Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][C:12](=O)[CH2:13][CH2:14][C:15]2([CH3:22])[C:19](=[O:20])[CH2:18][CH2:17][C:16]2=O)[CH:6]=[CH:7][CH:8]=1.O>C1C=CC=CC=1>[CH3:22][C@:15]12[CH2:14][CH2:13][C:12]3[C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH2:9][CH2:10][C:11]=3[C:16]1=[CH:17][CH2:18][C:19]2=[O:20]
Reactant: COc1cccc(CCCC(=O)CCC2(C)C(=O)CCC2=O)c1
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc2c(c1)CCC1=C2CC[C@]2(C)C(=O)CC=C12
Yield: 75.2 %

Procedure:
To 2-(6-m-methoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione (3 g) in benzene (100 cc) add polyphosphoric acid (from orthophosphoric acid, 15 g. and phosphorus pentoxide, 6 g.) and heat the mixture at 90° for 4 minutes under such reduced pressure as the need to control frothing will allow. Cool, add water, and extract the mixture with ether and ethyl acetate; isolate the product from the resulting solution to obtain the colorless crystalline 13β-methyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one (2 g), b.p. 115°-116°; ultraviolet absorption peak at 313 mμ (ε35,100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][C:7]=1[CH3:8].C(N(CC)CC)C.C(Cl)[Cl:24]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:9])=[N:6][C:7]=1[CH3:8].[CH3:12][C:11]([CH3:14])([CH3:13])[C:10]([Cl:24])=[O:15]
Reactant: ClCCl
Reactant: Cc1nc(NC(=O)C(C)(C)C)ccc1Br
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Cl
Product: Cc1nc(N)ccc1Br

Procedure:
This material was prepared in analogy to example 107 step A] from N-(5-bromo-6-methyl-pyridin-2-yl)-2,2-dimethyl-propionamide, 7.05 g—obtained via standard acylation of 5-bromo-6-methyl-pyridin-2-ylamine with 2,2-dimethyl-propionyl chloride in CH2Cl2, with triethylamine as base, as viscous brown oil, MS (ESI): 271.2 (MH+)- butyllithium (34.94 mL, 1.6 M in hexane, Agros) and N,N-dimethylformamide (4 mL) as an amorphous light brown solid (5.7 g). MS (EI): 220.1 (M+)
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH:5]=[O:6].[C:7]1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:18][OH:19]>>[CH3:18][O:19][CH:5]([O:6][CH3:7])[CH2:4][CH2:3][S:2][CH3:1]
Reactant: CO
Reactant: CSCCC=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(CCSC)OC

Procedure:
20.8 g (0.2 mole) of freshly distilled methional and 100 cc of methyl alcohol are heated under reflux in the presence of 0.5 g of p-toluene sulphonic acid.
Reaction SMILES: [H-].[Na+].C(OP(OCC)O[CH2:8][O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])C.[CH2:18]([O:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[I:32])[CH:27]=O)[CH3:19].O>O1CCCC1.C(OCC)(=O)C>[CH2:18]([O:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:26](/[CH:27]=[C:10](\[O:9][CH3:8])/[C:11]([O:13][CH3:14])=[O:12])[CH:29]=[CH:30][C:31]=1[I:32])[CH3:19].[CH2:18]([O:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:26](/[CH:27]=[C:10](/[O:9][CH3:8])\[C:11]([O:13][CH3:14])=[O:12])[CH:29]=[CH:30][C:31]=1[I:32])[CH3:19]
Reactant: CCOP(OCC)OCOCC(=O)OC
Reactant: CCOCCOc1cc(C=O)ccc1I
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOCCOc1cc(/C=C(/OC)C(=O)OC)ccc1I
Product: CCOCCOc1cc(/C=C(\OC)C(=O)OC)ccc1I
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
0.30 g (7.5 mmol) of sodium hydride is added portionwise to a solution at 0° C. of 1.80 g (7.5 mmol) of methyl (diethoxyphosphanyloxy)methoxyacetate (prepared according to Example 24b) in 20 mL of tetrahydrofuran. The reaction mixture is stirred for 45 minutes at room temperature and then 2 g (6.25 mmol) of 3-(2-ethoxyethoxy)-4-iodobenzaldehyde (prepared according to Example 38c) in 10 mL of tetrahydrofuran. The reaction is slightly exothermic, and the reaction mixture is maintained at a temperature of 25-30° C. with an ice-water bath. When the temperature has stabilized, the reaction mixture is stirred for 24 hours at room temperature. After addition of 50 mL of water and extraction with ethyl acetate, the organic phases are combined, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The crude product obtained is purified by chromatography on a column of silica eluted with a 95/5 heptane/ethyl acetate mixture to give 411 mg of methyl (Z)-3-[3-(2-ethoxyethoxy)-4-iodophenyl]-2-methoxyacrylate and 526 mg of methyl (E)-3-[3-(2-ethoxyethoxy)-4-iodophenyl]-2-methoxyacrylate in the form of colorless oils.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH:12]=O)[C:3]1=[O:14].[NH2:15][CH2:16][CH:17]([CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH2:12][NH:15][CH2:16][CH:17]([CH:24]2[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:3]1=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCC(C(CN)c2ccccc2)CC1
Reactant: Cn1c(=O)c(C=O)cc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cn1c(=O)c(CNCC(c2ccccc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc2ccccc21
Reaction time: 16 h

Procedure:
1-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (0.590 g, 3.15 mmol), tert-butyl 4-(2-amino-1-phenylethyl)piperidine-1-carboxylate (1.2 g crude, 3.94 mmol), and acetic acid (0.677 ml, 11.83 mmol) were combined in CH2Cl2 (20 ml). Sodium triacetoxyborohydride (2.506 g, 11.83 mmol) was added and the reaction stirred for 16 hours. The mixture was partitioned between CH2Cl2 and satd. bicarb, the aqueous portion extracted 3×CH2Cl2, and the organic portion dried (Na2SO4) then concentrated in vacuo. The product was carried on without further purification.
Reaction SMILES: Cl.[F:2][C:3]([F:12])([F:11])[CH:4]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][NH:5]1.O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+].F[C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=[O:33].CC(=O)OCC>CS(C)=O.O>[F:12][C:3]([F:2])([F:11])[CH:4]1[CH2:10][CH2:9][N:8]([C:30]2[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=2[CH:32]=[O:33])[CH2:7][CH2:6][NH:5]1
Reactant: O=Cc1ccccc1F
Reactant: FC(F)(F)C1CCNCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=Cc1ccccc1N1CCNC(C(F)(F)F)CC1
Temperature: 160 °C
Reaction time: 4 h
Yield: 31.9 %

Procedure:
A mixture of 5-trifluoromethyl-[1,4]diazepane hydrochloride (1.17 g; 4.83 mmol; 1.2 eq.), sodium carbonate decahydrate (2.13 g; 20.14 mmol; 5 eq.) and 2-fluoro-benzaldehyde (500 mg; 4.03 mmol; 1 eq.) in DMSO (20 mL) and water (20 mL) was stirred at 160° C. for 4 hours. The solution was diluted EA and the organic layer washed with water (3×) then brine (2×), dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (15% to 33% EA in heptanes) afforded the title compound (350 mg, 32%) as a yellow oil. HPLC (max plot) 97.9%; Rt 5.23 min.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:13]=[C:6]2[C:7]([CH3:12])=[N:8][CH:9]=[C:10]([CH3:11])[N:5]2[N:4]=1.[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCCl>[Cl-:1].[CH3:11][C:10]1[N:5]2[N:4]=[C:3]([CH2:2][P+:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:13]=[C:6]2[C:7]([CH3:12])=[N:8][CH:9]=1
Reactant: Cc1ncc(C)n2nc(CCl)nc12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: Cc1ncc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Product: [Cl-]
Temperature: 140 °C
Yield: 99.8 %

Procedure:
A mixture of 2-(chloromethyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (420 mg, 2.14 mmol) and triphenylphosphine (672 mg, 2.57 mmol) in 1,2-dichloroethane (10 mL) was heated to 140° C. in a microwave reactor for 1 h. The reaction mixture was cooled to room temperature and concentrated to give the title compound as a yellow solid (980 mg, yield 100%). ESI MS: m/z 424 [M−35]+.
Reaction SMILES: S(=O)(=O)(O)N.[CH3:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:21])[CH:19]=[O:20])=[CH:14][CH:13]=1.Cl([O-])=[O:23].[Na+].S([O-])(O)=O.[Na+]>O.C(Cl)(Cl)Cl>[CH3:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:21])[C:19]([OH:23])=[O:20])=[CH:14][CH:13]=1
Reactant: [O-][Cl+][O-]
Reactant: Cc1ccsc1-c1ccc(C(C)C=O)cc1
Agent: NS(=O)(=O)O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccsc1-c1ccc(C(C)C(=O)O)cc1
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
In 20 ml of water was dissolved 3.2 g (0.033 mole) of sulfamic acid. To the solution was added a solution of 5.0 g (0.0217 mole) of 2-[4-(3-methyl-2-thienyl)phenyl]propionaldehyde [obtained in (1)] in 20 ml of chloroform. To the mixture, while maintaining the temperature at 0° to 10° C., was added dropwise with stirring 10 ml of an aqueous solution containing 2.6 g (0.0242 mole) of sodium chlorite (84% pure). After completion of the addition, the mixture was stirred for 10 minutes, admixed with 2.6 g (0.025 mole) of sodium hydrogensulfite, further stirred for 30 minutes, and allowed to stand, upon which the mixture separated into two layers. The organic layer was washed with 20 ml of water and extracted by the addition of 25 ml of 1 N aqueous sodium hydroxide solution. To the alkaline extract layer, which had been admixed with 20 ml of cyclohexane, was added gradually with stirring 5% hydrochloric acid to adjust the pH to 4. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and freed from the solvent by distillation under reduced pressure to obtain an oily substance which was crystallized by the addition of a small quantity of n-hexane to yield 4.8 g (90% yield) of 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16](C)(C)C)CO)=[CH:6][CH:5]=1)[CH3:2].S(Cl)(Cl)=O.Br[C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[C:30]([NH2:35])[CH:29]=1.[F-].[Cs+].N[CH:39]1CCCCC1N>[Cu](I)I.C(O)=O>[NH:35]1[C:30]2[CH:29]=[CH:28][C:33]([N:13]3[C@@H:10]([C:7]4[CH:6]=[CH:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:21][CH3:22])=[CH:9][CH:8]=4)[CH2:16][O:15][C:14]3=[O:20])=[CH:32][C:31]=2[N:34]=[CH:39]1
Reactant: NC1CCCCC1N
Reactant: CCN(CC)c1ccc([C@H](CO)NC(=O)OC(C)(C)C)cc1
Reactant: Nc1ccc(Br)cc1N
Agent: I[Cu]I
Agent: [Cs+]
Agent: [F-]
Solvent: O=S(Cl)Cl
Solvent: O=CO
Product: CCN(CC)c1ccc([C@H]2COC(=O)N2c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized according to method 6 starting from tert-butyl (R)-1-(4-(diethylamino)phenyl)-2-hydroxyethylcarbamate (0.500 g, 21.623 mmol), thionyl chloride (0.95 mL, 12.98 mmol, 4-bromo1,2-diamino benzene (219 mg, 1.175 mmol), cesium fluoride (324 mg, 2.136 mmoles) and copper iodide (30 mg, 0.160 mmoles), 1,2-diaminocyclohexane (0.02, 0.1602 mmoles), formic acid (5 mL). Yield: 0.05 g (0.6%). MS m/z 351.4 (M+H)+; 1H-NMR (400 MHz, DMSO-d6): δ 12.44 (d, 1H); 8.17 (d, 1H); 7.56-7.13 (m, 5H); 6.55 (d, 2H); 5.54 (t, 1H); 4.75 (t, 1H); 4.09 (t, 1H); 3.39-3.20 (m, 4H); 1.23-0.98 (m, 6H), HPLC (λ=214 nm, [A]: rt 6.04 min (97.7%).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH2:18])(=[O:17])=[O:16])=[N:5][N:4]=1.C1([O:25][C:26](=O)[NH:27][C:28]2[N:33]=[C:32]([O:34][CH3:35])[N:31]=[C:30]([CH3:36])[N:29]=2)C=CC=CC=1.C1CCN2C(=NCCC2)CC1.Cl>O1CCOCC1.O>[CH3:35][O:34][C:32]1[N:31]=[C:30]([CH3:36])[N:29]=[C:28]([NH:27][C:26]([NH:18][S:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][C:6]2[S:7][C:3]([S:2][CH3:1])=[N:4][N:5]=2)(=[O:16])=[O:17])=[O:25])[N:33]=1
Reactant: COc1nc(C)nc(NC(=O)Oc2ccccc2)n1
Reactant: CSc1nnc(Cc2ccccc2S(N)(=O)=O)s1
Agent: Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2Cc2nnc(SC)s2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
By the procedure of Example 4, 0.3 g of the sulfonamide prepared in Example 3 was reacted with 0.29 g of phenyl(4-methoxy-6-methyl-1,3,5-triazin-2-yl)carbamate and 0.15 g of "DBU" in 10 ml of p-dioxane. After stirring two hours at room temperature the solution was diluted with about 75 ml of water and acidified with concentrated hydrochloric acid (red to litmus paper). Following filtration, the residue was washed with water (2×20ml) then with ether (1×20ml) and suction-dried to give 0.15 g of the subject compound; m.p. 140°-146° C. NMR (CDCl3): δ2.6(d,6H,SCH3, OCH3); 4.1 (S, 3H, CH3); 4.9(S, 2H, CH2); 7.4-7.7(m, 4H, Ar+NH); 8.3(d, 1H, Ar).
Reaction SMILES: I[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:10]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:9]2)[CH:5]=[N:4][CH:3]=1.[F:25][C:26]1[C:31]([C:32](N(OC)C)=[O:33])=[CH:30][CH:29]=[CH:28][N:27]=1>C1COCC1>[F:25][C:26]1[N:27]=[CH:28][CH:29]=[CH:30][C:31]=1[C:32]([C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:10]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:9]2)[CH:5]=[N:4][CH:3]=1)=[O:33]
Reactant: CC(C)C[C@H]1CN(c2cncc(I)n2)CCN1C(=O)OC(C)(C)C
Reactant: CON(C)C(=O)c1cccnc1F
Solvent: C1CCOC1
Product: CC(C)C[C@H]1CN(c2cncc(C(=O)c3cccnc3F)n2)CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
A solution of (S)-tert-butyl 4-(6-iodopyrazin-2-yl)-2-isobutylpiperazine-1-carboxylate (1.05 g, 2.353 mmol) in THF (15 mL) was cooled to −78° C. and nBuli 2.5M in hexanes (988.4 μL of 2.5 M, 2.471 mmol) was added slowly. The solution was stirred for 10 mins after which a solution of 2-fluoro-N-methoxy-N-methyl-pyridine-3-carboxamide (455.1 mg, 2.471 mmol) in THF (5 mL) was added and the solution stirred for 1 hr at −78° C. The reaction was quenched with Sat NH4Cl and extracted into EtOAc (3×30 ml). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated to give an orange oil. Columned on silica gel eluting with 1:1 EtOAc/hexanes to give (S)-tert-butyl 4-(6-(2-fluoronicotinoyl)pyrazin-2-yl)-2-isobutylpiperazine-1-carboxylate as a yellow oil (0.64 g, 61%).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]1([CH3:20])[CH3:19].[C:21]1([P:27](Cl)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:11]([O:10][CH:5]1[CH2:6][C:7]([CH3:9])([CH3:8])[N:2]([O:1][P:27]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:28])[C:3]([CH3:20])([CH3:19])[CH2:4]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OP(=O)(c1ccccc1)c1ccccc1
Yield: 84 %

Procedure:
Using 1-hydroxy-4-benzoyloxy-2,2,6,6-tetramethylpiperidine, prepared as described by: Kurumada T. et. al., loc. cit., and diphenylphosphinic chloride in a procedure otherwise similar to that for preparing the compound 101 gives an 84% yield of the compound 116 which is obtained in the form of colourless crystals; melting point: 169-173° C. (dichloromethane/hexane).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]=[C:18]([CH2:21][O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[NH:19][CH:20]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[S:36](Cl)([N:39]=[C:40]=[O:41])(=[O:38])=[O:37].[C:43]([OH:47])([CH3:46])([CH3:45])[CH3:44]>ClCCl>[F:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[N:17]=[C:18]([CH2:21][O:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:19][CH:20]=3)=[CH:14][CH:15]=2)[CH:6]=[CH:5][C:3]=1[NH:4][S:36]([NH:39][C:40](=[O:41])[O:47][C:43]([CH3:46])([CH3:45])[CH3:44])(=[O:38])=[O:37]
Reactant: Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1F
Reactant: CC(C)(C)O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NS(=O)(=O)Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1F
Reaction time: 2 h
Yield: 75 %

Procedure:
At 0° C., the compound 2-fluoro-4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}aniline (1.5 g, 4 mmol) and triethylamine (0.63 ml, 4.52 mmol) are solubilized in 10 ml of dichloromethane. A mixture containing sulfonyl isocyanate chloride (0.623 g, 4.40 mmol) and tert-butanol (0.325 g, 4.40 mmol) in 10 ml of dichloromethane is added to this solution at 0° C. The reaction medium is returned to ambient temperature then stirred for two hours. After evaporation of the solvent, the solid obtained is purified on a silica column (eluent: dichloromethane-methanol: 95-5). After washing in dichloromethane then filtration, a yellow-coloured powder is obtained with a yield of 75%.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[SH:11].Cl[CH2:13][CH2:14][CH2:15][CH2:16][OH:17].C(N(CC)CC)C.O>CC(C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][CH2:13][CH2:14][CH2:15][CH2:16][OH:17]
Reactant: Sc1ccc2ccccc2c1
Reactant: OCCCCCl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: OCCCCSc1ccc2ccccc2c1
Yield: 70.5 %

Procedure:
20 g of 2-naphthalene thiol was dissolved in 100 ml of acetone, and 13.39 g of 4-chloro-1-butanol and 25.04 g of triethylamine were added dropwise. The mixture was reacted for 12 hours at room temperature while stirring and poured into 100 ml of water. The reaction mixture was extracted three times with 50 ml of ethyl acetate. The resulting organic layer was washed three times with 50 ml of 10 wt % sodium carbonate aqueous solution and three times with 50 ml of 5 wt % oxalic-acid aqueous solution. The separated water layer was repeatedly washed with distilled water until pH 7. The organic layer was dried using 3 g of magnesium sulfate. After removing magnesium sulfate by filtration, the solvent was evaporated using a rotary evaporator to obtain 20.2 g of 4-(naphthalen-2-ylsulfanyl)butan-1-ol as a highly viscous oily liquid.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:21][CH3:22])[C:14]([C:23](=O)[CH2:24]Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:27]([O-:29])=O.[NH4+:30]>C(O)=O.O>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:21][CH3:22])[C:14]([C:23]3[N:30]=[CH:27][O:29][CH:24]=3)=[CH:13][CH:12]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(C(=O)CBr)c1OC
Reactant: O=C[O-]
Solvent: O=CO
Solvent: O
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2cocn2)c1OC
Temperature: 80 °C
Reaction time: 6 h
Yield: 27.8 %

Procedure:
A mixture of methyl 6-(benzenesulphonylmethyl)-3-(2-bromoacetyl)-2-methoxy-benzoate (Intermediate 51, 0.9 g) and ammonium formate (0.45 g) in formic acid (5 ml) was sealed in a vial and heated at 80° C. for 3 hours then at 100° C. for 6 hours. After standing at room temperature overnight, the mixture was heated at 120° C. for 4 hours. The mixture was diluted with water and extracted with ethyl acetate, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give methyl 6-(benzenesulphonylmethyl)-3-(oxazol-4-yl)-2-methoxy-benzoate (0.22 g) as a yellow gum which was used directly without further purification or characterisation.
Reaction SMILES: Cl.[CH3:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([N:10]2[CH2:15][C:14]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[O:13][CH2:12][CH2:11]2)=[O:9])[N:7]=1.[OH:21][CH2:22][C:23]1[CH:32]=[CH:31][C:26]([O:27][CH2:28][CH:29]=O)=[CH:25][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1.C(O)(=O)C.CO>[OH:21][CH2:22][C:23]1[CH:32]=[CH:31][C:26]([O:27][CH2:28][CH2:29][N:18]2[CH2:19][CH2:20][C:14]3([O:13][CH2:12][CH2:11][N:10]([C:8]([C:6]4[N:7]=[C:3]([CH3:2])[S:4][CH:5]=4)=[O:9])[CH2:15]3)[CH2:16][CH2:17]2)=[CH:25][CH:24]=1
Reactant: O=CCOc1ccc(CO)cc1
Reactant: Cc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCOc4ccc(CO)cc4)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2-Methylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone hydrochloride (example 1, step f) (0.38 g) was added to a solution of 2-(4-(hydroxymethyl)phenoxy)acetaldehyde (example 1, step h) (0.17 g) in NMP (10 mL) and acetic acid (0.06 mL). The resulting mixture was stirred for 30 min then cooled in an ice bath. Sodium triacetoxyborohydride (0.32 g) was then added and the reaction allowed to warm to room temperature and stirred for 16 h. The reaction was diluted with methanol (30 mL) and applied to a SCX cartridge pre-wetted with methanol. The cartridge was washed with methanol (250 mL) and eluted with 3M ammonia in methanol solution (150 mL). The eluent was evaporated in vacuo and the residue purified by column chromatography eluting with 95:5 ethyl acetate:triethylamine to give the subtitled compound as a gum. Yield 0.32 g.
Reaction SMILES: [Br:1][CH2:2][C:3]([CH2:5][CH:6]([CH3:8])[CH3:7])=[O:4].[C:9]1([P:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCOCC>C(Cl)Cl>[Br-:1].[CH2:5]([C:3]([CH2:2][P+:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:4])[CH:6]([CH3:8])[CH3:7]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)CC(=O)CBr
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)CC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.6 %

Procedure:
Bromomethylisobutyl ketone (53.6 g) and triphenylphosphine (78.5 g) are intimately mixed in a 500 ml round-bottom flask and, after the initially strong heat tonality subsides, are left for 12 hours under nitrogen at room temperature. After that, the solid reaction mass is taken up in 330 ml of methylene chloride and refluxed for 30 minutes. After adding 500 ml of ether, it is allowed to cool to room temperature and the product is isolated by filtration. After drying,111.7 g of the phosphonium salt with a melting point of 244-245° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[C:10]([CH3:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:18]1([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([N:26]3[CH2:27][CH2:28][CH:23]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[CH2:24][CH2:25]3)=[O:16])[C:10]([CH3:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1nn(-c2cccc(Cl)c2)c(C)c1C(=O)O
Product: Cc1nn(-c2cccc(Cl)c2)c(C)c1C(=O)N1CCC(N2CCCC2)CC1
Yield: 98 %

Procedure:
In analogy to the procedure described in Example 18], 1-(3-chloro-phenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid and 4-pyrrolidine-1-yl-piperidine gave the title compound in 98% yield as light brown solid. MS: 387.3 (MH+, Cl).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH3:12])[S:4][N:3]=1.[CH2:13](Br)[CH:14]=[CH2:15]>>[CH3:12][C:5]1[S:4][N:3]=[C:2]([NH:1][CH2:13][CH2:14][CH3:15])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1c(N)nsc1C
Reactant: C=CCBr
Product: CCCNc1nsc(C)c1C(=O)OCC

Procedure:
Ethyl 3-amino-5-methylisothiazole-4-carboxylate, prepared by the method of Hartke and Peshkar, Arch. Pharm.- Weinheim, 301(8), 611 (1968), is reacted with allyl bromide using the conditions described in Example 15A. This product is then hydrogenated using the procedure described in Example 15B to give ethyl 5-methyl-3-propylaminoisothiazole-4-carboxylate.