Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:15])=[C:4]([C:8]2([O:13][CH3:14])[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([N:10]1[CH2:11][CH2:12][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:15])([O:13][CH3:14])[CH2:9]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC1(c2cccc(Cl)c2F)CCNC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2cccc(Cl)c2F)CCN(Cc2ccccc2)C1
Yield: 79.8 %

Procedure:
Preparation according to Preparation 14. 3-(3-Chloro-2-fluorophenyl)-3-methoxypyrrolidine (3.44 g, 15 mmol), dry dimethyl formamide (5 mL), sodium hydride (60% dispersion in mineral oil, 0.720 g, 18 mmol). Benzylbromide (1.78 mL, 15 mmol) in dry dimethyl formamide (5 mL). Work up according to Preparation 14. Purification by flash column chromatography on silica gel (ethyl acetate) gave the title compound (3.83 g, 80%). MS m/z (rel. intensity, 70 eV) 304 (14), 289 (16), 133 (65), 132 (35), 91 (bp).
Reaction SMILES: CO[C:3](=[O:21])[C:4]([OH:20])=[CH:5][C:6](=[O:19])[N:7]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[O:8][CH3:9].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:30][N:31](C)[C:32](C1CN(C)C(=O)C=1O)=O>>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][N:7]([O:8][CH3:9])[C:6]([C:5]2[CH2:30][N:31]([CH3:32])[C:3](=[O:21])[C:4]=2[OH:20])=[O:19])=[CH:17][CH:16]=1
Reactant: COC(=O)C(O)=CC(=O)N(CCc1ccc(F)cc1)OC
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: CN
Product: CON(CCc1ccc(F)cc1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 38 %

Procedure:
3-{[2-(4-Fluorophenyl)-ethyl]-methoxy-carbamoyl}-2-hydroxy-acrylic acid methyl ester (Compound 52-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (38% yield); mp 157° C. dec. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.96 (2H, t, J=7.6 Hz, CH2), 3.14 (3H, s, NCH3), 3.71 (3H, s, OCH3), 3.93 (2H, t, J=7.6 Hz, CH2), 4.14 (2H, s, NCH2), 7.01 (2H, m, aromatics), 7.2 (2H, m, aromatics), 11.55 (1H, broad s, OH). Anal. calcd for C15H17FN2O4: C, 58.44; H, 5.56; N, 9.09. Found: C, 58.52; H, 5.66; N, 8.89.
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:11][C:12]1[C:21](Cl)=[N:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1.O(C(C)(C)C)[K]>>[Cl:11][C:12]1[C:21]([O:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: OCCOc1ccccc1
Agent: CC(C)(C)O[K]
Product: Clc1nc2ccccc2nc1OCCOc1ccccc1

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step 1, starting from 2-phenoxyethanol (3.7 g, 26.8 mmol), 2,3-dichloroquinoxaline (1.33 g, 6.7 mmol) and KO-t-Bu (0.75 g, 6.7 mmol): yield 0.74 g (37%); mp 99.5-101.5° C.; HRMS m/z calcd for C16H13ClN2O2 (M)+ 300.0666, found 300.0672. Anal. (C16H13ClN2O2) C, H, N.
Reaction SMILES: ClCCl.[Cl:4][C:5]1[C:10]([NH2:11])=[C:9]([NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:8]=[C:7]([CH3:17])[N:6]=1.[CH2:18]([O:20][CH2:21][C:22](Cl)=[O:23])[CH3:19]>C(N(CC)CC)C>[Cl:4][C:5]1[C:10]([NH:11][C:22](=[O:23])[CH2:21][O:20][CH2:18][CH3:19])=[C:9]([NH:12][CH2:13][CH:14]([CH3:15])[CH3:16])[CH:8]=[C:7]([CH3:17])[N:6]=1
Reactant: Cc1cc(NCC(C)C)c(N)c(Cl)n1
Reactant: CCOCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCC(=O)Nc1c(NCC(C)C)cc(C)nc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Anhydrous dichloromethane (300 ml), 2-chloro-N4-(2-methylpropyl)-6-methyl pyridin-3,4-diamine (4.14 g) from Part B and triethylamine (2.93 ml) were combined and cooled to 0° C. To the resulting mixture was added dropwise ethoxyacetyl chloride (2.49 g). After 1 hour the resulting reaction mixture was allowed to warm to room temperature. After 2 hours, the reaction, monitored by HPLC, was complete, and the solvent was removed under reduced pressure. The resulting yellow oil was dissolved in ethyl acetate, and the resulting solution was washed with water. The organic layer was dried with magnesium sulfate and concentrated to a yellow oil under reduced pressure. The yellow oil was put through a column of silica gel using 20/80 ethyl acetate/hexane. NMR analysis of the oil obtained after removal of the solvent under reduce pressure indicated desired product (3.64 g) of good purity for use in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([CH2:8][NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[CH:18]2[CH2:27][CH2:26][C:25]3[CH:24]=[C:23]([O:28]C(=O)C(C)(C)C)[CH:22]=[CH:21][C:20]=3[CH2:19]2)=O)=[CH:4][CH:3]=1.[N:37]1([C:44](=O)[CH2:45]Cl)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[N:37]1([CH2:44][CH2:45][O:1][C:2]2[CH:36]=[CH:35][C:5]([CH2:6][CH2:8][NH:9][C:10]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=3[CH:18]3[CH2:27][CH2:26][C:25]4[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21][C:20]=4[CH2:19]3)=[CH:4][CH:3]=2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)cc2)c1
Reactant: O=C(CCl)N1CCCCCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3CCCCCC3)cc2)c1
Yield: 8 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 1-azepan-1-yl-2-chloroethanone (18 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.1 mg) was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][NH:32][CH2:33][CH2:34][CH2:35][CH3:36]>O1CCOCC1>[CH2:33]([N:32]([CH3:31])[C:27]([NH:28][C:22]1[CH:21]=[C:20]([CH2:19][N:13]2[C:14]([CH3:18])([CH3:17])[C:15](=[O:16])[N:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:10][CH:9]=3)[C:12]2=[O:30])[CH:25]=[CH:24][N:23]=1)=[O:26])[CH2:34][CH2:35][CH3:36]
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Reactant: CCCCNC
Solvent: C1COCCO1
Product: CCCCN(C)C(=O)Nc1cc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)ccn1

Procedure:
This compound may be prepared as obtained in stage c) of Example 9, but starting with 150 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9, 3 mL of dioxane and 36.9 mg of N-methylbutan-1-amine. After chromatography on a column of silica, eluting with a mixture of heptane/ethyl acetate (gradient from 100/0 to 0/100 by volume), 77.8 mg of 1-butyl-3-(4-{[3-(4-tert-butyl-phenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)-1-methylurea are obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C:16]1[CH:25]=[C:24]([F:26])[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([F:27])[CH:17]=1)=O)(C)(C)C>ClCCl>[NH2:15][C:16]1[CH:17]=[C:18]([F:27])[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:24]([F:26])[CH:25]=1
Reactant: COC(=O)c1c(F)cc(NC(=O)OC(C)(C)C)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(F)cc(N)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At RT, 0.5 ml of TFA was added to a solution of 36 mg (0.125 mmol) of methyl 4-[(tert-butoxycarbonyl)amino]-2,6-difluorobenzoate in 1 ml of dichloromethane, and the mixture was stirred at RT for 30 min. The reaction mixture was then concentrated under reduced pressure and the residue was co-evaporated repeatedly with dichloromethane and toluene and dried under reduced pressure. The crude product was used for the next step without purification. Yield: 24 mg (quant.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1C(=O)C3C(=CC=CC=3)C1=O)[N:9]=[CH:8][CH:7]=[C:6]2[O:27][C:28]1[C:29]([CH3:38])=[N:30][C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2.NN>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH2:16])[N:9]=[CH:8][CH:7]=[C:6]2[O:27][C:28]1[C:29]([CH3:38])=[N:30][C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCN
Temperature: 25 °C
Reaction time: 4 h
Yield: 107.7 %

Procedure:
2-{2-[6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-ethyl}-isoindole-1,3-dione (compound 367) (20 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution, hydrazine (13 mg) was added to the solution, and the mixture was stirred at room temperature for 4 hr. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (16 mg, yield 98%).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[N:15]=[C:14]([CH2:16][CH2:17][C@@H:18]([NH:30]C(=O)OC(C)(C)C)[CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)[O:13][N:12]=3)[CH:8]=2)[NH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:30][C@@H:18]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:24][CH:25]=1)[CH2:17][CH2:16][C:14]1[O:13][N:12]=[C:11]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[CH2:10]3)[N:15]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1nc(-c2ccc3c(c2)CC(=O)N3)no1)Cc1ccc(C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](CCc1nc(-c2ccc3c(c2)CC(=O)N3)no1)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
tert-Butyl(R)-4-(3-(2-oxoindolin-5-yl)-1,2,4-oxadiazol-5-yl)-1-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate (200 mg, 0.37 mmol) was dissolved in 5.0 mL anhydrous DCM, and 5.0 mL TFA was added. After 30 minutes stirring at room temperature, the solvent was evaporated and the residue was taken up in 100 mL EtOAc. To the resulting solution was added 50 mL of saturated aqueous sodium bicarbonate and 30 mL 5% aqueous sodium carbonate. The organic layer was washed with brine and dried over sodium sulfate to afford the product as a white solid (130 mg, 81%). MS (API-ES) m/z (%): 417.1 (100%, M++H).
Reaction SMILES: [CH3:1][C:2]([CH3:37])([P:34](=[O:36])=[O:35])[N:3]([C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH2:21][NH:22][C:23]2[C:28](Cl)=[C:27](Cl)[N:26]=[C:25](Cl)[C:24]=2Cl)[CH:16]=[C:15]([CH3:33])[CH:14]=1)[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].C(N(CC)CC)C>CO.[Pd]>[CH3:1][C:2]([CH3:37])([P:34](=[O:36])=[O:35])[N:3]([C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH2:21][NH:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH:16]=[C:15]([CH3:33])[CH:14]=1)[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5]
Reactant: Cc1cc(OCCNc2c(Cl)c(Cl)nc(Cl)c2Cl)cc(N(C(C)(C)P(=O)=O)S(=O)(=O)c2ccccc2)c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cc(OCCNc2ccncc2)cc(N(C(C)(C)P(=O)=O)S(=O)(=O)c2ccccc2)c1

Procedure:
0.2 g (0.33 mmol) N-(dimethyloxophosphinyl-methyl)-N-{3-methyl-5-[2-(2,3,5,6-tetrachloropyridin-4-ylamino)-ethoxy]-phenyl}-benzenesulfonamide in 10 ml methanol was hydrogenated in the presence of 0.28 ml triethylamine and 0.1 g 10% palladium on carbon at room temperature and normal pressure. After 18 hours it was filtered, the residue was dissolved in 3 ml ethanol, 30 ml ether was added, it was filtered, washed with ether and 0.12 g (77%) of the title compound of Fp. 228°-232° C. was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:18]=[N:19][C:20]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[C:21]([CH3:24])[C:22]=3[CH3:23])[CH2:13][C@H:12]2[CH3:32])=[N:9][CH:10]=1)=[O:4].[OH-].[Na+]>CO>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:20]2[N:19]=[N:18][C:17]([N:14]3[CH2:15][CH2:16][N:11]([C:8]4[CH:7]=[N:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][N:9]=4)[C@H:12]([CH3:32])[CH2:13]3)=[C:22]([CH3:23])[C:21]=2[CH3:24])=[CH:26][CH:27]=1
Reactant: COC(=O)c1cnc(N2CCN(c3nnc(-c4ccc(F)cc4)c(C)c3C)C[C@H]2C)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(-c2ccc(F)cc2)nnc(N2CCN(c3cnc(C(=O)O)cn3)[C@H](C)C2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 122.9 %

Procedure:
To a solution of example 6 (0.74 g, 1.31 mmol) and methanol (10 mL) is added sodium hydroxide (100 mg). The mixture is stirred at room temperature overnight. Solvent is removed and the residue is dissolved in water and acidified with 3 N HCl to pH about 7, and extracted with ethyl acetate. The ethyl acetate layer is concentrated to afford the title compound (0.68 g, 96%) as a yellow solid.
Reaction SMILES: CS[C:3]1[N:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:6]2[CH2:15][CH2:16][CH2:17][CH2:18][C@H:5]2[N:4]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24]>ClCCl>[C:11]([O:10][C:8]([N:7]1[C@H:6]2[CH2:15][CH2:16][CH2:17][CH2:18][C@H:5]2[N:4]=[C:3]1[NH:24][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([F:19])[CH:21]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CSC1=N[C@@H]2CCCC[C@@H]2N1C(=O)OC(C)(C)C
Reactant: NCc1cccc(F)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(NCc2cccc(F)c2)=N[C@@H]2CCCC[C@@H]21
Temperature: 100 °C
Yield: 73.2 %

Procedure:
A mixture of intermediate 76 (200 mg, 0.0.740 mmol), 3-fluorobenzylamine (0.5 mL, 4.4 mmol) is heated at 100° C. (reaction block) overnight. The reaction mixture is cooled to RT. The reaction mixture is diluted with dichloromethane, washed with 0.1N HCl, and brine. The solvent is evaporated, and the residue triturated with EtOAc, and the insoluble material filtered to give 188 mg of the product 191. 1H NMR (CDCl3) δ 8.56 (s, 1 H), 7.45-7.20 (m, 3 H), 7.20-6.95 (m, 2 H), 5.20-4.95 (m, 2 H), 4.35-4.10 (m, 2 H), 2.75-2.55 (m, 1 H), 2.20-2.05 (m, 1 H), 1.80-1.05 (m, 15 H); MS: m/z 348 (M++1).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])[S:6][CH:7]=1.[CH:13]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:13]([N:26]1[CH2:31][CH2:30][N:29]([CH2:2][C:3]2[N:4]=[C:5]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])[S:6][CH:7]=2)[CH2:28][CH2:27]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: CC(=O)N(C)c1nc(CCl)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1nc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cs1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 31.2 %

Procedure:
A mixture of 4-chloromethyl-2-(N-methylacetamido)thiazole (2.05 g), 1-benzhydrylpiperazine (2.5 g) and potassium carbonate (1.4 g) in N,N-dimethylformamide (20 ml) was stirred at 80° C. for 1.5 hours. After the reaction mixture was poured into ice-water, the precipitated crystals were washed with water and then dried, followed by recrystallization from a mixture of ethyl acetate and n-hexane to obtain pale yellow crystals of 4-(4-benzhydrylpiperazin-1-ylmethyl)-2-(N-methylacetamido)thiazole (1.3 g), mp 140°-142° C.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH3:4][S:5](Cl)(=[O:7])=[O:6]>N1C=CC=CC=1>[CH3:1][N:2]([S:5]([CH3:4])(=[O:7])=[O:6])[N:3]([S:5]([CH3:4])(=[O:7])=[O:6])[S:5]([CH3:4])(=[O:7])=[O:6]
Reactant: CNN
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CN(N(S(C)(=O)=O)S(C)(=O)=O)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 48 h
Yield: 18.2 %

Procedure:
To an ice-cold stirred solution of methylhydrazine (4.6 g, 0.1 mol) in dry pyridine (30 ml) was added methanesulfonyl chloride (44.6 g, 0.39 mol) dropwise, while maintaining the temperature between 0° and 10° C. The reaction mixture was left in a freezer (-10° C.) for 2 days. It was then triturated with a mixture of ice and concentrated hydrochloric acid (1:1, v/v, 100 ml). The precipitate that formed was collected, washed with cold water and dried. This product was stirred with chloroform (200 ml) and filtered. The undissolved material, consisting mainly of 1,2-bis(methylsulfonyl)-1-methylhydrazine, was discarded and the filtrate was treated with decolorizing carbon, filtered and evaporated to dryness in vacuo to give a yellow solid, which was crystallized twice from ethanol (Norit A) to give 5.1 g (18%) of the title compound: m.p. 123°-124° C.; anal. (C4H12N2O6S3) C,H,N; 1H NMR (acetone-d6) δ 3.6 [s, 6H, N2 (SO2CH3)2 ], 3.5 (s, 3H, N-CH3), 3.2 (s, 3H, N1SO2CH3).
Reaction SMILES: [OH:1][C:2]1[C:3]([Se:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>O>[CH2:41]([O:40][C:38]([CH2:37][CH2:36][CH2:35][O:1][C:2]1[C:3]([Se:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=2)=[CH:4][C:5]2[C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1)=[O:39])[CH3:42]
Reactant: CCOC(=O)c1ccc([Se]c2cc3c(cc2O)C(C)(C)CCC3(C)C)nc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)CCCOc1cc2c(cc1[Se]c1ccc(C(=O)OCC)cn1)C(C)(C)CCC2(C)C
Temperature: 80 °C

Procedure:
432 mg (102.0 mmol) of ethyl 6-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro 2-naphthylselanyl)nicotinate, 276 mg (2 mmol) of potassium carbonate and 390 mg (2 mmol) of ethyl 4-bromobutanoate are introduced into a three-necked flask. The mixture is heated at 80° C. for 12 h. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out by settling, washed with water, dried over magnesium sulphate and evaporated. After purification by flash chromatography (9 heptane/1 EtOAc), 467 mg (85%) of the expected compound are collected in the form of an orange-coloured oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]2=[N:6][C:7]=1Cl.[C:13]1([S:19]([NH2:22])(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O>CC(N(C)C)=O>[Cl:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]2=[N:6][C:7]=1[NH:22][S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])=[O:20]
Reactant: Clc1nc2ccncc2nc1Cl
Reactant: NS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=S(=O)(Nc1nc2cnccc2nc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 4.5 %

Procedure:
2,3-dichloro-pyrido(3,4-b)pyrazine (300 mg, 1.5 mmol, 1 eq.), benzenesulfonamide (235.8 mg, 1.5 mmol, 1 eq.) and K2CO3 (207.3 mg, 1.5 mmol, 1 eq.) are taken up in anhydrous DMA (10 ml) under argon. The reaction mixture is stirred at room temperature for 3 days, then water (15 ml) is added. The aqueous phase is washed with EtOAc (4×10 ml) then lyophilized. The solid residue obtained is extracted with DCM and the solvent is evaporated to near dryness then purified by preparative HPLC using a gradient of H2O, TFA 0.1%/ACN, TFA 0.1%, to afford 21.7 mg (5%) of the title compound. 1H NMR (DMSO-d6) δ 9.13 (s, 1H), 8.42 (d. J=6.7 Hz, 1H), 8.03-7.97 (m, 2H), 7.56 (d, J=6.8 Hz, 1H), 7.51-7.45 (m, 3H). HPLC (max plot) 95%; Rt 1.71 min. LC/MS: (ES+): 321.0, (ES−): 319.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:10][C@H:9]1[CH2:24][OH:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:10][C@H:9]1[CH2:24][O:25][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccc3ccccc3c2)C[C@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccc4ccccc4c3)CN2C(=O)OC(C)(C)C)cc1
Yield: 93.4 %

Procedure:
To a stirred mixture of (2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylmethanol (640 mg, 1.86 mmol), methyl 4-hydroxybenzoate (283 mg, 1.86 mmol) and PPh3 (488 mg, 1.86 mmol) in THF (18 ml) was added DIAD (0.37 ml, 1.86 mmol) at room temperature under an atmosphere of nitrogen. The mixture was stirred over night. After removal of the solvent, the resulting residue was chromatographed on silica gel [100 g, n-hexane/EtOAc(2/1)], to give methyl 4-[(2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinyl]methoxybenzoate (830 mg, 93%) as a colorless oil. 1H-NMR (CDCl3) δ1.50 (d, J=8.3 Hz, 9H), 2.34 (m, 1H), 2.53 (d, J=14.2 Hz, 1H), 3.72-3.85 (m, 1H), 3.86 and 3.87 (s, 3H, amide isomers), 4.17 (m, 1H), 4.26-4.52 (m, 2H), 5.06 (br, 1H), 6.87 (d, J=8.8 Hz, 1H), 6.94 (d, J=8.8 Hz, 2H), 7.04 (br, 2H), 7.33 (t, J=7.3 Hz, 1H), 7.42 (t, J=7.3 Hz, 1H), 7.64-8.02 (m, 5H).
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([OH:44])=O)[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[N:48]1([C:54]2[CH:61]=[CH:60][C:57]([C:58]#[N:59])=[CH:56][CH:55]=2)[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([N:51]4[CH2:50][CH2:49][N:48]([C:54]5[CH:55]=[CH:56][C:57]([C:58]#[N:59])=[CH:60][CH:61]=5)[CH2:53][CH2:52]4)=[O:44])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:3])([CH3:5])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCN(c3ccc(C#N)cc3)CC2)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with 4-piperazin-1-yl-benzonitrile (Fluka) to give the title compound. HR-MS (ES, m/z) calculated for C46H53Cl2N8O3 [(M+H)+] 835.3612, observed 835.3611.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10]/[C:11](=[CH:12]/[CH:13]=[CH:14]/[CH:15]=[O:16])/[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:17]([O:23][CH3:24])(=[O:22])[CH2:18][C:19]([CH3:21])=[O:20]>>[CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10]/[C:11](=[CH:12]/[CH:13]=[CH:14]/[CH:15]([OH:16])[CH2:21][C:19](=[O:20])[CH2:18][C:17]([O:23][CH3:24])=[O:22])/[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C/C=C/C=C1/CCCCc2ccccc21
Reactant: COC(=O)CC(C)=O
Product: COC(=O)CC(=O)CC(O)/C=C/C=C1/CCCCc2ccccc21

Procedure:
By the method of Example 1, (2E,4Z)-4-(8,9-dihydro-6H, 7H-benzocyclohepten-5-ylidene)-2-butenal (2.6 g, 12 mmol) was reacted with methyl acetoacetate to form title product, 3.2 g.