was 1.38 g (69%) which was obtained as an oil. Purity 100% (HPLC). MS m/z 375 (M+H)+. HRMS m/z calcd for C23H26N4O (M)+ 374.2107, found 374.2113.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([C:12](=[O:39])[CH2:13][NH:14][C:15]([C@@H:17]2[CH2:21][C@@H:20]([S:22]C(=O)C)[CH2:19][N:18]2[S:26]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)(=[O:28])=[O:27])=[O:16])[CH3:11])=[CH:6][CH:5]=1.[CH3:41][O-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:40])[C:4]1[CH:5]=[CH:6][C:7]([N:10]([C:12](=[O:39])[CH2:13][N:14]([C:15]([C@@H:17]2[CH2:21][C@@H:20]([SH:22])[CH2:19][N:18]2[S:26]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)(=[O:28])=[O:27])=[O:16])[CH3:41])[CH3:11])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(N(C)C(=O)CNC(=O)[C@@H]2C[C@@H](SC(C)=O)CN2S(=O)(=O)c2ccc3ccccc3c2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(N(C)C(=O)CN(C)C(=O)[C@@H]2C[C@@H](S)CN2S(=O)(=O)c2ccc3ccccc3c2)cc1
Yield: 94 %

Procedure:
80 mg (0.134 mmol) (2S,4R)-4-[[[[4-Acetylsulfanyl-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carbonyl]-amino]-acetyl]-methyl-amino]-benzoic acid methyl ester in 5 ml methanol were treated with 335 μl 0.6M (0.2 mmol) sodium methanolate in methanol at 0° C. for 1 h. The solution was poured on EtOAc/1M KHSO4 and the inorganic phase was extracted with EtOAc, the organic phases were washed with brine, dried over Na2SO4 and were evaporated. Column chromatography with EtOAc yielded 70 mg (quant) (2S,4R)-4-[[[[4-Mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carbonyl]-methyl-amino]-acetyl]-methyl-amino]-benzoic acid methyl ester as white foam, MS: 556 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]=[C:14]([NH:17][C:18]3[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=3)[C:21]([O:23]CC)=[O:22])[N:15]=[CH:16][C:11]=2[CH:10]=1.[OH-].[Na+].C(O)(=O)C>CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]=[C:14]([NH:17][C:18]3[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=3)[C:21]([OH:23])=[O:22])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CCOC(=O)c1cccc(Nc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(C)c3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3cccc(C(=O)O)c3)nc21

Procedure:
A quantity of 0.065 g (0.139 mmol) of 3-[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-benzoic acid, ethyl ester of Example 89 was dissolved in 75 mL of boiling methanol. 2N Sodium hydroxide (2 mL) was added, and the clear solution was maintained at reflux for 2 hours. The solution was concentrated with stirring to ca. 15 mL volume. The turbid solution was filtered hot to remove traces of solid. The filtrate was concentrated to ca. 4 mL volume. Water (5 mL) was added to give a turbid mixture. Glacial acetic acid (1 mL) was added to precipitate a flocculent solid. The solid was filtered, washed well with water, and dried; wt 0.048 g. Purification was accomplished by dissolution in 4 mL of warm dimethylformamide and addition of 20 mL of ether, The crystals that slowly separated from the clear solution were filtered and washed with ether and then water (to remove any traces of sodium acetate); wt 0.025 g; mp >300° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][N:3]=1.C(O[CH:17]=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>>[CH3:13][O:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([NH:1][CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:3][CH:4]=1
Reactant: COc1cnc(N)c2ccccc12
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ncc(OC)c2ccccc12)C(=O)OCC
Reaction time: 0.1 h

Procedure:
A mixture of 1-amino-4-methoxyisoquinoline (297 mg., 1.7 mmoles) and diethyl ethoxymethylenemalonate (370 mg., 1.7 mmoles) was plunged into an oil bath at 110° and kept there for 6 minutes. The mixture melted and then solidified. The crude product, m.p. 150°-153°, was used without purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.[Pd].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>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH:19]=[C:20]([C:2]2[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][N:3]=2)[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1cc(Cl)ncn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ncn1
Reaction time: 0.25 h

Procedure:
0.5 g tetrakis(triphenylphosphine) palladium was added to 1.3 g 4-chloro-6-methoxy-pyrimidine and 4-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester) and 9 mL 2 mol/L sodiumcarbonate in 40 mL dioxane. The reaction was stirred 15 min. under microwave conditions. Water was added and the reaction was extracted with DCM. The organic layer was dried and evaporated. The residue was purified by HPLC to give 1.44 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:23]([NH2:25])[CH3:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([NH:25][CH2:23][CH3:24])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Reactant: CCN
Product: CCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1

Procedure:
This compound was prepared by a procedure similar to that described in Example 40 starting with 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 37 and ethylamine gas; mp 180°-182° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=[N:12][O:13][C:14]([C:17](=[O:30])[NH:18][NH:19][C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([OH:28])[CH:22]=2)([CH3:16])[CH3:15])[C:9]([OH:11])=O)[N:7]=1.[NH2:31][CH:32]1[C:70](=[O:71])[N:34]2[C:35]([C:54]([O:56]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:55])=[C:36]([CH2:39][S:40][C:41]3[N:46]4[N:47]=[C:48]([CH2:50][OH:51])[N:49]=[C:45]4[N:44]=[C:43]([CH2:52][OH:53])[CH:42]=3)[CH2:37][S:38][C@H:33]12.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.C(=O)([O-])O.[Na+:116]>CN(C=O)C.O.CCOCC>[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=[N:12][O:13][C:14]([C:17](=[O:30])[NH:18][NH:19][C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([OH:28])[CH:22]=2)([CH3:15])[CH3:16])[C:9]([NH:31][CH:32]2[C:70](=[O:71])[N:34]3[C:35]([C:54]([O-:56])=[O:55])=[C:36]([CH2:39][S:40][C:41]4[N:46]5[N:47]=[C:48]([CH2:50][OH:51])[N:49]=[C:45]5[N:44]=[C:43]([CH2:52][OH:53])[CH:42]=4)[CH2:37][S:38][C@H:33]23)=[O:11])[N:7]=1.[Na+:116]
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3cc(CO)nc4nc(CO)nn34)CS[C@H]12
Reactant: CC(C)(ON=C(C(=O)O)c1csc(N)n1)C(=O)NNC(=O)c1ccc(O)c(O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: COc1ccccc1
Product: CC(C)(ON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(CSc3cc(CO)nc4nc(CO)nn34)CS[C@H]12)c1csc(N)n1)C(=O)NNC(=O)c1ccc(O)c(O)c1
Reaction time: 0.25 h

Procedure:
In 30 ml of DMF were dissolved 3.22 g of 2-(2-amino-1,3-thiazol-4-yl)-2-{1-[3-(3,4-dihydroxybenzoyl)carbazoyl]-1-methylethoxyimino}acetic acid.hydrochloride, 5.32 g of diphenylmethyl 7-amino-3-[(2,5-bis(hydroxymethyl)-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylate obtained in Example 42 and 1.38 g of 1-hydroxybenzotriazole and ice-cooled. Then, 1.86 g of DCC was added thereto and the mixture was stirred for 15 minutes under ice-cooling, and further stirred at room temperature for one hour. After the reaction mixture was filtered, 15 ml of chloroform was added thereto and the mixture was added dropwise into 2 liters of ether. Precipitates were collected by filtration, washed with ether and then dried. Powder obtained was purified through silica gel column chromatography to obtain powder. A mixed solution of 30 ml of trifluoroacetic acid and 8 ml of anisole was icecooled and the powder previously obtained was added thereto, and the mixture was stirred for 30 minutes and added dropwise into 400 ml of ether. Precipitates were collected by filtration, washed with ether and then dried to obtain powder. The powder was suspended in 200 ml of water and dissolved at pH 7 by adding a 5 % sodium hydrogencarbonate solution. After the resulting solution was adsorbed to 200 ml of HP 20 column filled with water, it was washed with water. Subsequently, the mixture was eluted with a 50 % methanol - water. After evaporation of methanol, the residue was freeze-dried to obtain 4.16 g of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].C1N=CN(C(N2C=NC=C2)=O)C=1.[C:25](O)([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[C:25]([O:11][C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:12])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CC(C)(C)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.00 g (6.21 mmol) indole-2-carboxylic acid is dissolved in 15 ml absolute THF, mixed with 1.01 g (6.23 mmol) N,N-carbonyldiimidazole and stirred at room temperature for 1 hour. Thereafter, 0.77 g (6.86 mmol) potassium-tert-butylate and 9.12 g (123 mmol) tert-butanol are added. Following heating under reflux for 6 hours, quenching using 5 ml water, filtrating off, rinsing with THF, drying on sodium sulfate and concentration on the rotary evaporator, a brown solid is obtained as the crude product. Preliminary purification by means of column chromatography on silica gel using a short column with petroleum ether/ethyl acetate 95:5 leaves a white solid which is purified on silica gel by means of column chromatography (flow agent: petroleum ether/ethyl acetate 98:2) and yields the product as a white solid.
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6]C=C[C:3]=1[CH2:9][S:10]([C:13]1[N:22]=[C:21]([NH:23][CH:24]([CH2:27][OH:28])[CH2:25][OH:26])[C:20]2[N:19]=[CH:18][C:17](=[O:29])[NH:16][C:15]=2[N:14]=1)(=O)=O.[S:30]1C=CC=C1CS>>[OH:26][CH2:25][CH:24]([NH:23][C:21]1[C:20]2[N:19]=[CH:18][C:17](=[O:29])[NH:16][C:15]=2[N:14]=[C:13]([S:10][CH2:9][C:3]2[S:30][CH:6]=[CH:7][CH:2]=2)[N:22]=1)[CH2:27][OH:28]
Reactant: SCc1cccs1
Reactant: O=c1cnc2c(NC(CO)CO)nc(S(=O)(=O)Cc3cccc(F)c3F)nc2[nH]1
Product: O=c1cnc2c(NC(CO)CO)nc(SCc3cccs3)nc2[nH]1
Yield: 53.5 %

Procedure:
The titled compound (0.075 g) was prepared by the method of Example 13, step (c) using the product from example 23, step (a) (0.21 g) and 2-thienylmethylmercaptan (0.05 g).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:34]([O:36]C)=[O:35])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH2:18][C:17]4[CH:30]=[CH:31][CH:32]=[CH:33][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C1COCC1.CO.[OH-].[Na+]>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:34]([OH:36])=[O:35])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH2:18][C:17]4[CH:30]=[CH:31][CH:32]=[CH:33][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(CCN1CCOCC1)Cc1ccccc1-3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(CCN1CCOCC1)Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
The crude methyl 14-cyclohexyl-6-(2-morpholin-4-ylethyl)-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate was dissolved in THF/MeOH (1:1) and to that solution an excess of NaOH (1N) was added. The solution was stirred at RT overnight. The solvent was evaporated in vacuo. The crude was then purified by automated RP-MS-HPLC (stationary phase: column Waters XTERRA prep. C18, 5 um, 19×100 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound as a white powder (20%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.Cl[CH2:15][CH2:16][CH2:17][OH:18]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.[OH-].[Na+].CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH2:15][CH2:16][CH2:17][OH:18])=[CH:6][CH:7]=1
Reactant: OCCCCl
Reactant: Fc1ccc(Nc2nccs2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: OCCCN(c1ccc(F)cc1)c1nccs1

Procedure:
A mixture of N-(4-fluorophenyl)thiazol-2-amine (6.00 g, 30.0 mmol), 3-chloropropanol (3.87 mL, 46.4 mmol), tetra-n-butylammonium hydrogensulfate (1.05 g, 3.09 mmol) in toluene (100 mL) and NaOH (40% w/v in water)(20 mL) was refluxed for 3 h. On cooling, the reaction mixture was diluted with EtOAc (100 mL), washed with water (4×100 mL), brine (100 mL), dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography with 50-80% EtOAc in hexane to afford the title compound as a brown oil, 3.287 g. MS (M+H)+ 253.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>CS(C)=O>[C:11]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1)(=[O:13])[CH3:12]
Reactant: NC(=O)c1ccc(N)nc1
Reactant: CC(=O)OC(C)=O
Solvent: CS(C)=O
Product: CC(=O)Nc1ccc(C(N)=O)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-Amino nicotinamide 13.7 g (0.1 mole) is dissolved in 100 ml of dimethylsulfoxide and acetic anhydride 14.2 ml (0.15 mole) is added to the above solution. The mixture is stirred at room temperature for 16 hours. White crystals which are formed during the reaction are isolated by filtration and are purified by washing with 0.2 N HCl and ethanol. 6-Acetylamino nicotinamide 9.5 g thus synthesized is practically pure as shown by infrared spectroscopy and thin-layer chromatography.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.I[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21].Cl.CN(C)CC(O)=O>O1CCOCC1.[Cu]I>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][C:18]([O:12][C:9]2[CH:10]=[CH:11][C:6]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[CH:7][CH:8]=2)=[CH:19][CH:14]=1
Reactant: Oc1ccc(-c2nccs2)cc1
Reactant: COc1ccccc1I
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(Oc2ccc(-c3nccs3)cc2)cc1
Temperature: 100 °C
Yield: 85.4 %

Procedure:
A mixture of product from step 3 (0.55 g, 3.1 mmol), iodoanisole (1.1 g, 4.6 mmol), CsCO3 (3.0 g, 9.2 mmol), N,N-dimethylglycine HCl (0.43 g, 3.1 mmol) and CuI (0.3 g, 1.5 mmol) in dioxane (40 mL) was heated to 100° C. for 3 days. After the solids were filtered off, the filtrate was partitioned with EtOAc/H2O, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a column chromatography on silica gel to yield the title compound (0.75 g, 90%). 1HNMR (400 MHz, CDCl3) δ 3.82 (s, 3H), 6.90 (d, J=8 Hz, 2H), 6.97 (d, J=8.8 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 7.28 (d, J=3.6 Hz, 1H), 7.81 (d, J=3.6 Hz, 1H), 7.90 (d, J=8.8 Hz, 2H), MS m/z 284 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:27]#[N:28])=[C:4]([CH:24]=[CH:25][CH:26]=1)[O:5][CH2:6][C:7]([CH3:23])([CH3:22])[CH2:8][NH:9][C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:11].[S:29](Cl)(=[O:32])(=[O:31])[NH2:30]>>[S:29]([NH:1][C:2]1[C:3]([C:27]#[N:28])=[C:4]([CH:24]=[CH:25][CH:26]=1)[O:5][CH2:6][C:7]([CH3:23])([CH3:22])[CH2:8][NH:9][C:10]([NH:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)=[O:11])(=[O:32])(=[O:31])[NH2:30]
Reactant: COc1ccc(CNC(=O)NCC(C)(C)COc2cccc(N)c2C#N)cc1
Reactant: NS(=O)(=O)Cl
Product: COc1ccc(CNC(=O)NCC(C)(C)COc2cccc(NS(N)(=O)=O)c2C#N)cc1
Yield: 100 %

Procedure:
Prepared as in Example 215a from 1-(3-(3-amino-2-cyanophenoxy)-2,2-dimethylpropyl)-3-(4-methoxybenzyl)urea (Example 252b) and sulfamoyl chloride in 100% yield. MS 462 (MH+).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:25]3[C:26]([O:31]CC4C=CC(OC)=CC=4)=[N:27][CH:28]=[CH:29][CH:30]=3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.O1CCOCC1>C(Cl)Cl.O.C([O-])(O)=O.[Na+]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[C:24]([C:25]3[C:26](=[O:31])[NH:27][CH:28]=[CH:29][CH:30]=3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:16][CH:17]=1)=[O:11]
Reactant: COc1ccc(COc2ncccc2-c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccc(Oc2nccnc2-c2ccc[nH]c2=O)cc1)c1nc2ccccc2[nH]1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a suspension of (1H-benzo[d]imidazol-2-yl)(4-(3-(2-(4-methoxybenzyloxy)pyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone (0.050 g, 0.094 mmol) in DCM/water in a 50 mL round bottom flask was added DDQ (0.026 g, 0.113 mmol) and dioxane (1 mL). The mixture was stirred at 60° C. for 16 h. The mixture was diluted with saturated NaHCO3 and extracted with DCM (3×25 mL). The combined organic layer was washed with saturated NaHCO3 and brine. The insoluble material was collected, washed with ethanol, filtered and dried in vacuo to give 3-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)pyridin-2(1H)-one. MS (ESI, pos. ion) m/z: 410.2 (M+1). IC50 (uM) +++++.
Reaction SMILES: [F:1][C:2]1([F:25])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18](=O)/[CH:19]=[CH:20]/N(C)C)=[N:12]3)=[CH:10][C:4]=2[O:3]1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][NH2:34]>>[F:25][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18]4[N:33]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[F:26])[N:34]=[CH:20][CH:19]=4)=[N:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc3c(c2)OC(F)(F)O3)ccc1=O
Reactant: NNc1ccccc1F
Product: O=c1ccn(-c2ccc3c(c2)OC(F)(F)O3)nc1-c1ccnn1-c1ccccc1F

Procedure:
The product was obtained starting from 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-11) and 2-fluoro-phenylhydrazine according to the method described for example 91.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:13][OH:14])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:28]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)#[N:29].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([N:15]([S:36]([C:33]1[CH:32]=[CH:31][C:30]([C:28]#[N:29])=[CH:35][CH:34]=1)(=[O:38])=[O:37])[CH2:16][CH:17]([CH3:18])[CH3:19])[CH2:13][OH:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CN[C@H](CO)CCCCNC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CN([C@H](CO)CCCCNC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(C#N)cc1
Reaction time: 8 h
Yield: 36 %

Procedure:
(S)-(6-Hydroxy-5-isobutylamino-hexyl)-carbamic acid tert-butyl ester (4) (1.85 g) was dissolved in 50 mL CH2Cl2. Triethylamine (1.05 eq) and 4-cyano benzene sulfonylchloride (1 eq) were added and the mixture was stirred overnight. Saturated NaHCO3 (50 mL) was added, the mixture was well shaken. Organic layer was separated, dried on MgSO4, filtrated and evaporated. The crude compound was purified by column chromatography using EtOAc-heptane (1-3) as the eluent. Fractions containing the product were evaporated yielding (1.06 g, 36%) of a solid.
Reaction SMILES: [P:1]([Cl:4])(Cl)Cl.[CH3:5][C@H:6]1[CH2:10][CH2:9][C@H:8]([CH3:11])[N:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH3:5][C@H:6]1[CH2:10][CH2:9][C@H:8]([CH3:11])[N:7]1[C:12]1[CH:17]=[CH:16][C:15]([PH:1][Cl:4])=[CH:14][CH:13]=1
Reactant: C[C@H]1CC[C@H](C)N1c1ccccc1
Reactant: ClP(Cl)Cl
Solvent: c1ccncc1
Product: C[C@H]1CC[C@H](C)N1c1ccc(PCl)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of PCl3 (5.0 g, 36.4 mm) in 15 mL of pyridine was treated with (S, S)-2,5-dimethyl-1-N-phenylpyrrolidine (0.5 g, 2.87 mm) over a period of 5 min. The resulting mixture was then refluxed for 2 days to give the crude (S, S)-2,5-dimethyl-1-N(4′-dichlorophosphinophenyl)pyrrolidine (31P NMR: δ165.8 (s) ppm). After precipitates (Py. HCl) were filtered off, the excess PCl3 and pyridine solvent were removed from filtrates, a mixture of 10 mL of pyridine and 20 mL of THF was added to the resulting residue. Next, polymer-supported secondary amines from Example 1 (2.0 g, 1.1 mmol/g, 2.2 mmol) was slowly added into the mixture above while stirring at room temperature for a period of 10 min. The resulting suspension was stirred at room temperature overnight before the solution was filtered off. The resin was washed with THF (2×10 mL), hexane (3×10 mL), CH2Cl2 (4×10 mL), and hexane (2×10 mL). The resulting resin was dried in vacuum overnight to yield the polymer-supported (S,S)-2,5-dimethyl-1-N(4′-chlorophosphinophenyl)pyrrolidine. 31P NMR (122 MHz, CDCl3): δ147.6 ppm.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH2:39][CH:40]([CH2:45][CH3:46])[CH2:41][CH2:42][CH2:43][CH3:44])=[O:37])=[CH:30][CH:29]=1>CN(C)C=O>[OH:6][C:5]1[C@@H:7]([C@H:9]([OH:10])[CH2:11][O:12][C:28]2[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH2:39][CH:40]([CH2:45][CH3:46])[CH2:41][CH2:42][CH2:43][CH3:44])=[O:37])=[CH:30][CH:29]=2)[O:8][C:2](=[O:1])[C:3]=1[OH:4]
Reactant: CCCCC(CC)COC(=O)/C=C/c1ccc(O)cc1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CN(C)C=O
Product: CCCCC(CC)COC(=O)/C=C/c1ccc(OC[C@@H](O)[C@H]2OC(=O)C(O)=C2O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
20 g of ascorbic acid (113.5 mmol; 1 eq.) are dissolved in 100 ml of di-methylformamide in an argon-flushed 3-necked flask, 32.76 g of triphenyl-phosphine are added, and 25.3 g of diisopropyl azodicarboxylate (124.9 mmol; 1.1 eq) are slowly added dropwise at 0° C. After 30 min, the 2-ethylhexyl(E)-3-(4-hydroxyphenyl)acrylate (32.95 g; 1.05 eq; 119.2 mmol) dissolved in 45 ml of dimethylformamide is added dropwise. After 30 min at 0° C., the mixture is stirred at room temperature for a further 6 hrs. The reaction solution is evaporated to dryness, suspended in 100 ml of ethyl acetate/hexane 1:2, filtered, and the product is precipitated as a white solid by addition of 100 ml of hexane.