Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[CH2:15]([O:22][C@H:23]1[C@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:26]([CH2:36][O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:25][CH:24]1Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC#N>[Cl:1][C:2]1[N:3]([C@@H:24]2[O:25][C@H:26]([CH2:36][O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C@@H:27]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@@H:23]2[O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: ClC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: Clc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1cc2nc(Cl)n([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Compound 5 (598 mg 2.7 mmole) was dissolved in dry CH3CN(60 ml) and 97% NaH (80 mg, 3 mmole) was added. The mixture was stirred under N2 for 1 hour at room temperature. Then 2,3,5-tri-O-benzyl-D-arabinofuranosyl chloride (prepared from 2,3,5-tri-O-benzyl-1-D-p-nitrobenzoyl-D-arabinofuranose) (1.83 g, 3 mmole)) dissolved in dry CH3CN (20 ml) was added dropwise. The mixture was stirred under N2 for overnight at room temperature. The reaction solution was filtered through Celite. The filtrate was evaporated to give a syrup and this syrup was subjected to flash column chromatography on silica gel (Kieselgel 60, 230-400 mesh) and eluted with CH2Cl2. The fractions containing 133 were combined and evaporated to give 1.6 g (95.0%) of 133. (IR KBr cm-1 : 1140-1060 (C--O--C)).
Reaction SMILES: COC([N:6]1[N:10]=[N:9][C:8]([CH3:11])=[N:7]1)(C)C.C([Li])CCC.[C:17]1([C:23]2[CH:28]=[CH:27][C:26]([N:29]([CH2:41][C:42]3[CH:47]=[CH:46][C:45]([CH:48]=[O:49])=[CH:44][CH:43]=3)[C:30]([NH:32][C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([Cl:40])[CH:34]=3)=[O:31])=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1.C(O)(=O)C>C1COCC1>[C:17]1([C:23]2[CH:24]=[CH:25][C:26]([N:29]([CH2:41][C:42]3[CH:43]=[CH:44][C:45]([CH:48]([OH:49])[CH2:11][C:8]4[N:9]=[N:10][NH:6][N:7]=4)=[CH:46][CH:47]=3)[C:30]([NH:32][C:33]3[CH:34]=[C:35]([Cl:40])[CH:36]=[C:37]([Cl:39])[CH:38]=3)=[O:31])=[CH:27][CH:28]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: O=Cc1ccc(CN(C(=O)Nc2cc(Cl)cc(Cl)c2)c2ccc(C3=CCCCC3)cc2)cc1
Reactant: COC(C)(C)n1nnc(C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(Nc1cc(Cl)cc(Cl)c1)N(Cc1ccc(C(O)Cc2nn[nH]n2)cc1)c1ccc(C2=CCCCC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(1-methoxy-1-methylethyl)-5-methyl-2H-tetrazole (1000 mg, 6.41 mmol) in THF (5 ml) cooled to −78° C. on a dry-ice-acetone bath was added dropwise a solution of n-butyl lithium in hexanes (4.0 ml, 1.6 M, 6.4 mmol). The mixture was stirred at −78° C. for 30 min, and at 0° C. for an additional 30 min, then recooled to −78° C. 1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)-1-(4-formylbenzyl)urea (250 mg, 0.52 mmol, from step 2, example 12) was then added as a solid, and the mixture was maintained at −78° C. for 20 min. Reaction temperature was raised to 0° C. and the mixture was stirred for 20 min before addition of acetic acid (2 ml). Upon standing, a white solid starts to precipitate, which is collected and washed with cold acetonitrile. The solid is oven dried under vacuum, to yield 582 mg (95%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH3:31])[CH2:12][O:11][S:10](=[O:13])[N:9]1[CH:14]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH2:32]>CC#N>[C:1]([O:5][C:6]([C:8]1([CH3:31])[CH2:12][O:11][S:10](=[O:32])(=[O:13])[N:9]1[CH:14]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(c2ccc(OC)cc2)N2S(=O)OCC2(C)C(=O)OC(C)(C)C)cc1
Reactant: O
Solvent: CC#N
Product: COc1ccc(C(c2ccc(OC)cc2)N2C(C)(C(=O)OC(C)(C)C)COS2(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89 %

Procedure:
A solution of the diastereomeric sulfamidites 13a (97 mg, 0.22 mmol) in 4 mL of CH3CN was cooled in an ice bath and treated successively with 1.1 eq of NaIO4 (51 mg), a catalytic amount of RuO2.H2O (˜1 mg) and 2.4 mL of H2O. After 5 minutes of stirring the ice bath was removed, and the reaction was continued for 20 minutes. The reaction mixture was diluted in 10 mL of EtOAc and washed with 10 mL of saturated NaHCO3 solution. The aqueous layer was extracted with 2×10 mL of EtOAc, and the combined organic layers were washed with 10 mL brine followed by usual work up. The crude product was purified by silica gel column chromatography (30% EtOAc in hexane) to provide the cyclic sulfamidate 14a as a light yellow solid (90 mg, 89%): mp 143.5-145 EC (EtOAc.hexane); 1H NMR (CDCl3) δ 1.29 (3H, s), 1.51 (9H, s), 3.77 (3H, s), 3.80 (3H, s), 4.16 (1H, d, J=8.8), 4.73 (1H, d, J=8.8), 5.98 (1H, s), 6.82-6.89 (4H, m), 7.38-7.44 (4H). Anal. (C23H29NO7S)C,H,N.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:40])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:40])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccccc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
192 mg (0.352 mmol) of (2R*,4S*)-2-benzyl-1-(2-phenylacetyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 40 with 141 μl (0.704 mmol) of 5N sodium hydroxide solution in 1 ml of tetrahydrofuran and 1 ml of methanol. The title compound ##STR67## is obtained (73 mg, 46%) as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.43, FD-MS: M+ =449.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[F:10][C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=1[C:21]1[N:26]=[C:25]([CH3:27])[C:24]([CH2:28]O)=[CH:23][CH:22]=1>ClCCl>[Cl:3][CH2:28][C:24]1[C:25]([CH3:27])=[N:26][C:21]([C:12]2[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[F:10])=[CH:22][CH:23]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2F)ccc1CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2F)ccc1CCl
Temperature: 0 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
1.67 g (1.017 ml, 14.02 mmol) thionyl chloride were added drop by drop at 0° C. to a solution of 0.2 ml N,N-dimethylformamide (DMF) and 2.0 g (70.1 mmol) [6-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyridin-3-yl]-methanol in 115 ml dichloromethane and stirred for 3 h at 0° C. The mixture was poured on ice/sodium bicarbonate solution and the organic phase separated. The water phase is extracted with dichloromethane. The combined organic phases were washed with water, dried (sodium sulphate) and evaporated. Chromatography on silica (eluent: ethyl acetate/n-heptane 1:6) gave 1.79 g (83%) of 3-Chloromethyl-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyridine.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].[F:14][CH:15]([F:40])[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]2[CH:24]=[C:25]([C:30]3[CH:31]=[N:32][N:33]([CH2:35][CH:36]([OH:39])[CH2:37][OH:38])[CH:34]=3)[CH:26]=[C:27]([CH3:29])[CH:28]=2)[N:17]=1>CN(C=O)C.CCOC(C)=O>[Si:10]([O:38][CH2:37][CH:36]([OH:39])[CH2:35][N:33]1[CH:34]=[C:30]([C:25]2[CH:26]=[C:27]([CH3:29])[CH:28]=[C:23]([NH:22][C:18]3[N:17]=[C:16]([CH:15]([F:14])[F:40])[CH:21]=[CH:20][N:19]=3)[CH:24]=2)[CH:31]=[N:32]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CC(O)CO)c2)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CC(O)CO[Si](C)(C)C(C)(C)C)c2)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Imidazole (0.28 g, 4.16 mmol) and tert-butylchlorodimethylsilane (0.574 g, 3.81 mmol) were added to a solution of 3-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)propane-1,2-diol (1.3 g, 3.46 mmol) in DMF (12 mL) at 0° C. The mixture was stirred at 0° C. for 90 minutes. The mixture was allowed to warm to room temperature, diluted with EtOAc, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% EtOAc/Hexane) to afford 1-((tert-butyldimethylsilyl)oxy)-3-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)propan-2-ol. MS ESI calc'd. for C24H34F2N5O2Si [M+H]+ 490. found 490.
Reaction SMILES: [CH2:1]([O:8][NH:9][C@H:10]1[CH2:15][N:14]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C@H:13]([C:22]([OH:24])=O)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][O:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[C:32]([O:31][C:30]([NH:29][CH2:28][CH2:27][O:26][NH:25][C:22]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]([NH:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:15][N:14]1[C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])=[O:24])=[O:36])([CH3:35])([CH3:33])[CH3:34]
Reactant: O=C(O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1C(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCCON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCONC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1C(=O)C(F)(F)F
Reaction time: 3 h
Yield: 83.5 %

Procedure:
(2S,5R)-5-(Benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylic acid (0.879 g, 2.54 mmol) described in Example 98 and tert-butyl 2-(aminooxy)ethylcarbamate (0.559 g) of Reference Example 9 were dissolved in N,N-dimethylformamide (11 mL), and to which was added 1-hydroxybenzotriazole.monohydrate (0.489 g), followed by ice-cooling. To this was added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.613 g), and the temperature was elevated to room temperature, followed by reacting for 3 h. Water was added to the reacted mixture, and extracted with ethyl acetate. After the organic layer was washed with 10% citric acid aqueous solution, water, 6.5% sodium bicarbonate aqueous solution and saturated brine sequentially, and then the solvent was distilled off under reduced pressure. The resulting oil residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/2) to afford 1.07 g of the title compound (yield 84%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([N:21]([CH2:29][C:30]3[N:35]=[N:34][C:33]4[O:36][CH2:37][CH2:38][O:39][C:32]=4[CH:31]=3)C(=O)OC(C)(C)C)[CH2:17][CH2:16]1)[C:7](=[O:40])[CH:6]=[N:5]2.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>C(Cl)Cl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[N:34]1[C:33]2[O:36][CH2:37][CH2:38][O:39][C:32]=2[CH:31]=[C:30]([CH2:29][NH:21][CH:18]2[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][N:8]3[C:9]4[C:4](=[CH:3][C:2]([F:1])=[C:11]([F:12])[CH:10]=4)[N:5]=[CH:6][C:7]3=[O:40])[CH2:20][CH2:19]2)[N:35]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(nn1)OCCO2)C1CCN(CCn2c(=O)cnc3cc(F)c(F)cc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1cnc2cc(F)c(F)cc2n1CCN1CCC(NCc2cc3c(nn2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
A solution of 1,1-dimethylethyl {1-[2-(6,7-difluoro-2-oxo-1(2H)-quinoxalinyl)ethyl]-4-piperidinyl}(6,7-dihydro[1,4]dioxino[2,3-c]pyridazin-3-ylmethyl)carbamate (0.17 g, 0.305 mmol) in DCM (0.65 ml) was treated with trifluoroacetic acid (0.43 ml, 5.78 mmol) stirred at rt for 1 h and evaporated. The residue was triturated with ether and dried at 50° C. under vacuum to give the title compound (0.149 g).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[CH:15][C:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#N)=[CH:19][CH:18]=4)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.C[OH:35].[OH-].[Na+]>C1COCC1.O>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[CH:15][C:14]([C:17]4[CH:24]=[CH:23][C:20]([CH:21]=[O:35])=[CH:19][CH:18]=4)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1
Reactant: CO
Reactant: N#Cc1ccc(-c2ccc(N3CCN(CC4CC4)CC3)nc2)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccc(N3CCN(CC4CC4)CC3)nc2)cc1
Temperature: -40 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a solution of 4-[6-(4-cylopropylmethyl-piperazin-1-yl)-pyridin-3-yl]-benzonitrile (2.0 g, 6.3 mmol) dissolved in THF (40 mL) was added DIBAL-H (25 mL, 1 N) at −40° C. The mixture was stirred 2 h at −40° C. and then CH3OH (15 mL), water (100 mL) and 1 N NaOH (15 mL) was added at −40° C. The mixture was extracted with EtOAc (3×300 mL). The combined organic extracts were washed with water (3×50 mL), dried (Na2SO4) and concentrated under reduced pressure to give 1.7 g (51%) of 4-[6-(4-cyclopropylmethyl-piperazin-1-yl)-pyridin-3-yl]-benzaldehyde.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12]>ClC1C=CC=CC=1Cl>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]1[C:21]2[CH:20]=[C:17]([C:18]#[N:19])[CH:16]=[CH:15][C:14]=2[O:13][C:2]([CH3:22])([CH3:1])[CH:3]=1
Reactant: COc1ccccc1C#CC(C)(C)Oc1ccc(C#N)cc1
Solvent: Clc1ccccc1Cl
Product: COc1ccccc1C1=CC(C)(C)Oc2ccc(C#N)cc21
Yield: 48.5 %

Procedure:
0.99 g of 4-[1,1-dimethyl-3-(2-methoxyphenyl)-2-propynyloxy]benzonitrile was dissolved in 10 ml of 1,2-dichlorobenzene and heated at reflux for 1.5 hours. After cooling the solution was evaporated and the residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:4) for the elution. After recrystallization from petroleum ether (boiling point 60°-80° C.) there were obtained 480 mg of 4-(2-methoxyphenyl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile of melting point 109°-111° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:18]=[CH:19]/[CH:20]=[CH:21]/[C:22]([OH:24])=O)[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[O:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15].C(N(CC)CC)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:47][CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][CH:53]([C:56]2[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[NH:58][CH:57]=2)[CH2:52][CH2:51]1>CN(C)C=O>[CH3:17][O:16][C:7]1[CH:6]=[C:5](/[CH:18]=[CH:19]/[CH:20]=[CH:21]/[C:22]([NH:47][CH2:48][CH2:49][N:50]2[CH2:51][CH2:52][CH:53]([C:56]3[C:64]4[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=4)[NH:58][CH:57]=3)[CH2:54][CH2:55]2)=[O:24])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: COCCOCOc1c(OC)cc(/C=C/C=C/C(=O)O)cc1OC
Reactant: NCCN1CCC(c2c[nH]c3ccccc23)CC1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCOCOc1c(OC)cc(/C=C/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)cc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a stirred mixture of 5-[3,5-dimethoxy-4-{(2-methoxyethoxy)methoxy}phenyl]-(2E,4E)-2,4-pentadienoic acid (1.35 g) and triethylamine (1.17 ml) in dry N,N-dimethylformamide (8 ml) was added slowly diphenyl phosphinic chloride (0.97 g) at -10° to -15° C. under an inert atmosphere. After being stirred for 1 hour, a solution of 1-(2-aminoethyl)-4-(3-indolyl)piperidine (0.97 g) in dry N,N-dimethylformamide (8 ml) was added slowly to the reaction mixture at the same temperature. After being stirred for 40 minutes at the same temperature, the reaction mixture was poured into ice-water (160 ml) and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over magnesium sulfate. The solvent was evaporated to give syrup of 1-[2-[5-[3,5-dimethoxy-4-{(2-methoxyethoxy)methoxy}phenyl]-(2E,4E)-2,4-pentadienoylamino]ethyl]-4-(3-indolyl)piperidine (1.97 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:20]([O:21][CH3:22])=[CH:19][C:13]2[CH:14]=[CH:15][C:16](=[O:18])[O:17][C:12]=2[CH:11]=1)(=O)=O.[C:23]1([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>C(O)(C)C>[CH3:22][O:21][C:20]1[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:32]2[CH2:33][CH2:34][CH:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:30][CH2:31]2)=[CH:11][C:12]2[O:17][C:16](=[O:18])[CH:15]=[CH:14][C:13]=2[CH:19]=1
Reactant: COc1cc2ccc(=O)oc2cc1OCCCOS(C)(=O)=O
Reactant: c1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ccc(=O)oc2cc1OCCCN1CCC(c2ccccc2)CC1
Yield: 73 %

Procedure:
Method B (20 h at 60° C.); starting materials: 7-[3-(methanesulfonyloxy)propoxy]-6-methoxy-2H-1-benzopyran-2-one (example 68) and 4-phenylpiperidine; yield 73%; fusion point 97°-99° C. (from isopropanol). Hydrochloride: method G; yield 93%; fusion point 198°-200° C. (from isopropanol).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[N:13]=[CH:12][C:11]([S:14][C:15]3[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=3)=[CH:10][C:9]=2[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.CN(C=O)C>O>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[C:9]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:10][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:37][CH2:38][N:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)[CH:16]=3)=[CH:12][N:13]=2)[S:5][CH:6]=1
Reactant: Cc1csc(Nc2ncc(Sc3cccc(O)c3)cc2Oc2ccccc2)n1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1csc(Nc2ncc(Sc3cccc(OCCN4CCCCC4)c3)cc2Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.3 %

Procedure:
A mixture of 3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)phenol (prepared according to Example 57; 70.0 mg, 0.172 mmol), potassium carbonate (71.2 mg, 0.515 mmol), 1-(2-chloroethyl)piperidine hydrochloride (31.6 mg, 0.172 mmol), and DMF (2 mL) was stirred at room temperature for 30 minutes and heated to 50° C. overnight. The reaction was cooled to room temperature and water (15 mL) was added and extracted with ether. A white precipitate formed in the ether layer and was filtered to afford N-(4-methylthiazol-2-yl)-3-phenoxy-5-(3-(2-(piperidin-1-yl)ethoxy)phenylthio)pyridin-2-amine (34.2 mg, 38.4% yield) as a white solid. 1H NMR (d6-DMSO) δ 9.56 (s, 1H), 8.29 (dd, 1H), 7.50 (dd, 1H), 7.28 (m, 2H), 7.11 (t, 1H), 7.00 (t, 1H), 6.82 (m, 2H), 6.65 (m, 1H), 6.58 (m, 1H), 6.54 (m, 1H), 6.35 (m, 1H), 3.79 (t, 2H), 2.23 (s, 3H), 2.17 (m, 4H), 2.12 (t, 2H), 1.38 (m, 4H), 1.31 (m, 2H); Mass spectrum (esi) m/z=519.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Br:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Br:20])=[CH:17][CH:18]=3)[N:13]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Br)ccc23)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Sc2c(C)n(Cc3ccccc3)c3cc(Br)ccc23)c1
Temperature: 0 °C

Procedure:
3(6-Bromo-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (1.13 g, 3.0 mmol) was dissolved in DMF and cooled to 0° C. then sodium hydride (60% dispersion in mineral oil, 0.156 g, 3.9 mmol) was added. After 5 minutes benzyl bromide (0.500 mL, 4.2 mmol) was added and the reaction was allowed to warm to room temperature. After 1 hour the reaction was re-cooled to 0° C. then quenched with aqueous HCl (5 mL, 1N). After extraction the crude product was purified by silica gel chromatography (0-30% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1.Br[C:25]1C=C(C=C[CH:32]=1)C#N>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[CH:32][CH:25]=[C:21]([C:20]#[N:19])[CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cccnc2)n1
Reactant: N#Cc1cccc(Br)c1
Product: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cccc(C#N)c2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide (example 14) in accordance with the general method of example 20 using 3-Bromobenzonitrile instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow solid, MS (ISP): m/e=350.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[CH2:14][C:13](=O)[CH2:12][C:11](=[O:16])[CH2:10]1.C([O-])(=O)C.[NH4+:21]>C(O)C>[NH2:21][C:13]1[CH2:14][CH:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])[CH2:10][C:11](=[O:16])[CH:12]=1
Reactant: O=C1CC(=O)CC(c2c(Cl)cccc2Cl)C1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC1=CC(=O)CC(c2c(Cl)cccc2Cl)C1
Yield: 79.7 %

Procedure:
A mixture of 5-(2,6-dichlorophenyl)cyclohexane-1,3-dione (1.8 g) and ammonium acetate (1.7 g) in ethanol (20 ml) was refluxed for 60 hours, and the reaction solution was concentrated under reduced pressure. To the residue were added ethyl acetate (80 ml) and water (20 ml), and the mixture was shaken and separated. The ethyl acetate layer was washed with water (10 ml, thrice) and concentrated under reduced pressure. To the residue was added ethyl acetate (8 ml) to precipitate crystals, which were filtered and dried to give 1-amino-5-(2,6-dichlorophenyl)cyclohexen-3-one (1.43 g) as pale yellow crystals.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]([C:14]3[C:15]4[CH2:23][CH2:22][CH2:21][CH2:20][C:16]=4[S:17][C:18]=3[NH2:19])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:24][O:25][C:26]([CH:28]1[CH2:33][CH2:32][CH:31]([C:34](Cl)=[O:35])[CH2:30][CH2:29]1)=[O:27]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]([C:14]3[C:15]4[CH2:23][CH2:22][CH2:21][CH2:20][C:16]=4[S:17][C:18]=3[NH:19][C:34]([CH:31]3[CH2:30][CH2:29][CH:28]([C:26]([O:25][CH3:24])=[O:27])[CH2:33][CH2:32]3)=[O:35])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Nc1sc2c(c1C(=O)NCc1ccc3c(c1)OCO3)CCCC2
Reactant: COC(=O)C1CCC(C(=O)Cl)CC1
Product: COC(=O)C1CCC(C(=O)Nc2sc3c(c2C(=O)NCc2ccc4c(c2)OCO4)CCCC3)CC1

Procedure:
Analogously to Example 1, the reaction of N-(benzo[1,3]dioxol-5-ylmethyl)-2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide with 4-methoxycarbonylcyclohexanecarbonyl chloride ("B") gives the compound methyl 4-{3-[(benzo[1,3]dioxol-5-ylmethyl)carbamoyl]-4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylcarbamoyl}cyclohexanecarboxylate, m.p. 173°.