Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:7]=[CH:6]2.[CH:19]1([O:24][C:25]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][C:26]=2[C:27](O)=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1.C(OCC)(=O)C>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:14][CH2:15][N:16]([C:27]([C:26]3[CH:30]=[C:31]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:32]=[CH:33][C:25]=3[O:24][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:28])[CH2:17][CH2:18]1)[CH:7]=[CH:6]2
Reactant: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Reactant: Clc1ccc2nc(N3CCNCC3)ccc2c1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)N2CCN(c3ccc4cc(Cl)ccc4n3)CC2)c1

Procedure:
Prepared in analogy to example 1.1 (b) from 6-chloro-2-piperazin-1-yl-quinoline hydrochloride and 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (example 2.3) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[C:9]2[C:8](=[O:20])[N:7]([CH3:21])[C:6](=[O:22])[NH:5][C:4]=2[N:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:30][CH3:31].[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C=O)C.O.CS(C)=O>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=1[CH2:11][N:10]1[C:9]2[C:8](=[O:20])[N:7]([CH3:21])[C:6](=[O:22])[N:5]([CH2:30][CH3:31])[C:4]=2[N:3]=[C:2]1[N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CCI
Reactant: C1CCNCC1
Reactant: Cn1c(=O)[nH]c2nc(Br)n(Cc3c(F)cccc3Cl)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: O
Product: CCn1c(=O)n(C)c(=O)c2c1nc(N1CCCCC1)n2Cc1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 17.9 %

Procedure:
A solution of 8-bromo-7-(2-chloro-6-fluorobenzyl)-1-methyl-3,7-dihydro-1H-purine-2,6-dione (200 mg, 0.52 mmol) and K2CO3 (86 mg, 0.62 mmol) in 5.2 mL DMF was treated with iodoethane (412 μL, 5.2 mmol). The reaction was stirred at room temperature for 15 hr. The reaction mixture was diluted with H2O, and extracted 3× with 50% EtOAc:hexanes. The organic layers were combined and the solvent removed under reduced pressure (50 mg, 23% yield). The crude product (50 mg, 0.12 mmol) was dissolved in 200 μL DMSO and treated with piperidine (36 μL, 0.36 mmol). The reaction mixture was heated to 100° C. for 15 hr. The reaction mixture was cooled, diluted with H2O, and extracted 3× with 50% EtOAc:hexanes. The organic layers were combined and evaporated under reduced pressure. The crude product was purified by preparative thin layer chromatography (silica gel, 1 mm plate, EM Science 20×20 cm silica gel 60 F264) eluting with EtOAc:hexane (2:3) to give 27 mg (54% yield) of the title compound as a white solid: 1H NMR (CDCl3, 400 MHz) 7.22-7.15 (m, 1H), 7.15-7.11 (m, 1H), 6.98-6.91 (m, 1H), 5.55 (s, 2H), 4.10 (q, 2H, J=7.1 Hz), 3.30 (s, 3H), 3.08-3.01 (m, 4H), 1.53-1.47 (m, 6H), 1.30 (t, 3H, J=7.1 Hz); MS (ESP+) m/e 420 (MH+); TLC (EtOAc:hexanes/1:2) Rf=0.24.
Reaction SMILES: Cl.[F:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[N:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[C@@H:23](O)[CH2:22]2.C1C=CC2N(O)N=NC=2C=1>C(#N)C>[N:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[C@@H:23]([O:11][C:10](=[O:12])[CH:9]([NH:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:20][CH:19]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:22]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(NCc1ccc(F)cc1)c1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: O=C(O[C@H]1CN2CCC1CC2)C(NCc1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 21 %

Procedure:
A mixture of (4-fluoro-benzylamino)-phenyl-acetic acid hydrochloride (233 mg, 0.79 mmol), (R)-quinuclidin-3-ol (200 mg, 1.57 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (596 mg, 1.57 mmol), TEA (0.22 mL, 1.57 mmol) and HOBT (241 mg, 1.57 mmol) in acetonitrile (10 mL) is stirred at RT for 48 hours. THF is removed under vacuum and the crude is partitioned between EtOAc and water. The organic phase is dried over sodium sulphate, filtered and evaporated to dryness. The crude is purified by preparative HPLC. The combined fractions are dried and partitioned between EtOAc and 2M K2CO3. The organic phase is dried over sodium sulphate, filtered and evaporated to dryness to achieve the title compound as colorless oil (61 mg, 21% yield, mixture of diastereoisomers).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:21][C:22]([C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=2)[C:27]([O:29]C)=[O:28])=[O:23])[CH2:9][N:10]([CH3:20])[C:11]([O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[Li].O>C1COCC1.O>[CH:1]1([CH2:7][C@H:8]([NH:21][C:22]([C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=2)[C:27]([OH:29])=[O:28])=[O:23])[CH2:9][N:10]([CH3:20])[C:11]([O:13][CH2:14][CH2:15][Si:16]([CH3:17])([CH3:18])[CH3:19])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CN(C[C@H](CC1CCCCC1)NC(=O)c1cccc(C(=O)O)c1)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A mixture of (S)-methyl 3-(1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-2-ylcarbamoyl)benzoate (1.397 g) and LiOH.H2O (0.430 g, 10 mmol, 5.7 equiv) in THF (50 mL) and H2O (10 mL) was vigorously stirred at rt for 23 h. The reaction mixture was quenched with 2 N HCl (6 mL). After the organic solvent was removed in vacuo, the aqueous phase was extracted with CH2Cl2 (3×) and the combined organic layers were dried over Na2SO4. The crude (S)-3-(1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamoyl)benzoic acid (0.923 g) was used in the next step without further purification. LC-MS (3 min) tR=2.06 min, m/z 485 (M+Na+), 435, 391. 13C NMR (100 MHz, CDCl3) δ 168.45, 166.95, 157.89, 135.27, 132.73, 132.34, 129.95, 128.47, 128.42, 64.25, 52.86, 45.49, 40.59, 34.58, 34.26, 33.77, 33.13, 26.46, 26.23, 26.11, 17.64, −1.61.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[C:6]([NH:8][N:9]1[C:13](I)=[C:12]([CH3:15])[N:11]=[C:10]1[CH2:16][CH2:17][CH3:18])=[O:7])[CH3:2].[Cu][C:24]#[N:25].N1C=CC=CC=1>ClCCl>[C:24]([C:13]1[N:9]([NH:8][C:6](=[O:7])[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[O:3][CH2:1][CH3:2])[C:10]([CH2:16][CH2:17][CH3:18])=[N:11][C:12]=1[CH3:15])#[N:25]
Reactant: N#C[Cu]
Reactant: CCCc1nc(C)c(I)n1NC(=O)c1ccccc1OCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1nc(C)c(C#N)n1NC(=O)c1ccccc1OCC
Temperature: 100 °C

Procedure:
2-Ethoxy-N-(5-iodo-4-methyl-2-propylimidazol-1-yl)benzamide from Example 1a (0.5 g, 1.2 mmol) and copper(I) cyanide (0.7 g, 7.5 mmol) are introduced into 10 ml of pyridine and heated at 100° C. for three hours. The reaction mixture is cooled to room temperature, 50 ml of dichloromethane are added, and the solid is removed by filtration. The filtrate is washed three times with 50 ml of water each time, and the organic phase is re-extracted with 50 ml of dichloromethane. The combined organic phase is dried with sodium sulphate and concentrated. To remove the remaining pyridine, the residue is taken up in 50 ml of dichloromethane and washed six times with 100 ml of water each time. The organic phase is dried with sodium sulphate and concentrated in a rotary evaporator. The residue is finally mixed with 100 ml of toluene and concentrated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[CH3:15][O:16][C:17](=[O:24])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21]>>[CH3:15][O:16][C:17](=[O:24])[CH2:18]/[C:19](/[C:20]([O:22][CH3:23])=[O:21])=[CH:6]\[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=1
Reactant: COC(=O)CCC(=O)OC
Reactant: COc1cc(C=O)cc(OC)c1OC
Product: COC(=O)C/C(=C\c1cc(OC)c(OC)c(OC)c1)C(=O)OC

Procedure:
3,4,5-Trimethoxybenzaldehyde and succinic acid dimethyl ester are treated in the same manner as in Reference Example 1 to give (E)-3-methoxycarbonyl-4-(3,4,5-trimethoxyphenyl) -3-butenoic acid methyl ester as pale yellow syrup.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:17]2[CH:22]3[CH2:23][CH2:24][CH:18]2[CH2:19][CH:20]([OH:25])[CH2:21]3)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.Cl.[NH:27]1[CH2:31][CH2:30][CH:29]([C:32]([NH2:34])=[O:33])[CH2:28]1.C(N(CC)CC)C>C(#N)C>[OH:25][CH:20]1[CH2:19][CH:18]2[N:17]([C:4]3[C:5]4[C:10]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)=[CH:9][S:8][C:6]=4[N:7]=[C:2]([N:27]4[CH2:31][CH2:30][CH:29]([C:32]([NH2:34])=[O:33])[CH2:28]4)[N:3]=3)[CH:22]([CH2:23][CH2:24]2)[CH2:21]1
Reactant: NC(=O)C1CCNC1
Reactant: OC1CC2CCC(C1)N2c1nc(Cl)nc2scc(-c3ccccc3)c12
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NC(=O)C1CCN(c2nc(N3C4CCC3CC(O)C4)c3c(-c4ccccc4)csc3n2)C1
Temperature: 150 °C
Yield: 81.6 %

Procedure:
8-(2-Chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-ol (44 mg, 0.12 mmol) was suspended in acetonitrile (3 mL). Pyrrolidine-3-carboxamide hydrochloride (36 mg, 0.24 mmol) and triethylamine (0.067 mL, 0.47 mmol) were added and the mixture was heated to 150° C. for 30 min in a microwave (twice). Further batches of pyrrolidine-3-carboxamide hydrochloride (36 mg, 0.24 mmol) and triethylamine (0.067 mL, 0.47 mmol) were added and the mixtures were heated to 150° C. for 30 min in a microwave. The solvent was evaporated and the residue was purified by LCUV (acidic method 1) to give the target compound as a white solid (44 mg). m/z [M+H]+450.1. Retention time 3.75 min (LCMS method+ve 6 min).
Reaction SMILES: BrN1C(=O)CCC1=O.[N:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[CH:10]=1.[OH:17][C:18]1[CH:19]=[C:20]([C:24]([NH2:26])=[O:25])[CH:21]=[CH:22][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)(Cl)Cl.CN(C=O)C.C(Cl)Cl>[CH3:15][C:13]1[CH:12]=[C:11]([CH2:16][O:17][C:18]2[CH:19]=[C:20]([C:24]([NH2:26])=[O:25])[CH:21]=[CH:22][CH:23]=2)[CH:10]=[N:9][CH:14]=1
Reactant: Cc1cncc(C)c1
Reactant: NC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cncc(COc2cccc(C(N)=O)c2)c1
Yield: 7.2 %

Procedure:
N-Bromosuccinimide (2.13 g, 12 mmol) and subsequently α,α′-azoisobutyronitrile (16 mg, 0.1 mmol) were added to a solution of 3,5-lutidine (1.14 ml, 10 mmol) in CCl4 (40 ml). The reaction mixture was stirred at reflux for 2 hrs. After cooling, succinimide was removed by filtration and the filtrate was evaporated to smaller volume (10 ml). To this filtrate, a mixture of 3-hydroxybenzenecarboxamide (550 mg, 4 mmol) and K2CO3 (830 mg, 6 mmol) in DMF (5 ml) was added and the new reaction mixture was stirred at 60° C. for 24 h. After diluting with CH2Cl2 (100 ml), the solution was washed with Na2CO3 solution (40 ml) and water (40 ml), dried (Na2SO4) and evaporated to dryness, under reduced pressure. The brown oil residue was extracted by trituration with Et2O (2×10 ml), and from the Et2O extracts, the precipitant solid was filtered and washed with pentane, to give 70 mg (7.2% yield) of the desired product. Mp 152-154° C., HPLC-MS: m/z 243 [M+H]+, Rt=2.28 min.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[CH:33]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1>N1C=CC=CC=1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:38]([CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:39])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)C1CCCC1
Agent: Cl
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)C3CCCC3)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 μmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, cyclopentanecarbonyl chloride (26 mg, 197 μmol, 3 eq.) was added. After 12 h, analysis of the reaction by HPLC showed substantial conversion. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Reprosil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (14.6 mg, 41% of theory).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[C:16]2[C:11](=[C:12]([N+:20]([O-:22])=[O:21])[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[C:10]([N+:23]([O-:25])=[O:24])=[CH:9][CH:8]=1>>[ClH:6].[N+:23]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=2[N+:20]([O-:22])=[O:21])[C:7]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:8][CH:9]=1)([O-:25])=[O:24]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c2c([N+](=O)[O-])ccc(Cl)c2c1
Product: Cl
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c2c([N+](=O)[O-])ccc(N3CCCC3)c2c1
Yield: 22 %

Procedure:
Pyrrolidine (2.5 mL) was added to 1-chloro-4,5,7-trinitronaphthalene (100 mg, 0.33 mmol, Bassilios et al, Recueil., 1962, 81, 209-214) which resulted in an immediate, highly exothermic reaction. Volatiles were removed in vacuo and purification as in 159JP06 afforded 23 mg (22%) of 159JP09 as a red solid. The product was converted to the corresponding hydrochloride salt as described above.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:16]([O:18][C:19](=[O:37])[CH:20](Br)[C:21]1[CH:26]=[CH:25][C:24]([S:27]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)(=[O:29])=[O:28])=[CH:23][CH:22]=1)[CH3:17]>C(#N)C.O>[CH2:16]([O:18][C:19](=[O:37])[CH:20]([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:21]1[CH:22]=[CH:23][C:24]([S:27]([N:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)(=[O:28])=[O:29])=[CH:25][CH:26]=1)[CH3:17]
Reactant: CCOC(=O)C(Br)c1ccc(S(=O)(=O)N2CCCCC2)cc1
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)N2CCCCC2)cc1
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
2,4-Difluorophenol (0.38 ml, 3.89 mmol) and cesium carbonate (0.76 gm, 2.33 mmol) were taken in acetonitrile (30 ml) under argon atmosphere and was stirred for 30 minutes. Bromo-[4-(piperidine-1-sulfonyl)-phenyl]-acetic acid ethyl ester (1.4 gm, 3.86 mmol) in acetonitrile (15 ml) was added to the mixture and stirred at 25° C. for 3 hour. Reaction mixture was diluted with water (30 ml), extracted with ethyl acetate (3×20 ml), organic layer was washed with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a gummy mass which was purified by flash column chromatography using over silica gel using 40-60% ethyl acetate in hexane as eluent to give (2,4-difluoro-phenoxy)-[4-(piperidine-1-sulfonyl)-phenyl]-acetic acid ethyl ester (1.31 gm).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29](Cl)(=[O:31])=[O:30].O.Cl>N1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29]([NH:20][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([O:8][C:9]2[S:10][C:11]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[C:6]([Cl:19])[CH:5]=1)(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1)c1ccc(Cl)cc1Cl
Yield: 46.4 %

Procedure:
A solution of 3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine (102) (2.0 g, 5.79 mmol) and 2,4-dichloro benzenesulfonylchloride (1.5 g, 6.08 mmol) in pyridine (10 mL) was stirred at room temperature for 12 h. Water was added to the reaction mixture, which was then acidified by 2N HCl. Reaction mixture was extracted twice with AcOEt. Organic layer was washed by brine, dried over MgSO4 and concentrated. Crude residue was purified by column chromatography (H/A=4/1, 80 g of silica gel) to afford title compound (104) (1.49 g, 46%) as a white solid. Mp 73-75° C. 1H NMR (300 MHz, DMSO-d6) δ 7.29 (2H, s), 7.46 (1H, dd, J=2.2, 8.8 Hz), 7.69 (1H, d, J=8.8 Hz), 7.71 (1H, dd, J=2.2, 8.4 Hz), 7.95 (1H, d, J=2.2 Hz), 8.14 (1H, d, J=2.2 Hz), 8.18 (1H, d, J=8.4 Hz), 11.5 (1H, br s). MS (M+H) 553.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:8]=2)[CH2:3][CH2:2]1.[OH:24]O>S(=O)(=O)(O)O>[O:24]=[S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: OO
Reactant: Fc1cccc2c(N3CCSCC3)nc(N3CCNCC3)cc12
Agent: O=S(=O)(O)O
Product: O=S1CCN(c2nc(N3CCNCC3)cc3c(F)cccc23)CC1
Yield: 31 %

Procedure:
1-(1-Oxido-thiomorpholino-3-piperazino-5-fluoro-isoquinoline was prepared analogous to Example 12 from 1-thiomorpholino-3-piperazino-5-fluoro-isoquinoline by oxidation with hydrogen peroxide in dilute sulfuric acid. M.p. 213°-215°C (from n-propanol/petroleum ether). Yield: 31% of theory.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH:22]([CH:25]([C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=1)[C:26](Cl)=[O:27])([CH3:24])[CH3:23]>C(Cl)Cl>[CH:22]([CH:25]([C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]([F:37])([F:38])[F:39])=[CH:31][CH:30]=1)[C:26]([O:12][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)=[O:27])([CH3:24])[CH3:23]
Reactant: CC(C)C(C(=O)Cl)c1ccc(OC(F)(F)F)cc1
Reactant: OCc1cccc(Oc2ccccc2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C(C(=O)OCc1cccc(Oc2ccccc2)c1)c1ccc(OC(F)(F)F)cc1
Reaction time: 8 h

Procedure:
To a solution of m-phenoxybenzyl alcohol (1.89 g) and pyridine (1 ml) in methylene chloride (6 ml) is added a methylene chloride (7 ml) solution of α-isopropyl-4-trifluoromethoxyphenylacetyl chloride, prepared from the corresponding acid (2.46 g) as illustrated in Example 15. After stirring the reaction mixture overnight, it is washed with water, diluted hydrochloric acid solution, dilute potassium hydroxide solution, water and evaporated to an orange oil. Purification by silica gel chromatography gives the desired ester (2.76 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([CH3:14])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(=O)(O)[O-].[K+]>C(OCC)(=O)C.O>[CH3:1][O:2][C:3](=[O:15])[CH:4]([CH3:14])[CH2:5][N:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:19]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1
Reactant: COC(=O)C(C)CNCc1ccccc1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)CN(Cc1ccccc1)c1nc(Cl)ncc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 69.9 %

Procedure:
To a mixture of 2.73 g (0.010 mole) of (rac)-3-benzylamino-2-methyl-propanoic acid methyl ester, 1.84 g (0.010 mole) of 2,4-dichloro-5-nitro-pyrimidine, 50 mL of ethyl acetate and 25 mL of water was added 3.0 g (0.030 mole) of potassium bicarbonate. The mixture was stirred for 3 hours, then diluted with 50 mL of ethyl acetate and 50 mL of water. The layers were separated, and the aqueous layer extracted twice with 100 mL of ethyl acetate. The organic layers were washed with 100 mL of brine, combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-ethyl acetate (100:0-97:3) to give 2.55 g of (rac)-3-[benzyl-(2-chloro-5-nitro-pyrimidin-4-yl)-amino]-2-methyl-propanoic acid methyl ester (IV-42) as pale yellow oil.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.[H][H].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:26]([S:27]([N:30](C(OCC(C)C)=O)[C:31]3[C:36]([O:37][CH3:38])=[N:35][C:34]([CH3:39])=[CH:33][N:32]=3)(=[O:29])=[O:28])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1>C1COCC1>[CH3:14][CH2:15][O:10][CH2:9][CH3:5].[CH3:38][O:37][C:36]1[C:31]([NH:30][S:27]([C:26]2[C:21]([C:18]3[CH:17]=[CH:16][C:15]([CH2:14][O:10][CH2:9][C:5]4[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=4)=[CH:20][CH:19]=3)=[N:22][CH:23]=[CH:24][CH:25]=2)(=[O:29])=[O:28])=[N:32][CH:33]=[C:34]([CH3:39])[N:35]=1
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(CBr)cc1
Reactant: [H][H]
Reactant: OCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCC
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(COCc2cccnc2)cc1
Reaction time: 2 h
Yield: 67.8 %

Procedure:
Oil-free sodium hydride (240 mg) was added to a stirred solution of 3-pyridyl carbinol (1.09 g) in dry THF (20 ml). When evolution of hydrogen ceased, 2-(4-bromomethylphenyl)-N-(isobutoxycarbonyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (549 mg) was added and the mixture was stirred for 2 hours. Volatile material was removed by evaporation and saturated ammonium chloride solution (10 ml) was added to the residue. The mixture was extracted with ethyl acetate (3×20 ml) and the extracts were dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by flash chromatography, eluting with methanol/ethyl acetate (1:19 v/v), to give after trituration with ether N-(3-methoxy-5-methylpyrazin-2-yl)-2-{4-[(3-pyridyl)methoxymethyl]phenyl}pyridine-3-sulphonamide (187 mg), m.p. 183-185° C.; microanalysis found: C, 60.9; H, 4.9; N, 14.2%; C24H23N5O4S requires: C, 60.4; H, 4.85; N, 14.7%.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:7]=1[I:14]>O.CO>[I:14][C:7]1[CH:8]=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:6]=1[C:5]([OH:15])=[O:4]
Reactant: COC(=O)c1cc(C#N)ccc1I
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(I)c(C(=O)O)c1
Reaction time: 20 h
Yield: 66.2 %

Procedure:
A solution of sodium hydroxide (0.44 g, 11 mmol) in water (10 ml) was added to 2-iodo-5-cyanobenzoic acid methyl ester (2.7 g, 9.4 mmol) in methanol. The mixture was stirred for 20 h, then most of the solvent was evaporated and the residue acidified with 2N hydrochloric acid. The resulting precipitate was filtered off and dried to give a white solid (1.7 g). MS (−CI) m/z 272 [M-H]+.