Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[O:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:9]([CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[N-:21]=[N+:22]=[N-:23].[Na+].O.C(O)C>CN(C)C=O>[N:21]([CH2:2][C:3]1[C:12]2[O:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:9]([CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[N+:22]=[N-:23]
Reactant: Cc1c(-c2ccccc2)oc2c(CCl)cccc2c1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: Cc1c(-c2ccccc2)oc2c(CN=[N+]=[N-])cccc2c1=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 22.8 g of Intermediate XIX and 6.8 g of sodium azide in 110 ml of dimethylformamide was stirred for 3 hours at 100° C. After cooling to ambient temperature, 130 ml of water and 88 ml of ethanol were added to the reaction mixture. After 1 hour, the crystals were collected by vacuum filtration, washed with water, and desiccated. Yield: 22 g of the title product. A sample recrystallized from ethanol had a melting point of 132°-134° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O-:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:27]1([C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](=[CH:37][CH2:38]Br)[O:29]1)=[O:28].O.C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O:20][CH2:38][CH:37]=[C:30]4[C:31]5[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:27](=[O:28])[O:29]4)=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: O=C1OC(=CCBr)c2ccccc21
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCC=C3OC(=O)c4ccccc43)=CCS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.2 %

Procedure:
To a solution of sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) (1.4 g) in N,N-dimethylformamide (40 ml) was added 3-phthalidylideneethyl bromide (1.0 g), and the mixture was stirred at ambient temperature for 15 minutes. The reaction mixture was poured into a mixture of water and ethyl acetate (each 200 ml) with stirring. The separated organic solution was washed with 5% aqueous sodium bicarbonate and then water, followed by drying over magnesium sulfate. The resultant solution was evaporated to dryness to give 2-(3-phthalidylidene)ethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) (1.5 g), mp 150° to 156° C. (dec.).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[C:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>>[CH:1]1([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)[CH:12]=[C:11]3[C:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CC=C(c2c[nH]c3ccc(OC4CCCCC4)cc23)CC1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)n2cc(C3=CCN(C)CC3)c3cc(OC4CCCCC4)ccc32)cc1

Procedure:
(18.7 mg, 51%); from 5-cyclohexyloxy-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4c, 25.6 mg, 0.082 mmol) and 4-methoxybenzoyl chloride (30 uL, 0.20 mmol); HRMS-FAB+ for C28H32N2O3 : calculated MH+ : 445.2491 1; found: 445.25149.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)(=[O:20])=[O:19])=[CH:14][CH:15]=2)[C:10]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:9]1)=O)(C)(C)C.I[Si](C)(C)C.N>C(Cl)(Cl)Cl>[F:27][C:23]1[CH:22]=[C:21]([S:18]([NH:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][N:9]=[C:10]3[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)(=[O:20])=[O:19])[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)n1nc(-c2ccccc2)c2cc(NS(=O)(=O)c3cccc(F)c3)ccc21
Agent: C[Si](C)(C)I
Agent: N
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Nc1ccc2[nH]nc(-c3ccccc3)c2c1)c1cccc(F)c1
Temperature: 20 °C
Reaction time: 18 h
Yield: 31.8 %

Procedure:
3-Fluoro-N-(3-phenyl-1H-indazol-5-yl)-benzenesulfonamide can be obtained in the following way: a solution of 0.4 g of N-(N-tert-butoxycarbonyl-3-phenyl-1H-indazol-5-yl)-3-fluorobenzenesulfonamide, of 3.5 ml of chloroform and of 0.127 ml of iodotrimethylsilane is maintained with stirring for 18 hours at a temperature in the region of 20° C. 10 ml of 5% aqueous ammonia are added to the reaction medium, which is extracted with 40 ml of dichloromethane. The organic phase is dried over magnesium sulfate, filtered and concentrated by evaporation under reduced pressure. The residue thus obtained is purified by chromatography on a silica column with a dichloromethane/methanol (99/1 by volume) mixture. The gray solid thus obtained is recrystallized from 25 ml of dichloromethane in the presence of 3 S black. 0.1 g of 3-fluoro-N-(3-phenyl-1H-indazol-5-yl)benzenesulfonamide is thus obtained in the form of a white solid melting at 200° C. (analysis C19H14FN3O2S % calculated C, 62.11; H, 3.84; F, 5.17; N, 11.44. % found C, 62.09; H, 3.69; F, 4.88; N, 11.44).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:12]([O:14][CH2:15][C:16]1[N:17]([CH2:29][C:30](=[O:33])[CH2:31][CH3:32])[C:18]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:28]=1)[CH3:13].[OH-].[NH4+:35].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:35][C:20]1[C:19]2[N:28]=[C:16]([CH2:15][O:14][CH2:12][CH3:13])[N:17]([CH2:29][C:30](=[O:33])[CH2:31][CH3:32])[C:18]=2[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC(=O)CC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(=O)CC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
mCPBA (2.11 g, 8.57 mmol) was added to a solution of 1-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butan-2-one (1.96 g, 6.59 mmol) in chloroform (30 mL) at room temperature. The reaction mixture was stirred for 1 hour, then was cooled to 0° C. Concentrated ammonium hydroxide (10 mL) and p-toluenesulfonyl chloride (1.38 g, 7.25 mmol) were added. The mixture was stirred at 0° C. for 1 hour, then was filtered. The filtrate was diluted with dichloromethane (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (25 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated to yield a brown solid. The solid was purified by chromatography on a HORIZON High-Performance Flash Chromatography (HPFC) instrument (available from Biotage, Inc, Charlottesville, Va., USA) (silica gel, gradient elution with 0-35% of a solution comprised of 80% CHC13, 18% MeOH, and 2% conc. NH4OH (CMA) in chloroform) to afford a tan solid that was recrystallized from chloroform/hexanes. The crystals were isolated by filtration and dried in a vacuum oven at 80° C. to afford 0.718 g of 1-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butan-2-one as pale pink needles, mp 187-188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[OH:28][CH2:29][C:30]([NH:33][S:34]([C:37]1[S:41][C:40]([NH2:42])=[N:39][C:38]=1[CH3:43])(=[O:36])=[O:35])([CH3:32])[CH3:31]>>[OH:28][CH2:29][C:30]([NH:33][S:34]([C:37]1[S:41][C:40]([NH:42][C:25]([C:24]2[CH:23]=[N:22][N:15]3[C:16]([C:18]([F:19])([F:21])[F:20])=[CH:17][C:12]([C:4]4[CH:5]=[CH:6][C:7]([C:8]([F:10])([F:11])[F:9])=[C:2]([Cl:1])[CH:3]=4)=[N:13][C:14]=23)=[O:26])=[N:39][C:38]=1[CH3:43])(=[O:36])=[O:35])([CH3:32])[CH3:31]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(Cl)c3)nc12
Reactant: Cc1nc(N)sc1S(=O)(=O)NC(C)(C)CO
Product: Cc1nc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(Cl)c4)nc23)sc1S(=O)(=O)NC(C)(C)CO

Procedure:
The title compound was prepared from 5-(3-chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.17) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.3) according to general procedure II. Yellow solid. MS (ISP) 655.1 [(M−H)−]; mp 274° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[C:30]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH:42]=O)=[CH:36][CH:35]=1)([OH:32])=[O:31].C(OCC)C>C1(C)C=CC=CC=1.O1CCCC1>[CH3:2][O:3][CH:4]=[CH:42][CH2:41][CH2:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][C:30]([OH:32])=[O:31])=[CH:39][CH:38]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCCc1ccc(CC(=O)O)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC=CCCc1ccc(CC(=O)O)cc1
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
To 3.77 g (11 mmol) of methoxymethyltriphenyl phosphonium chloride in 10 ml of toluene at 0° C. under nitrogen was added 11 ml (11 mmol) of 1M potassium t-butoxide in tetrahydrofuran over 20 minutes. The resulting solution was stirred for 10 minutes, then 1.92 g (10 mmol) of 3-(4-carboxymethylphenyl)-propanal in 10 ml of toluene was added over 15 minutes. After stirring the mixture for 20 minutes 40 ml of ethyl ether were added. The resulting precipitate was filtered with diatomaceous earth, collected, washed with 20 ml of water, 20 ml of saturated sodium chloride and dried with a 9:1 sodium sulfate: saturated sodium chloride mixture. Vacuum concentration of the filtered solution and trituration of the residue with hexane gave 1.72 g of 1-methoxy-4-(4-carboxymethyl phenyl)-1-butene. Chromatography of the above product (silica gel, 8:2 hexane: ethyl acetate) gave 1.0 g of a mixture of geometric isomers (Z/E-6:4) of the above product in a combined yield of 45 percent. b.p. 140° C. @8 0.07 torr. 1H NMR (CDCl3) δ2.23 (dq, J=1.0, 8.1 Hz), 2.40 (dq, J=1.3, 8.0 Hz) total 2H, 2.70 (t, J=8.1 Hz), 2.71 (t, J=8.0 Hz), total 2H, 3.48 (s), 3.55 (s), total 3H, 3.89 (s), 3.90 (s), total 3H, 4.32 (q, J=6.2 Hz), 4.71 (dr, J=7.3, 12.6 Hz), total 1H, 5.87 (dr, J=1.3, 6.2 Hz), 6.28 (dt, J=1.0, 12.6 Hz), total 1H, 7.23 (d, J=8.2 Hz), 7.27 (d, J=8.2 Hz), total 1H, 7.94 (d, J=8.2 Hz), 7.95 (d, J=8.2 Hz), total 2H; 13C NMR (CDCl3) δ25.2, 29.3, 36.0, 37.4, 51.9, 56.0, 59.5, 101.8, 101.9, 105.5, 127.9, 128.0, 128.5, 128.6, 129.6, 129.7, 146.9, 147.5, 147.9, 148.0, 167.1, 167.2; IR (CHCl3) 3025, 2954, 1716, 1656, 1610, 1437, 1284, 1112 cm-1 ; MS(FD) m/z 220 (M+).
Reaction SMILES: [OH:1][N:2]=[C:3]([CH3:17])[CH2:4][CH2:5][N:6]1C(=O)C2=CC=CC=C2C1=O.O.NN.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[NH:24][CH:25]=[N:26]2.C(N(C(C)C)C(C)C)C>CO.O.CCOCC>[OH:1][N:2]=[C:3]([CH3:17])[CH2:4][CH2:5][NH:6][C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[NH:24][CH:25]=[N:26]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CC(CCN1C(=O)c2ccccc2C1=O)=NO
Agent: NN
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: CC(CCNc1ncnc2nc[nH]c12)=NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
0.232 g (1.00 mmol) of N-[3-(N-hydroxyimino)butyl]phthalimide was dissolved in 6 ml of methanol and to the solution was added 60 μl (1.2 mmol) of hydrazine hydrate, followed by being refluxed for 5 hours. The reaction mixture was cooled to room temperature and then, 20 ml of ether was added thereto and the mixture was left to stand at 0° C. for 1 hour to sufficiently precipitate solids. The solids were removed by suction filtration and the filtrate was dried over sodium sulfate and concentrated to 1 ml by an evaporator. This concentrated filtrate was dissolved in 5 ml of isopropanol and to the solution were added 75 mg (0.50 mmol) of 6-chloropurine and 101 μl of ethyldiisopropylamine, followed by being refluxed on an oil bath for 5 hours. The reaction mixture was poured into 20 ml of water and extracted with chloroform (15 ml×5). The extract was dried over magnesium sulfate and the solvent was distilled off. The residue was purified by a thin layer chromatography (silica gel, developing agent: 15% ethanol-chloroform) to give 45.1 mg (yield 22%) of the titled compound as white solids.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[CH:31]=[C:15]2[C:16](=[O:30])[NH:17][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=3)=[CH:19][N:14]2[N:13]=1)=O)C.Cl>C1COCC1.CO>[C:26]([C:23]1[CH:22]=[CH:21][C:20]([C:18]2[NH:17][C:16](=[O:30])[C:15]3[N:14]([N:13]=[C:12]([CH2:10][OH:9])[CH:31]=3)[CH:19]=2)=[CH:25][CH:24]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)c1cc2c(=O)[nH]c(-c3ccc(C(C)(C)C)cc3)cn2n1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2cn3nc(CO)cc3c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen, 43.4 mg (1.14 mmol) lithiumaluminiumhydride is added to a solution of 194 mg (0.571 mmol) 6-(4-tert-butyl-phenyl)-4-oxo-4,5-dihydro-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester (for preparation see previous example) in 20 ml THF. The reaction mixture is stirred at ambient temperature for two hours. A few drops of methanol and then 2 ml 2 N aqueous HCl solution are added slowly to the reaction mixture. It is then filtered over a pad of celite. The filtrate is evaporated and the residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 6-(4-tert-butyl-phenyl)-2-hydroxymethyl-5H-pyrazolo[1,5-a]pyrazin-4-one (“A18”) as white powder; HPLC/MS: 1.72 (C), [M+H] 298; 1H NMR (400 MHz, DMSO-d6) δ [ppm] 11.46 (s, 1H), 7.94 (s, 1H), 7.67 (d, J=8.5, 2H), 7.49 (d, J=8.5, 2H), 6.91 (s, 1H), 5.28 (bs, 1H), 4.59 (s, 2H), 1.31 (s, 9H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1)[CH3:2].[F:15][C:16]([F:30])([F:29])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26](O)=[O:27].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:15][C:16]([F:29])([F:30])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([N:12]1[CH2:11][CH2:10][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=2)[CH2:14][CH2:13]1)=[O:27]
Reactant: O=C(O)Cc1ccccc1OCC(F)(F)F
Reactant: CCc1cccc(N2CCNCC2)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCc1cccc(N2CCN(C(=O)Cc3ccccc3OCC(F)(F)F)CC2)c1
Reaction time: 48 h

Procedure:
1-(3-ethylphenyl)piperazine from the previous step was dissolved in 1 mL dry DMF, and to the solution was added 0.03 g (0.128 mmol) 2-(2,2,2-trifluoroethoxy)phenylacetic acid, 0.017 g (0.128 mmol) HOBT, and 0.024 g (0.128 mmol) EDC. The reaction was stirred for 2 days, after which time the solvent was removed in vacuo and the resulting residue partitioned between EtOAc/H2O. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with H2O, brine, dried over Na2SO4 and filtered. Removal of the solvent and subsequent purification via preparative TLC (2:1 Hexane/EtOAc) yielded the title compound as the free base. This was dissolved in 20 mL EtOAc and an excess of ethanolic HCl was added. The solvent was removed to give the Hcl salt of the title compound.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[CH3:30][NH:31][C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][C:33]=1[N+:47]([O-:49])=[O:48].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:35]3[CH:36]=[CH:37][C:32]([NH:31][CH3:30])=[C:33]([N+:47]([O-:49])=[O:48])[CH:34]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: CNc1ccc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc(NC)c([N+](=O)[O-])c3)sc2c1-c1ccc(Cl)cc1
Temperature: 105 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (497 mg, 1.00 mmol) in 1,4-dioxane (6 mL) was added N-methyl-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (417 mg, 1.50 mmol), Pd(PPh3)4 (58 mg, 0.05 mmol) and potassium carbonate solution (2 M aqueous, 1.5 mL, 3.0 mmol). The reaction mixture was stirred at 105° C. for 3 h and was then cooled to rt. EtOAc and H2O were added. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude mixture was purified by CombiFlash (EtOAc/Hex) to give (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(4-(methylamino)-3-nitrophenyl)benzo[d]thiazol-6-yl)acetate. 1H NMR (400 MHz, CD3OD):δ 8.71 (s, 1H), 8.40 (m, 1H), 8.05 (dd, J=8.8, 2.4 Hz, 1H), 7.73 (s, 1H), 7.51-7.58 (m, 4H), 7.06 (d, J=8.8 Hz, 1H), 5.22 (s, 1H), 4.22 (m, 2H), 3.05 (d, J=4.8 Hz, 3H), 2.55 (s, 3H), 1.22 (t, J=7 Hz, 3H), 0.97 (s, 9H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[C:11](=[O:14])([O-])[O-].[K+].[K+]>N1CCCC1=O.O.[Cu]>[N+:8]([C:4]1[CH:3]=[C:2]([N:8]2[CH2:4][CH2:3][CH2:2][C:11]2=[O:14])[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: O=C([O-])[O-]
Agent: [Cu]
Agent: O=C1CCCN1
Agent: [K+]
Solvent: O
Product: O=C1CCCN1c1cccc([N+](=O)[O-])c1
Temperature: 200 °C
Yield: 29.1 %

Procedure:
A suspension of 1-iodo-3-nitrobenzene (24.9 g, 0.1 mol), copper bronze (320 mg, 5 mmol) and potassium carbonate (15.2 g, 0.11 mol) in 2-pyrrolidinone was heated under a stream of nitrogen at 200° C. for 45 minutes. The reaction was cooled to ambient temperature, diluted with water (2000 ml) and extracted with diethyl ether (800 ml). The organic phase was then washed with water (2×800 ml), brine and dried over anhydrous sodium sulphate containing decolourising charcoal (2 g). Filtration and evaporation to dryness gave a yellow solid which was triturated with isohexane to give 1-(3nitrophenyl)pyrrolidin-2-one as a yellow powder (3.0 g, 15%). δH (360 MHz, CDCl3) 2.19-2.27 (2H, m), 2.67 (2H, t, J 8), 3.94 (2H, t, J 7), 7.54 (1H, t, J 8), 8.00 (1H, ddd, J 8, 2 and 1), 8.22 (1H, ddd, J 8, 2 and 1), 8.35 (1H, t, J 2).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:4]([NH:16]C(=O)C2C(C)=CC=CC=2C)=[N:3]1.[I-].[Na+].B(F)(F)F.CCOCC>C(#N)C>[NH2:16][C:4]1[CH:5]=[C:6]([CH2:7][O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:2]([CH3:1])[N:3]=1
Reactant: Cc1cccc(C)c1C(=O)Nc1cc(COCc2ccccc2)n(C)n1
Agent: FB(F)F
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: Cn1nc(N)cc1COCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.8 %

Procedure:
To a cooled (0° C.) suspension of N-(1-methyl-5-benzyloxymethylpyrazol-3-yl)-2,6-dimethyl benzamide (9 g, 0.025M) and sodium iodide (19 g, 0.125M) in acetonitrile (250 ml) was added boron trifluoride etherate (18,3 g, 0,125M) in acetonitrile (60 ml) under nitrogen atmosphere. After being stirred for 2 hours at room temperature and usual work-up, the crude material was purified by column chromatography on silica gel using CH2Cl2, then CH2Cl2 /CH3OH=97.5/2.5 and 95/5 as eluents to give 1.5 g (23%) of a white solid.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.CCCCCC.C(NC(C)C)(C)C.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([OH:28])=[O:27])=[N:24][CH:25]=1.BrCC>O1CCCC1.O>[Cl:19][C:20]1[CH:21]=[C:22]([CH2:1][CH3:2])[C:23]([C:26]([OH:28])=[O:27])=[N:24][CH:25]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCc1cc(Cl)cnc1C(=O)O
Reaction time: 0.5 h
Yield: 10 %

Procedure:
In a three necked round bottom flask under a nitrogen atmosphere at −78° C., a solution of n-butyllithium in hexane (1.6 M, 7 ml, 11.1 mmol) was added dropwise to a solution of diisopropylamine (1.56 ml, 11.1 mmol) in tetrahydrofuran (10 ml). The solution was stirred for 30 minutes, then a solution of 5-chloropyridine-2-carboxylic acid (800 mg, 5.0 mmol) in tetrahydrofuran (50 ml) was added dropwise over 1 hour and the reaction was stirred for 1 hour at −78° C. This solution was added dropwise via cannula to a solution of bromoethane (1.89 ml, 25.3 mmol) in tetrahydrofuran (10 ml) at −30° C. The reaction mixture was stirred overnight at room temperature. For the workup, water (10 ml) was added and the mixture was concentrated; hydrochloric acid (1 N) was added to reach pH 5 and the solution obtained was evaporated to dryness. The solid was solubilized in methanol and poured into acetonitrile. The solid formed was filtered off; the solution was collected and evaporated. The crude product was purified by chromatography to give the 5-chloro-3-ethyl-pyridine-2-carboxylic acid (90 mg, 10% of theory) as a white solid. Mass (calculated) C8H8ClNO2 [185.611]; (found) [M+H]+=185, [M+2-H]+=187.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH2:11]([O:18][C@@H:19]1[C@@H:23]([CH2:24][OH:25])[O:22][C@@H:21]([N:26]2[CH:33]=[C:32]([F:34])[C:30](=[O:31])[NH:29][C:27]2=[O:28])[CH2:20]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH2:11]([O:18][C@@H:19]1[C@@H:23]([CH2:24][O:25][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=2)[O:22][C@@H:21]([N:26]2[CH:33]=[C:32]([F:34])[C:30](=[O:31])[NH:29][C:27]2=[O:28])[CH2:20]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccccc3)[C@@H](CO)O2)cc1F
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1ccccc1)c1cccnc1
Reaction time: 3 h
Yield: 69 %

Procedure:
A 0.21 g quantity of nicotinoyl chloride hydrochloride was added to a solution of 0.20 g of 3'-O-benzyl-2'-deoxy-5-fluorouridine in 10 ml of pyridine, and the mixture was left to stand at 80° C. for 3 hours. The solvent was distilled off and the residue was dissolved in 30 ml of ethyl acetate. The solution was washed twice with 20 ml of water. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated. The concentrate was placed on a silica gel column and eluted with chloroform, giving 0.18 g of the title compound in a yield of 69%.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:40]=[C:39](B(O)O)[CH:38]=[CH:37][N:36]=1>>[Cl:34][C:35]1[CH:40]=[C:39]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH2:25][CH2:24]2)=[O:22])[CH:38]=[CH:37][N:36]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: CC(C)C(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1
Product: CC(C)C(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3n2-c2ccnc(Cl)c2)CC1
Yield: 43 %

Procedure:
The title compound was synthesized in analogy to example 5, after stirring for 6.5 days at 35° C., from 1-{4-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carbonyl]-piperazin-1-yl}-2-methyl-propan-1-one (example 31) and 2-chloropyridine-4-boronic acid to afford the desired product as light-brown foam (43%). MS (ISP): 565.4 (M+H)+.