Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[CH:15]=[C:16](\[Cl:24])/[C:17]([O:19]C(C)(C)C)=[O:18])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].C(OC)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[CH:15]=[C:16](\[Cl:24])/[C:17]([OH:19])=[O:18])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CON=C(C(=O)OC)c1ccccc1/C=C(\Cl)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COC(C)(C)C
Product: CON=C(C(=O)OC)c1ccccc1/C=C(\Cl)C(=O)O
Yield: 82 %

Procedure:
29 g of methyl 2-methoxyimino-2-{2-[2-chloro-2-tert-butyloxycarbonyl-(Z)-ethenyl]phenyl}acetate from Example 3 are stirred in a mixture of 40 ml of trifluoroacetic acid and 160 ml of dichloromethane for 2.5 hours at room temperature. The dark solution is then stirred into 500 ml of saturated sodium carbonate solution (pH 9). After the addition of 200 ml of methyl tert-butyl ether, the organic phase is separated off. The aqueous phase is again extracted with methyl tert-butyl ether and the pH is adjusted to 2-3 with 6N hydrochloric acid. The product separates out as an emulsion and is isolated by extracting three times with methyl tert-butyl ether and ethyl acetate. The combined organic phases are washed until neutral with saturated NaCl solution and dried over sodium sulfate. The solvent is removed, leaving 20 g of the title compound as a dark oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(=O)C)=[C:11]([N+:19]([O-:21])=[O:20])[CH:10]=2)[CH2:3]1.[OH-].[Na+]>CO>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([N+:19]([O-:21])=[O:20])[CH:10]=2)[CH2:3]1
Reactant: CC(=O)Nc1ccc(OC2CCCN(C)C2)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1CCCC(Oc2ccc(N)c([N+](=O)[O-])c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-[4-(1-methyl(3-piperidyloxy))-2-nitrophenyl]acetamide was dissolved in 1:1 MeOH:6N NaOH (aq) solution (0.03 M). After stirring at room temperature for 2 hours, MeOH was removed in vacuo. The remaining solution was extracted with EtOAc (3×). The combined organic extracts were then dried over Na2SO4 and concentrated in vacuo to give 4-(1-methyl(3-piperidyloxy))-2-nitrophenylamine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][C@H:25]5[CH2:27][O:26]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[OH:26][C@H:25]([CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H]1CO1
Reactant: C1COCCN1
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H](O)CN1CCOCC1
Yield: 90.4 %

Procedure:
Using an analogous procedure to that described in Example 292, (2R)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (300 mg, 0.83 mmol), (prepared as described for the starting material in Example 292), was reacted with morpholine (211 mg, 2.49 mmol) to give (2R)-7-(2-hydroxy-3-morpholinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline (338 mg, 85%).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[F:21][C:22]([F:26])([F:25])[CH:23]=O.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH2:23][C:22]([F:26])([F:25])[F:21])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: O=CC(F)(F)F
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NCC(F)(F)F)ccc2F)N=C1N

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and trifluoro-acetaldehyde using decaborane yielded the title compound as a colorless waxy solid. MS (ESI): m/z=361.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].ClC(Cl)(O[C:18](=[O:24])[O:19][C:20](Cl)(Cl)Cl)Cl.[N-:26]=[C:27]=[O:28]>CCOC(C)=O.CN(C=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:27]([NH:26][C:3]1[C:4]2[NH:5][C:18](=[O:24])[O:19][C:20]=2[CH:8]=[CH:9][CH:2]=1)=[O:28]
Reactant: [N-]=C=O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCc1ccc(C(F)(F)F)cc1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(C(F)(F)F)cc1Cl)Nc1cccc2oc(=O)[nH]c12
Temperature: 80 °C
Yield: 10 %

Procedure:
Commercially available 2-chloro-4-trifluoromethylbenzylamine (572 mg, 2.7 mmol) was dissolved in 20 ml of AcOEt and at 0° C. triphosgene (809 mg, 2.7 mmol) was added to the solution. The mixture was warmed at 80° C. for 4 hours then evaporated and dissolved in 5 ml of DMF. The solution of the isocyanate was added dropwise to a solution in DMF (5 ml) of compound 1b (270 mg, 1.8 mmol) and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt). The solvent was evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by chromatographic column gave 70 mg of a white solid. Yield=10% 1HNMR (DMSO, 400 MHz) δ 4.45 (2H, d, J=6 Hz), 6.97 (2H, d, J=4.4 Hz), 7.07 (2H, m), 7.63 (1H, d, J=8 Hz), 7.74 (2H, d), 7.86 (1H, s), 8.61 (1H, bs), 10.90 (1H, bs); [M+1] 386.6 (C16H11ClF3N3O3 requires 385.7).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12](OCC)=[O:13])[CH:9]=[C:8]([O:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[C:6]=2[CH:7]=1.[CH3:28][O-:29].[Na+].[OH2:31].Cl>C1COCC1.CO>[CH3:28][O:29][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([OH:13])=[O:31])[CH:9]=[C:8]([O:17][C:18]3[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=3)[C:6]=2[CH:7]=1
Reactant: O
Reactant: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(CBr)oc2c1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COCc1cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)O)cc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of ethyl 2-(bromomethyl)-4-(4-(methylsulfonyl)phenoxy)benzofuran-6-carboxylate (285a) (750 mg, 1.65 mmol) in THF and MeOH (3:1, 15 mL) was added NaOMe in MeOH (25% w/w, 1 mL) drop-wise at 0° C. After the solution was stirred at 0° C. for 2 hours, water was added and the stirring was continued for 14 h. The solvents were reduced under reduced pressure. To the aqueous solution was added 1N HCl until the pH˜1. The product was extracted with CHCl3 and dried over MgSO4. The solution was concentrated to give the title compound (610 mg, 98%) as a white solid. The product was used in the next step without further purification. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 3.07 (s, 3 H) 3.46 (s, 3 H) 4.56 (s, 2 H) 6.58 (s, 1 H) 7.07-7.17 (m, 2 H) 7.67 (d, J=1.13 Hz, 1 H) 7.85-7.99 (m, 2 H) 8.13 (d, J=1.13 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11](Br)[CH:10]=2)=[O:5])[CH3:2].[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:25][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([F:18])=[CH:20][CH:21]=1)[CH:10]=2)=[O:5])[CH3:2]
Reactant: NC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)c1ncc2cc(Br)ccc2c1O
Product: CCOC(=O)c1ncc2cc(NC(=O)c3ccc(F)cc3)ccc2c1O

Procedure:
7-(4-Fluoro-benzoylamino)-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester was prepared from 7-Bromo-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester under conditions analogous to Example 116(a) using 4-Fluorobenzamide. 1H NMR (200 MHz, CDCl3): δ ppm=11.87 (s, 1H), 8.79 (s, 1H), 8.58 (s, 1H), 8.36 (d, 1H), 8.12 (br s, 1H), 7.95 (m, 2H), 7.74 (d, 1H), 7.15-7.24 (m, 3H), 4.56 (q, 2H), 1.51 (t, 3H.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][N:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:27]4[CH:28]=[CH:29][C:24]([NH2:23])=[N:25][CH:26]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Reactant: Nc1ccc(Br)cn1
Product: Nc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)cn1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.4) (322 mg, 1.0 mmol) and 2-amino-5-bromopyridine (173 mg, 1.0 mmol) according to general procedure II. Obtained as an orange solid (71 mg, 17%). MS (ISP) 414.3 [(M+H)+].
Reaction SMILES: [C:1]([C:4]1[CH:11]=[C:10]([Cl:12])[C:7]([C:8]#[N:9])=[C:6]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]=1[O:18][CH2:19][CH3:20])(=[O:3])[CH3:2].[BH4-].[Na+]>CO.C(OCC)(=O)C>[Cl:12][C:10]1[C:7]([C:8]#[N:9])=[C:6]([N:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)[C:5]([O:18][CH2:19][CH3:20])=[C:4]([CH:1]([OH:3])[CH3:2])[CH:11]=1
Reactant: CCOc1c(C(C)=O)cc(Cl)c(C#N)c1N1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOc1c(C(C)O)cc(Cl)c(C#N)c1N1CCCC1
Reaction time: 1 h
Yield: 101.8 %

Procedure:
The 4-acetyl-6-chloro-3-ethoxy-2-pyrrolidin-1-ylbenzonitrile (0.045 g, 0.15 mmol) was dissolved in methanol (3 mL) and cooled in an ice bath. The sodium tetrahydroborate (0.0058 g, 0.15 mmol) was added and the reaction was monitored by LC/MS. After stirring for 1 h, the reaction was taken up in ethyl acetate and washed with water, sodium bicarbonate, brine and dried over magnesium sulfate to give crude 6-chloro-3-ethoxy-4-(1-hydroxyethyl)-2-pyrrolidin-1-ylbenzonitrile as a clear oil (0.045 g, 100%). LCMS calculated for C15H20ClN2O2(M+H)+: m/z=295.1; found 295.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][CH2:8][N:7]([C:12](=[O:14])[CH3:13])[C:6]=2[CH:15]=1.CN[C:18]([C:20]1[S:21][CH:22]=[CH:23][C:24]=1[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[C:28](Cl)[N:27]=1)=[O:19].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=[O:36]>C(O)(C)C.CS(C)=O>[C:12]([N:7]1[C:6]2[CH:15]=[C:2]([NH:1][C:28]3[N:27]=[C:26]([NH:25][C:24]4[CH:23]=[CH:22][S:21][C:20]=4[C:18]([OH:19])=[O:36])[C:31]([Cl:32])=[CH:30][N:29]=3)[CH:3]=[CH:4][C:5]=2[O:11][CH2:10][CH2:9][CH2:8]1)(=[O:14])[CH3:13]
Reactant: CNC(=O)c1sccc1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: CC(=O)N1CCCOc2ccc(N)cc21
Solvent: CC(C)O
Solvent: CS(C)=O
Product: CC(=O)N1CCCOc2ccc(Nc3ncc(Cl)c(Nc4ccsc4C(=O)O)n3)cc21

Procedure:
1-(2-Amino-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-ethanone (55 mg, 0.27 mmol), 3-(2,5-Dichloro-pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methylamide (88 mg, 0.29 mmol), and 10-Camphorsulfonic acid (12 mg, 0.052 mmol) in Isopropyl alcohol (2 mL) was irradiated in a CEM microwave (120° C., 40 min; 140° C. 20 min, 140° C. 60 min, 140° C. 20 min). The mixture was conc. in vacuo and suspended in DMSO (3.5 mL), which resulted in a significant amount of solid to form. The solids were triturated in hexane:EtOAc, washed with hexane and dried in vacuo to give 3-[2-(9-Acetyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-ylamino)-5-chloro-pyrimidin-4-ylamino]-thiophene-2-carboxylic acid methylamideas an off white solid (45 mg, 36%). MP>260° C.; LCMS: 473 (M+H); 1H-NMR (DMSO): 11.64 (s, 1H), 9.56 (s, 1H), 8.43 (s, 1H), 8.26 (m, 2H), 7.75 (d, 1H, J=4 Hz), 7.70 (s, 1H), 7.48 (d, 1H, J=7.1 Hz), 7.07 (d, 1H, J=8.4 Hz), 4.60 (m, 1H), 4.32 (m, 1H), 3.64 (m, 1H), 2.77 (m, 4H), 1.97 (m, 1H), 1.80 (m, 4H).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([Cl:14])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)C.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[Cl:14][C:8]1[C:9]([O:11][CH2:12][CH3:13])=[CH:10][C:5]([CH2:4][OH:3])=[CH:6][C:7]=1[O:15][CH2:16][CH3:17]
Reactant: CCOC(=O)c1cc(OCC)c(Cl)c(OCC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CCOc1cc(CO)cc(OCC)c1Cl
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a solution of 4-chloro-3,5-diethoxy-benzoic acid ethyl ester (5.0 g, 18.33 mmol, 1.0 equiv) in dichloromethane (25 mL) was added slowly over a time period of 15 min under slight cooling to −30° C. a solution of diisobutylaluminium hydride (55.0 mL, 55.00 mmol, 3.0 equiv; 1.0 M solution in THF). After 30 min, the excess hydride was quenched by cautious addition of methanol (10 mL) and water (2 mL). The mixture was stirred for 30 min, a solution of 1 M HCl was added and the aqueous layer extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure providing 4.0 g (95%) of the title compound. 1H NMR (300 MHz, CDCl3): δ1.45 (t, J=7.0 Hz, 6H), 1.93 (br s, 1H), 4.09 (q, J=7.0 Hz, 4H), 4.62 (s, 2H), 6.57 (s, 2H). 13C NMR (75 MHz, CDCl3): δ14.74, 64.96, 65.18, 104.30, 110.65, 140.29, 155.66. MS (ISP): 231.4 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][C@H:13]1[CH2:26][OH:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1(O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:14][C@H:13]1[CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CO)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](COc2ccccc2)C1
Temperature: 25 °C
Yield: 76.3 %

Procedure:
A solution of tert-butyl (1R,3R,4S)-4-benzyloxycarbonylamino-3-(hydroxymethyl)cyclohexylcarbamate (120 mg) in tetrahydrofuran (3 mL) was treated with phenol (45 mg) and triphenylphosphine (125 mg). The mixture was stirred at rt and treated dropwise over about 3 minutes with diethyl azodicarboxylate (74 μL). The mixture was stirred for 3.5 h, then was concentrated under vacuum. The residue was purified by flash chromatography on silica gel, eluting with 1:5 v/v ethyl acetate/hexane, to provide tert-butyl (1R,3R,4S)-4-benzyloxycarbonylamino-3-(phenoxymethyl)cyclohexylcarbamate as a white glassy foam (110 mg). MS found: (M+H)+=455.3.
Reaction SMILES: [C:1]1([S:7]([NH:10][CH2:11][CH2:12][C:13]2[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(=O)C)(=O)C.[N+:31]([O-])([OH:33])=[O:32].Cl>C(O)(=O)C>[C:1]1([S:7]([NH:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[C:22]([N+:31]([O-:33])=[O:32])[CH:23]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)COc1ccc(CCNS(=O)(=O)c2ccccc2)cc1
Reactant: O=[N+]([O-])O
Agent: Cl
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)COc1ccc(CCNS(=O)(=O)c2ccccc2)cc1[N+](=O)[O-]

Procedure:
5 g of 4-(2-benzenesulfonylaminoethyl)phenoxyacetic acid are added to 30 ml of acetic anhydride, and 3 ml of a mixture of conc. nitric acid and acetic acid (1:2) are added thereto under ice-cooling and stirring. After the mixture is reacted for 4 hours at room temperature, the mixture is poured into a mixture of diluted hydrochloric acid and ice, extracted with ethyl acetate, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform: ethanol=60:1) and recrystallized from a mixture of ethyl acetate and n-hexane. 3.70 g of 4-(2-benzenesulfonylaminoethyl)-2-nitrophenoxyacetic acid are obtained as colorless needles.
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:4]=1[CH2:5]Cl.[CH3:12][N:13]([CH:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=[O:22])[CH3:14].[Cl-].[NH4+]>CCOCC>[ClH:2].[Cl:2][C:3]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:4]=1[CH2:5][C:17]1([OH:22])[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[CH:15]([N:13]([CH3:12])[CH3:14])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: CN(C)C(c1ccccc1)C1CCCCC1=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)C(c1ccccc1)C1CCCCC1(O)Cc1ccc(Cl)cc1Cl
Product: Cl
Temperature: 25 °C
Yield: 13.5 %

Procedure:
0.38 g (15.6 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 3.04 g (15.6 mmole) of 2,4-dichlorobenzyl chloride dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 3.0 g (13.0 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 15 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 30 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with 60 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 2.14 g of crude base (97.0% of theory) were obtained, from which a hydrochloride was precipitated according to Example 1 (3rd stage) with chlorotrimethylsilane/water in 2-butanone. The base was freed from the hydrochloride with 20 ml of water and 3 ml of caustic soda (32 m %), extracted three times, each time with 20 ml of ether, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 1.19 g of crude base were obtained, from which 0.45 g of 1-(2,4-dichlorobenzyl)-2-(dimethylaminophenylmethyl)cyclohexanol, hydrochloride (8.1% of theory) was obtained according to the procedure described in Example 1 (3rd stage) with chlorotri-methylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 140° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=O.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[CH3:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>CN(C)C(=O)C.O1CCCC1>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:41]=[CH:42][C:43]([CH3:44])=[C:22]([NH:21][C:7]([C:3]5[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=5)=[O:9])[CH:23]=4)=[N:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Cn1cccc1C(=O)O
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1cccn1C
Yield: 5.6 %

Procedure:
Using 1-methyl-1H-pyrrole-2-carboxylic acid (93 mg, 0.74 mmol), tetrahydrofuran (4.0 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (135 μL, 1.48 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol) and N,N-dimethylacetamide (4.0 mL), and in the same manner as in Example 119, the title compound (15 mg, 6%) was obtained as a white powder.
Reaction SMILES: CO.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([S:10][CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[CH2:12][CH2:13][CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])=[N:8][CH:9]=1.[OH2:28].[OH:29]OS([O-])=O.[K+]>C(OCC)(=O)C.ClCCl>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[CH2:12][CH2:13][CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])(=[O:29])=[O:28])=[N:8][CH:9]=1
Reactant: O
Reactant: CS(=O)(=O)CCCCC(Sc1ccc(Cl)cn1)c1cc(F)ccc1F
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)CCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 22 h
Yield: 56 %

Procedure:
To a methanol (2 ml) solution of 5-chloro-2-[[1-(2,5-difluorophenyl)-5-(methylsulfonyl)pentyl]thio]pyridine (100 mg, 0.25 mmol) was added a water (2 ml) solution of Oxone (potassium peroxymonosulfate compound, 2 KHSO5.KHSO4.K2SO4) (303 mg, 0.49 mmol) at 0° C. After shaking at room temperature for 22 hours, the reaction mixture was added with dichloromethane and the mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=1:1 eluate was concentrated under reduced pressure, whereby the title compound (61 mg, 0.14 mmol, 56%) was obtained as a colorless foam.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)(Cl)=O.[C:10]1([S:16][CH2:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl.C(N(CC)CC)C>[OH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[CH:17][S:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(CSc1ccccc1)c1ccccc1O
Reactant: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Oc1ccccc1C(=CSc1ccccc1)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 1.02 g of imidazole, 1.52 g of triethylamine and 30 ml of dry methylene chloride, 1.78 g of thionyl chloride was added with ice-cooling. The resultant mixture was stirred for 30 minutes, followed by addition of 2.44 g of 2-phenylthio-2'-hydroxyacetophenone and a solution consisting of 1.16 g of triethylamine and 5 ml of dry methylene chloride. The reaction mixture was stirred at room temperature for further 2 hours. Ice water was then added to the reaction mixture, followed by its extraction with methylene chloride. The organic, i.e., methylene chloride layer was washed with water, dried over magnesium sulfate, and then concentrated. The residue was dissolved in chloroform. The chloroform solution was subjected to chromatography on a silica gel column. Upon concentration of the resulting eluate, 0.2 g of Isomer A (Compound 61; m.p. 235.5°-237° C.) and 0.9 g of Isomer B (Compound 62; m.p. 152.5°-154° C.) of 1-(2-hydroxyphenyl)-1 -imidazolyl-2-phenylthioethylene were obtained respectively as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[NH:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[N:11]([C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (1.84 g, prepared according to the procedure described in WO 96/31478 Step B page 94) in dry dichloromethane (50 mL) was treated with triethylamine (1.1 mL), then benzoyl chloride (0.91 mL). After stirring at room temperature for a further 5 hours the reaction mixture was treated with further dichloromethane (150 mL) and then washed twice with a saturated aqueous solution of sodium hydrogen carbonate (50 mL) and twice with brine (50 mL). The organic phase was then dried over magnesium sulfate and evaporated to give the title compound (2.58 g) as an orange oil, MS: 363 [MH]+. 1H NMR [(CD3)2SO]: δ 7.50–7.34 (m, 5H), 5.20–5.00 (s, 1H), 4.44–4.36 (m, 1H), 4.21–4.13 (m, 2H), 3.87–3.78 (m, 1H), 3.73–3.69 (bs, 1H), 3.30–3.20 (m, 2H), 2.98–2.90 (m, 1H), 1.45–1.38 (s, 9H) and 1.27–1.20 (m, 3H).