Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[C:2]1([CH2:8][CH2:9][N+:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pt](=O)=O.CO>[C:2]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc[n+](CCc2ccccc2)cc1
Agent: O=[Pt]=O
Agent: [Br-]
Solvent: CO
Product: CCOC(=O)C1CCN(CCc2ccccc2)CC1
Reaction time: 1.5 h
Yield: 89.9 %

Procedure:
A mixture of 5.90 g (17.5 mmol) of 1-(2-phenylethyl)-4-carboethoxypyridinium bromide, 0.60 g of platinum (IV) oxide and 100 mL of methanol was hydrogenated at 50 p.s.i. and room temperature for 1.5 hours. The reaction mixture was filtered, concentrated and the residue dissolved in water. The aqueous solution was made alkaline to pH 9-10 with aqueous potassium carbonate and extracted with ethyl acetate. The organic extracts were washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried and evaporated to afford 4.11 g of 1-(2-phenylethyl)-4-carboethoxypiperidine as a yellow oil. NMR (CDCl3) δ7.16-7.32 (m, 5H); 4.08-4.19 (q, 2H); 2.91-3.02 (m, 2H); 2.77-2.88 (m, 2H); 2.53-2.65 (m, 2H); 2.23-2.35 (m, 1H); 2.03-2.15 (m, 2H); 1.87-1.98 (m, 2H); 1.72-1.88 (m, 4H); 1.20-1.30 (t, 3H).
Reaction SMILES: [Br:1]C1N=C(CBr)C=CN=1.[Cl:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[N:12]=1>>[Br:1][CH2:17][C:13]1[N:12]=[C:11]([Cl:10])[CH:16]=[CH:15][N:14]=1
Reactant: Cc1nccc(Cl)n1
Reactant: BrCc1ccnc(Br)n1
Product: Clc1ccnc(CBr)n1

Procedure:
Prepared according to the same procedure as 2-bromo-4-(bromomethyl)pyrimidine, starting with 4-chloro-2-methylpyrimidine. 1H NMR (500 MHz, DMSO-d6) δ 8.83 (d, J=5.5 Hz, 1H), 7.69 (d, J=5.5 Hz, 1H), 4.68 (s, 2H), Mass spec.: 208.9 (MH)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:25](Br)[CH2:26][CH3:27]>>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH3:27])[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(-c2n[nH]c3ncccc23)cc(C(C)(C)C)c1O
Reactant: CCCBr
Product: CCCn1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cccnc21

Procedure:
3-(3,5-Di-tertiary butyl-4-hydroxyphenyl)-1-propyl-1H-pyrazolo[3,4-b]pyridine, melting at 97°-98° C. is prepared by reacting the compound of Example 1 with propyl bromide in a similar manner as Example 9, and recrystallizing from hexane.
Reaction SMILES: [N:1]1([C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH3:25])[C:17](=[O:26])[C:16]=1[C:27]#[N:28]>C1(C)C=CC=CC=1>[CH3:25][N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)=[O:8])[CH2:2][CH2:3]2)=[C:16]([C:27]#[N:28])[C:17]1=[O:26]
Reactant: O=C(c1cccs1)N1CCNCC1
Reactant: Cn1c(=O)c(C#N)c(Cl)c2ccccc21
Solvent: Cc1ccccc1
Product: Cn1c(=O)c(C#N)c(N2CCN(C(=O)c3cccs3)CC2)c2ccccc21
Temperature: 120 °C
Yield: 97.7 %

Procedure:
Piperazine-1-yl-thiophen-2-yl-methanone (600 mg, 3.06 mmol) was added to a solution of Compound 3 (319 mg, 1.46 mmol) in toluene (40 mL) and heated overnight at 120° C. The solvent was removed under vacuum. The residue was suspended in water, sonicated, and filtered to yield 540 mg (98%) of white solids. M.P. 247° C. 1H NMR (DMSO-d6): δ 3.58 (s, 3H), 3.63 (m, 4H), 3.92 (m, 4H), 7.16 (t, J=4.8 Hz, 1H), 7.33 (t, J=7.5 Hz, 1H), 7.48 (d, J=3.5 Hz, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.75 (t, J=7.25, 2H), 7.79 (d, J=4.8 Hz, 1H) 7.92 (d, J=7.5 Hz, 1H). EIMS m/z 379 (M+1), 401 (M+23). Anal. (C20H18N4O2S) C,H, N.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[NH:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7].[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([N:13]1[CH2:12][C:11]2([CH2:24][CH2:25][N:8]([C:6](=[O:7])[C:5]3[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:4]=3)[CH2:9][CH2:10]2)[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:14]1=[O:23])(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: Cc1ccccc1N1C(=O)NCC12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: CC(=O)N1CC2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)N(c2ccccc2C)C1=O

Procedure:
The title compound, MS: m/e=528.1 (M+H+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-2-one and acetyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[NH:8][CH2:7][CH2:6]2.[Cl:19][C:20]1[CH:33]=[CH:32][C:23]2[S:24][C:25]([S:28](Cl)(=[O:30])=[O:29])=[C:26]([CH3:27])[C:22]=2[CH:21]=1>>[Cl:19][C:20]1[CH:33]=[CH:32][C:23]2[S:24][C:25]([S:28]([N:8]3[C:9]4[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([N:12]5[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]5)[CH:10]=4)[CH2:6][CH2:7]3)(=[O:29])=[O:30])=[C:26]([CH3:27])[C:22]=2[CH:21]=1
Reactant: COc1cc2c(cc1N1CCN(C)CC1)NCC2
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Product: COc1cc2c(cc1N1CCN(C)CC1)N(S(=O)(=O)c1sc3ccc(Cl)cc3c1C)CC2

Procedure:
The title compound (E124) was prepared from 5-methoxy-6-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indole (WO95/06637 intermediate 3) (99 mg, 0.4 mmol) and 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (113 mg, 0.4 mmol) using the method of Example 1 (194 mg, 92%) MH+=492/494.
Reaction SMILES: Br[C:2]1[C:3]([O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][CH:20]=[N:21]3)=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.[SH:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(OCC)(=O)C>[CH3:14][C:12]1[N:13]=[C:9]([NH:8][C:5]2[N:6]=[CH:7][C:2]([S:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:3]([O:15][C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][CH:20]=[N:21]4)[CH:4]=2)[S:10][CH:11]=1
Reactant: COC(=O)CCS
Reactant: Cc1csc(Nc2cc(Oc3cccc4ncccc34)c(Br)cn2)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)CCSc1cnc(Nc2nc(C)cs2)cc1Oc1cccc2ncccc12
Temperature: 93 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
A flask was charged with tris(dibenzylideneacetone)dipalladium (0) (0.05539 g, 0.06049 mmol), 5-bromo-N-(4-methylthiazol-2-yl)-4-(quinolin-5-yloxy)pyridin-2-amine (0.500 g, 1.210 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.05250 g, 0.09074 mmol), methyl 3-mercaptopropanoate (0.5360 ml, 4.839 mmol), and N-ethyl-N-isopropylpropan-2-anine (0.4215 ml, 2.420 mmol), and degassed dioxane (40 mL) was added. The reaction was stirred at 93° C. overnight. Water was added and the reaction was extracted with ethyl acetate. The organic layer was dried, filtered and concentrated. The residue was purified using silica gel column chromatography with 20-30-40-60-80% ethyl acetate in hexanes and then with ethyl acetate to give the desired product (0.469 g, 85% yield) as yellow solid. 1H NMR (CDCl3) δ 8.93 (m, 1H), 8.37 (d, 1H), 8.19 (m, 1H), 8.02 (dd, 1H), 7.66 (t, 1H), 7.36 (dd, 1H), 7.19 (d, 2H), 6.11 (s, 1H), 3.60 (s, 3H), 2.60 (t, 2H), 1.71 (s, 3H), 1.22 (t, 2H).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][C@H:9]1[C:13]([CH3:15])([CH3:14])[O:12][C:11]([CH3:17])([CH3:16])[O:10]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:16][C:11]1([CH3:17])[O:10][C@@H:9]([CH2:8][CH2:7][OH:6])[C:13]([CH3:15])([CH3:14])[O:12]1
Reactant: CC1(C)O[C@@H](CCO[Si](C)(C)C(C)(C)C)C(C)(C)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)O[C@@H](CCO)C(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
Step F To the solution of tert-butyl-dimethyl-[2-((S)-2,2,5,5-tetramethyl-[1,3]dioxolan-4-yl)-ethoxy]-silane (4.56 g, 15.8 mmol) in tetrahydrofuran (20 mL) at 0° C. was added a solution of tetrabutylammonium fluoride (1 M, 20 mL, 20 mmol). The reaction mixture was stirred at room temperature for 1 h. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated to give 2-((S)-2,2,5,5-tetramethyl-[1,3]dioxolan-4-yl)-ethanol as a yellow oil (2.7 g, 100%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:28][CH2:27][N:26]([C:29]([CH3:33])([CH3:32])[C:30]#[N:31])[CH2:25][CH2:24]5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:34])=[N:5]1)([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:36]>C(=O)([O-])[O-].[Na+].[Na+]>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([CH:23]5[CH2:28][CH2:27][N:26]([C:29]([CH3:32])([CH3:33])[C:30]([NH2:31])=[O:36])[CH2:25][CH2:24]5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][C:6]([CH3:34])=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCN(C(C)(C)C#N)CC4)cc2OCC3)n(C(C)C)n1
Reactant: O=S(=O)(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCN(C(C)(C)C(N)=O)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 9 %

Procedure:
To 2-{-4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidin-1-yl}-2-methyl-propionitrile (140 mg, 0.31 mmol) was added concentrated sulfuric acid (1.75 mL). The mixture was stirred at RT for 3.5 hours before the reaction was diluted with ice and neutralised with sodium carbonate. The aqueous mixture was extracted with 10% MeOH in DCM (×5) before the organic phase was dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2, gradient 0-10% MeOH in DCM). The material was triturated with diethyl ether before being purified by reverse phase HPLC (C18, gradient 20-70% MeOH/0.1% formic acid in water/0.1% formic acid). The resultant residue was taken up into MeOH (1.2 mL) and treated with 0.2 M HCl in diethyl ether. The solution was concentrated in vacuo affording 289 (14 mg, 0.03 mmol, 9%). LCMS: RT=2.65 min, [M+H]+=478. 1H NMR δ (ppm) (DMSO-d6): 9.50 (1H, m), 8.33 (1H, d, J=8.29 Hz), 7.97 (1H, s), 7.93 (1H, s), 7.86 (1H, s), 7.02 (1H, dd, J=8.36, 1.75 Hz), 6.87 (1H, d, J=1.71 Hz), 5.78-5.71 (1H, m), 4.50-4.44 (4H, m), 3.19-3.04 (2H, m), 2.91-2.80 (1H, m), 2.25 (3H, s), 2.12 (2H, d, J=13.49 Hz), 1.98 (2H, d, J=13.54 Hz), 1.51 (6H, s), 1.43 (6H, d, J=6.59 Hz). 2H obscured by solvent.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13](Cl)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:44]2[CH:45]=[C:46]([NH:50][C:51]([CH:53]3[CH2:58][O:57][CH2:56][CH2:55][O:54]3)=[O:52])[CH:47]=[CH:48][CH:49]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13]([C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([NH:50][C:51]([CH:53]5[CH2:58][O:57][CH2:56][CH2:55][O:54]5)=[O:52])[CH:45]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(Cl)nc43)cc2)CCC1
Reactant: CC1(C)OB(c2cccc(NC(=O)C3COCCO3)c2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(NC(=O)C6COCCO6)c5)nc43)cc2)CCC1
Temperature: 80 °C
Yield: 65.3 %

Procedure:
To a suspension of tert-butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (50 mg) and N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,4-dioxane-2-carboxamide (68 mg) and potassium phosphate (65 mg) and PdCl2(dppf)CH2Cl2 (8 mg) in dioxane (2 mL) and H2O (0.2 mL) was degassed for 5 minutes and then heated to 80° C. for 18 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (2 times: 0-10% methanol in chloroform then 0-10% methanol in ethyl acetate) gave the product (44 mg, 66%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])O.[Na+].I[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[S:36]([CH3:39])(=[O:38])=[O:37])(=[O:29])=[O:28])[CH:24]=2)[N:19](C(OC(C)(C)C)=O)[N:18]=1.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([NH:26][S:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[S:36]([CH3:39])(=[O:38])=[O:37])(=[O:28])=[O:29])[CH:24]=3)[NH:19][N:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Reactant: OB(O)c1cccc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cccc(Br)c3)c2c1
Temperature: 20 °C
Yield: 69.4 %

Procedure:
N-[3-(3-Bromophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide can be obtained in the follow way: 1.6 g of (3-bromophenyl)boronic acid, 8.7 ml of a saturated aqueous sodium hydrogencarbonate solution and 0.11 g of tetrakis(triphenylphosphine)palladium[0] are added successively to a suspension, maintained under an atmosphere of argon, of 2.3 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate in 90 ml of dimethylformamide. The reaction mixture is refluxed for 5 hours. After cooling to a temperature in the region of 20° C., the reaction mixture is hydrolyzed with 200 ml of water and extracted with 200 ml and then 100 ml of ethyl acetate. The pooled organic extracts are dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The brown oil thus obtained is purified by chromatography on a silica column (particle size 63-200 μm), eluting with a dichloromethane/methanol (99/1 by volume) mixture. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 1.4 g of N-[3-(3-bromophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide are obtained in the form of a yellow lac. This product is repurified by chromatography on a silica column (particle size 63-200 μm), with pure dichloromethane as eluent. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 0.73 g of N-[3-(3-bromophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide are obtained in the form of a white foam melting at 104° C.
Reaction SMILES: [C:1]([O:4][CH:5]([CH:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:10][O:11][C:12](=[O:14])[CH3:13])[C:6](Cl)=[O:7])(=[O:3])[CH3:2].[Br-:19].[Li+]>C(Cl)Cl>[C:1]([O:4][CH:5]([CH:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:10][O:11][C:12](=[O:14])[CH3:13])[C:6]([Br:19])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(=O)Cl
Reactant: [Br-]
Agent: [Li+]
Solvent: ClCCl
Product: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(=O)Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.5 %

Procedure:
2,3,4-Triacetoxybutanoyl chloride (39.9 g, 0.142 mol), prepared according to the liteature procedure Glattfeld, J. and Kribben, B., J.Am. Chem. Soc. 61 (1939) 1720) was mixed with lithium bromide (30.9 g, 0.356 mol) in methylene chloride (400 ml) and stirred at ambient temperature for 24 h. The mixture was filtered, the solid was washed with additional methylene chloride (50 ml) and the filtrate was evaporated at ambient temperature to give 45 g (97%) of the crude product as an oil.
Reaction SMILES: [OH:1][CH:2]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][C:10](Cl)=[CH:11][CH:12]=1)=[O:6].[N:18]1([C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:35])([F:34])[F:33])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[OH:1][CH:2]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][C:10]([N:21]2[CH2:22][CH2:23][N:18]([C:24](=[O:25])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:33])[F:34])[CH2:19][CH2:20]2)=[CH:11][CH:12]=1)=[O:6]
Reactant: CC(C)(C)C(O)CNC(=O)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: CC(C)(C)C(O)CNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (2-hydroxy-3,3-dimethylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a brown solid (75% yield). m.p. 236-240° C. 1H NMR (300 MHZ, CDCl3) δ 7.90, 7.83-7.79, 7.75-7.73, 7.69-7.65, 7.54-7.52, 7.30, 4.29, 3.91-3.73, 3.43-3.32, 3.20-3.11, 2.81, 2.77, 0.95. MS (ES+) m/z 480 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25]C(=O)C)[C@@H:17]([O:18]C(=O)C)[C@H:12]2[O:13]C(=O)C)=[C:4](Cl)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:36]([CH:38]([NH2:41])[CH2:39][CH3:40])[CH3:37]>C(O)(C)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:41][CH:38]([CH2:39][CH3:40])[CH2:36][CH3:37])[C:5]2[N:6]=[CH:7][N:8]([C:9]=2[N:10]=1)[C@@H:11]1[O:23][C@H:22]([CH2:24][OH:25])[C@@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCC(N)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCC(CC)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 54 °C
Reaction time: 24 h

Procedure:
A mixture of 2,6-dichloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-9H-purine ** (10.1 g, 22.6 mM), iso-propanol (300 ml), K2CO3 (5 g) and 1-ethylpropylamine (2.17 g, 24.84 mM) was stirred at 20 C. for 24 hrs. The reaction mixture was heated at 54° C. for 73 hrs. Solvent was removed in vacuo, water (50 ml) was added, extracted with ethyl acetate (3×80 ml), the combined extracts were dried (MgSO4) affording the title compound as a creamy light brown foam (9.44 g). LC/MS system A Rt=2.66 min, m/z=372 MH+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[C:38]([O:42][C:43](=[O:51])[NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43](=[O:51])[NH:44][CH:45]1[CH2:50][CH2:49][N:48]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:47][CH2:46]1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: CC(C)(C)OC(=O)NC1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and piperidin-4-yl-carbamic acid t-butyl ester according to conditions described in general procedure C. Mp: 214-216° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.33-1.41 (m, 14 H), 2.47-3.41 (m, 4H), 3.25-3.28 (m, 4H), 3.75-3.78 (m, 4 H), 4.20 (s, 1 H), 6.20 (d, J=5.5 Hz, 1H), 6.77-6.79 (m, 1 H), 7.00-7.05 (m, 1H), 7.18-7.26 (m, 1H), 7.38-7.63 (m, 5H), 7.85 (d, J=9.2 Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 8.26 (d, J=5.5 Hz, 1H), 10.47 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([Cl:14])[C:5]=1F.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([Cl:14])[C:5]=1[N:17]=[N+:18]=[N-:19]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(Cl)c1F
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(Cl)c1N=[N+]=[N-]
Temperature: 50 °C
Yield: 95.5 %

Procedure:
To a solution of 7 g (28.16 mmol) of 4-amino-3-chloro-2-fluoro-5-nitro-benzoic acid methyl ester (known from WO 03/077914) in 140 mL of DMF, 5.49 g (84.44 mmol) of sodium azide and 908 mg (2.82 mmol) of tetrabutyl ammonium bromide is added. Then the mixture is stirred and heated at 50° C. for 4 h. After cooling to ambient temperature, the mixture is diluted in EtOAc and washed with H2O (5 times). The organic phase is dried on Na2SO4, filtrated and evaporated. The crude compound (7.3 g, 26.88 mmol, 95%) obtained as a yellow solid is used without more purification in the next step. 1H-NMR (CDCl3, 300 MHz): ? ppm=3.95 (s, 3H), 8.82 (s, 1H).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:7])[CH2:5][CH3:6])[CH3:2].[CH3:8][OH:9]>F[B-](F)(F)F.C[N+](C)(C)C>[CH3:8][O:9][CH:1]([NH:3][C:4](=[O:7])[CH2:5][CH3:6])[CH3:2]
Reactant: CCNC(=O)CC
Reactant: CO
Agent: C[N+](C)(C)C
Agent: F[B-](F)(F)F
Product: CCC(=O)NC(C)OC
Temperature: 40 °C

Procedure:
36.9 g of methanol was charged into an electrolysis cell according to Example 5, wherein 0.37 g of tetramethyl ammonium tetrafluoroborate were dissolved as conducting salt. After switching on the electrolysis current, the anode current density was 2 A/dm2. The temperature was maintained at 40° C. during the electrolysis. Agitation was performed by a magnetic stirrer at from 30 to 35 revolutions per minute. After the passage of a current quantity of 4.06 Faraday per mole of N-ethylpropionic acid amide, the current was switched off. The calculated average cell tension was 54.9 volts. After work up of the electrolysis solution in known manner there were obtained 24.4 g of N-(α-methoxyethyl)-propionic acid amide (melting point 29°-32° C., nD35 = 1.4333), representing a material efficiency of 80.7% and a current efficiency of 40.4%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[C:20]([N+:22]([O-])=O)[CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)=[O:8])([O-])=O.[H][H]>[Pd].O1CCOCC1>[NH2:22][C:20]1[CH:19]=[C:6]([CH:5]=[C:4]([NH2:1])[CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1)=[O:8]
Reactant: O=C(Nc1cccc([N+](=O)[O-])c1)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1cccc(NC(=O)c2cc(N)cc(N)c2)c1

Procedure:
A solution of 13.29 gm. (0.04 mole) of 3,3',5-trinitrobenzanilide in 150 ml. of dioxane is hydrogenated at three atmospheres of hydrogen using 1 gm. of 10% palladium-on-charcoal catalyst. The catalyst is removed by filtration, the filtrate evaporated to dryness under reduced pressure, and the residue dried by distilling 200 ml. of benzene from the reaction mixture.