Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[Br:12][C:13]1[C:18]([C:19]2[C:30]([CH3:31])=[N:29][C:22]3[N:23]=[C:24](SC)[N:25]=[CH:26][C:21]=3[CH:20]=2)=[CH:17][C:16]([NH:32][C:33]([NH:35][CH2:36][CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:34])=[C:15]([F:42])[CH:14]=1.[CH3:43][NH2:44].C1COCC1>C(Cl)Cl>[Br:12][C:13]1[C:18]([C:19]2[C:30]([CH3:31])=[N:29][C:22]3[N:23]=[C:24]([NH:44][CH3:43])[N:25]=[CH:26][C:21]=3[CH:20]=2)=[CH:17][C:16]([NH:32][C:33]([NH:35][CH2:36][CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:34])=[C:15]([F:42])[CH:14]=1
Reactant: CN
Reactant: CSc1ncc2cc(-c3cc(NC(=O)NCCC(C)(C)C)c(F)cc3Br)c(C)nc2n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNc1ncc2cc(-c3cc(NC(=O)NCCC(C)(C)C)c(F)cc3Br)c(C)nc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13 %

Procedure:
Add mCPBA (0.152 g, 0.616 mmol) portion wise to a solution of 1-(4-bromo-2-fluoro-5-(7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3,3-dimethylbutyl)urea (0.26 g, 0.513 mmol) in DCM (10 mL) and stir at RT for 2 h. Add methylamine in THF (2.0M, 1.027 mL, 2.054 mmol) and stir at RT overnight. Add water, extract with DCM (3×), wash the combined organics with saturated. NaHCO3, then brine, dry over MgSO4, concentrate to dryness and purify via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). Combine fractions, remove the organics under reduced pressure and neutralize the resulting aqueous residue with NaHCO3. Extract the mixture with EtOAc (2×), wash the combined organics with saturated. NaHCO3, then brine, dry over Na2SO4, concentrate to dryness, treat with 1:1 MeCN/H2O, freeze and lyophilize to afford the title compound as a pale yellow solid (34 mg, 13% yield). MS (m/z): 489.1 (M+1)/491.1 (M+3).
Reaction SMILES: [CH:1]1([C:7]#[N:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:20]1[S:21][CH:22]=[CH:23][N:24]=1>C1(C)C=CC=CC=1>[S:21]1[CH:22]=[CH:23][N:24]=[C:20]1[C:1]1([C:7]#[N:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1nccs1
Reactant: N#CC1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CC1(c2nccs2)CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
To a solution of cyclohexanecarbonitrile (0.913 g, 8.36 mmol) in toluene (25 ml) at 0° C. was added sodium bis(trimethylsilyl)amide (1M solution in THF, 10.0 ml, 10.0 mmol) and the resulting mixture was stirred for 1 hr at 0° C. 2-Chlorothiazole (1 g, 8.36 mmol) was then added dropwise as a solution in toluene (0.5 mL) over a period of 5 minutes and the resulting mixture was allowed to warm up from 0° C. to room temperature over 16 hrs. The reaction mixture was quenched with saturated aqueous NH4Cl (20 mL), and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (60 mL, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (gradient elution 2% to 12% EtOAc in Hexanes) to afford 1-(1,3-thiazol-2-yl)cyclohexanecarbonitrile (686 mg, 3.57 mmol, 42.7% yield) as a pale yellow oil which solidified upon standing. MS ESI: [M+H]+ m/z 193.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][C:15]=2[N+:23]([O-:25])=[O:24])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[CH3:33][S:34]([N:37]1[CH2:42][CH2:41][C:40]2[N:43]([CH2:56][CH:57]3C[O:58]3)[N:44]=[C:45]([C:46]3[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=3)[C:39]=2[CH2:38]1)(=[O:36])=[O:35]>C(Cl)Cl>[N+:23]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([N+:20]([O-:22])=[O:21])[C:14]=1[N:11]1[CH2:10][CH2:9][N:8]([CH2:6][CH:57]([OH:58])[CH2:56][N:43]2[C:40]3[CH2:41][CH2:42][N:37]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:38][C:39]=3[C:45]([C:46]3[CH:51]=[CH:50][C:49]([C:52]([F:54])([F:55])[F:53])=[CH:48][CH:47]=3)=[N:44]2)[CH2:13][CH2:12]1)([O-:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCN(c2c([N+](=O)[O-])cccc2[N+](=O)[O-])CC1
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCN(c3c([N+](=O)[O-])cccc3[N+](=O)[O-])CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
4-(2,6-Dinitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (220 mg, 0.63 mmol) was dissolved in 5.0 mL of CH2Cl2 and treated with 3.0 mL of trifluoroacetic acid. The reaction mixture was stirred at 25° C. for 1 h before all volatiles were removed. The solid was treated with CH2Cl2 (20 mL) and aqueous KOH (4 N, 10 mL). The organic layer was separated, dried over Na2SO4, and concentrated. The crude oil (67 mg) was dissolved in absolute EtOH (1.2 mL) and treated with 141 mg (0.35 mmol, 1.3 eq) of 5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine. The reaction mixture was refluxed at 85° C. for 3 h and then the solvent was removed. Column chromatography purification (silica, 10-20% acetone/CH2Cl2) provided 150 mg (85%) of 1-[4-(2,6-dinitro-phenyl)-piperazin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol. TLC (silica, 10% acetone/CH2Cl2): Rf=0.3. MS (electrospray): exact mass calculated for C27H30F3N7O7S, 653.19; m/z found, 654.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.71 (d, J=8.2 Hz, 2H), 7.64 and 7.58 (AB pattern, J=8.4 Hz, 4H), 7.20 (t, J=8.2 Hz, 1H), 4.54 (s, 2H), 4.29-4.12 (m, 2H), 3.66 (t, J=5.3 Hz, 2H), 3.70-2.95 (m, 9H), 2.91 (s, 3H), 2.67-2.32 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH2:11][CH3:12])[N:3]=1.O.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([NH:21][C:5]1[N:4]([CH2:11][CH3:12])[N:3]=[C:2]([Br:1])[C:6]=1[N+:7]([O-:9])=[O:8])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: CCn1nc(Br)c([N+](=O)[O-])c1Br
Solvent: O
Product: CCn1nc(Br)c([N+](=O)[O-])c1NCc1ccccc1
Yield: 76 %

Procedure:
6.3 g (21 mmoles) of 3,5-dibromo-1-ethyl-4-nitropyrazole are heated in 10 ml benzylamine for 1 hour at 80° C. The reaction mixture is then poured on 50 ml water and the separated oil is collected. The product is crystallized from the oil by adding 20 to 30 ml acetic acid ethyl ester. After recrystallizing from methanol once, 5.2 g (76 percent of theory) of 5-benzylamino-3-bromo-1-ethyl-4-nitropyrazole are obtained n the form of bright yellow needles with a melting point of 92° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13]3)=[C:6]([O:20]COC)[C:5]=1[O:24][CH3:25])[CH3:2].Cl>CO>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:18]=2[CH2:17][CH2:16][C:15]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:24][CH3:25])[CH3:2]
Reactant: CCOc1ccc(-c2ccc3c(c2)CCC3=O)c(OCOC)c1OC
Agent: Cl
Solvent: CO
Product: CCOc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC
Temperature: 60 °C
Yield: 97.6 %

Procedure:
To a stirring solution of 5-(4-ethoxy-3-methoxy-2-(methoxymethoxy)phenyl)-2,3-dihydro-1H-inden-1-one (1 g, 2.92 mmol) in methanol (20 mL) was added conc. hydrochloric acid (3 mL) and heated to 60° C. for 1 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was basified with sodium bicarbonate solution and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as a solid (850 mg, 97.7%).
Reaction SMILES: CS(C)=O.C(=O)=O.CC(C)=O.C(Cl)(=O)C(Cl)=O.[OH:18][CH2:19][C@H:20]1[C@@H:25]([NH:26][C:27](=[O:42])[CH2:28][NH:29][C:30](=[O:41])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)[CH2:24][CH2:23][C@@H:22]([N:43]([CH:51]([CH3:53])[CH3:52])[C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:21]1.C(N(CC)CC)C>C(Cl)Cl>[CH:19]([C@H:20]1[C@@H:25]([NH:26][C:27](=[O:42])[CH2:28][NH:29][C:30](=[O:41])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)[CH2:24][CH2:23][C@@H:22]([N:43]([CH:51]([CH3:53])[CH3:52])[C:44](=[O:50])[O:45][C:46]([CH3:47])([CH3:48])[CH3:49])[CH2:21]1)=[O:18]
Reactant: CC(C)N(C(=O)OC(C)(C)C)[C@@H]1CC[C@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)[C@H](CO)C1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C=O
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)N(C(=O)OC(C)(C)C)[C@@H]1CC[C@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)[C@H](C=O)C1
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
A solution of DMSO (0.42 g, 5 mmol) in 30 ml of methylene chloride was cooled to −78° C. (dry ice-acetone bath) and treated drop-wise with oxalyl chloride (0.38 g, 3.0 mmol). After the addition was complete and solution was stirred for 30 minutes and then treated drop-wise with a solution of tert-butyl (1R,3R,4S)-3-(hydroxymethyl)-4-(2-(3-(trifluoromethyl)-benzamido)acetamido)cyclohexyl(isopropyl)carbamate (0.50 g, 0.97 mmol; see Example 8b, Step 6) in 20 ml of methylene chloride. After the addition was complete and solution was stirred for 40 minutes and then treated 1 ml of triethylamine (1 g, 10 mmol) and stirred for 30 minutes before removing the cooling bath and stirring at room temperature for 1 hour. The mixture was quench with 100 mL of saturated sodium bicarbonate and the organic layer was separated and washed successively with water and brine, and then dried over Na2SO4. The drying agent is filtered and the solvent removed on a rotary evaporator to give 0.45 mg of tert-butyl(1R,3R,4S)-3-formyl-4-(2-(3-(trifluoromethyl)benzamido)acetamido)-cyclohexyl(isopropyl)carbamate as a white solid which was used without further purification. MS found: (M+H)+=514.29.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][CH2:21][C:20]([C:28]([O:30]C)=[O:29])=[CH:19][C:18]=3[CH:32]=2)=[CH:10][CH:9]=1)[CH2:2][CH3:3].[OH-].[Na+].Cl>C(O)C.C1COCC1>[CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][CH2:21][C:20]([C:28]([OH:30])=[O:29])=[CH:19][C:18]=3[CH:32]=2)=[CH:10][CH:9]=1)[CH2:2][CH3:3]
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCCN3CCC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCCN3CCC)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 75.1 %

Procedure:
To a solution of methyl 8-[4-(2-propoxyethoxy)phenyl]-1-propyl-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylate (1.10 g) in a mixture of ethanol-THF (20-10 ml) was added an aqueous 1N sodium hydroxide solution (5.0 ml) at room temperature. The mixture was stirred at 60° C. for 16 hours and cooled to 0° C. 1N Hydrochloric acid (6 ml) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropylether to give 8-[4-(2-propoxyethoxy)phenyl]-1-propyl-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylic acid (0.80 g) as yellow crystals.
Reaction SMILES: [C:1]([Si:5]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[O:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[C:24]([Cl:25])=[CH:23][C:22](OS(C(F)(F)F)(=O)=O)=[CH:21][C:20]=3[Cl:34])[C:14]2=[O:35])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH3:48][O:49][C:50]([C:52]1[CH:57]=[CH:56][C:55](B(O)O)=[CH:54][CH:53]=1)=[O:51].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:48][O:49][C:50]([C:52]1[CH:57]=[CH:56][C:55]([C:22]2[CH:21]=[C:20]([Cl:34])[C:19]([CH2:18][N:15]3[CH2:16][CH2:17][CH:13]([CH:10]4[CH2:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:4])[CH3:2])([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[CH2:12][CH2:11]4)[C:14]3=[O:35])=[C:24]([Cl:25])[CH:23]=2)=[CH:54][CH:53]=1)=[O:51]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)[Si](OC1CCC(C2CCN(Cc3c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc3Cl)C2=O)CC1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2cc(Cl)c(CN3CCC(C4CCC(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)CC4)C3=O)c(Cl)c2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
Bring a mixture of trifluoro-methanesulfonic acid 4-{3-[4-(tert-butyl-diphenyl-silanyloxy)-cyclohexyl]-2-oxo-pyrrolidin-1-ylmethyl}-3,5-dichloro-phenyl ester (0.61 g, 0.84 mmol), 4-methoxycarbonylphenylboronic acid (0.18 g, 1 mmol), sodium carbonate (0.267 g, 2.52 mmol) in THF (15 mL) and water (5 mL) to 60° C. To the mixture at 60° C., add Pd(PPh3)4 (0.048 g, 0.04 mmol). Raise the reaction temperature to 80° C. and stir for 1 hour. Cool the reaction, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify on silica gel column with 25% ethyl acetate in hexanes to afford 0.56 g (93%) of the titled product. MS (m/z): 714 (M+).
Reaction SMILES: C[Si](C)(C)[O-].[K+].[Cl:7][C:8]1[CH:9]=[C:10]2[NH:32][C:31]([O:33][C@H:34]3[CH2:39][CH2:38][C@H:37]([C:40]([O:42]CC)=[O:41])[CH2:36][CH2:35]3)=[N:30][C:11]2=[N:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1>O1CCCC1>[Cl:7][C:8]1[CH:9]=[C:10]2[NH:32][C:31]([O:33][C@H:34]3[CH2:35][CH2:36][C@H:37]([C:40]([OH:42])=[O:41])[CH2:38][CH2:39]3)=[N:30][C:11]2=[N:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](Oc2nc3nc(-c4ccc(-c5ccc(S(C)(=O)=O)cc5)cc4)c(Cl)cc3[nH]2)CC1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2ccc(-c3nc4nc(O[C@H]5CC[C@H](C(=O)O)CC5)[nH]c4cc3Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium trimethylsilanolate (278 mg, 2.16 mmol) was added to a tetrahydrofuran (3 mL) solution of ethyl trans-4-({6-chloro-5-[4′-(methylsulfonyl)biphenyl-4-yl]-1H imidazo[4,5-b]pyridin-2-yl}oxy)cyclohexanecarboxylate (240 mg, 0.43 mmol), and the mixture was stirred at rt for 16 h. The reaction mixture was partitioned between EtOAc and 10% aqueous citric acid. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated. Trituration of the resulting crude product with acetonitrile (10 mL) provided the title compound as an off-white solid. LC-MS: calculated for C26H24ClN3O5S 526.0, observed m/e: 526.3 (M+H)+ (Rt 0.8/2 min). 1H NMR δ (ppm) (DMSO-d6): 8.03-7.99 (5 H, m), 7.86 (2 H, d, J=8.16 Hz), 7.79 (2 H, d, J=8.12 Hz), 5.01-4.97 (1 H, m), 2.30 (1 H, m), 2.24 (3 H, d, J=10.17 Hz), 2.00 (3 H, m), 1.58-1.49 (4 H, m).
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[N:18](OCCCC)=[O:19]>C(O)C>[CH2:7]([O:6][C:4](=[O:5])[C:3](=[N:18][OH:19])[C:2](=[O:1])[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:8]
Reactant: CCOC(=O)CC(=O)CCc1ccccc1
Reactant: CCCCON=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(=NO)C(=O)CCc1ccccc1
Reaction time: 0.75 h

Procedure:
To a solution of 22.0 g. of ethyl 3-oxo-5-phenylvalerate in 100 ml. of ethanol is added 40 ml. of 38% hydrochloric acid, and after 10 minutes 11.3 ml. of n-butyl nitrite is added thereto. The resulting mixture is allowed to stand at room temperature for 45 minutes, and then the ethanol portion is essentially removed under reduced pressure to obtain an oily residue. The residue is poured into about 500 ml. of water and extracted 3 times with 200 ml. of chloroform. The combined extracts are dried over anhydrous sodium sulfate, then evaporated to obtain the title compound as a residue.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].C1C(=O)N([Br:20])C(=O)C1>C(Cl)Cl>[Br:20][C:8]1[C:7]([C:9]([F:10])([F:11])[F:12])=[CH:6][C:4]([NH2:5])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(N)cc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cc1cc(N)cc(C(F)(F)F)c1Br
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-methyl-5-(trifluoromethyl)aniline (4.84 g, 0.011 mol) was dissolved in CH2Cl2 and cooled to 0° C. NBS (4.92 g, 1 eq) was added and the mixture stirred overnight. The reaction mixture was loaded onto silica gel and eluted with 0-20% EtOAc in hexane to give 2.3 g of M21-1.
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]([CH:7]=[C:8]([C:14](=O)[CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([O:25][CH3:26])[CH:4]=1)#[N:2].[NH2:27][C:28]([CH3:33])=[CH:29][C:30](=[O:32])[CH3:31]>C(O)(C)C>[C:30]([C:29]1[CH:7]([C:6]2[CH:23]=[CH:24][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[O:25][CH3:26])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:14]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[NH:27][C:28]=1[CH3:33])(=[O:32])[CH3:31]
Reactant: CC(=O)C=C(C)N
Reactant: CCOC(=O)C(=Cc1ccc(C#N)cc1OC)C(=O)C(OCC)OCC
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C(OCC)OCC)NC(C)=C(C(C)=O)C1c1ccc(C#N)cc1OC
Yield: 28.4 %

Procedure:
720 mg (1.992 mmol) of ethyl 2-(4-cyano-2-methoxybenzylidene)-4,4-diethoxy-3-oxobutanoate are taken up in 15 ml of isopropanol, 197.5 mg (4.84 mmol) of 4-amino-3-penten-2-one are added, and the mixture is heated at the reflux temperature overnight. The mixture is then concentrated and the residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 250 mg (28.6% of theory) of ethyl 5-acetyl-4-(4-cyano-2-methoxyphenyl)-2-(diethoxymethyl)-6-methyl-1,4-dihydropyridine-3-carboxylate are obtained [LC-MS (method 11): Rt=2.48 min; [M+H]+ (EIpos): m/z=443].
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:25])=[CH:4][C:5]([Cl:24])=[C:6]([CH:23]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:16]=2)[N:13]=1.[CH3:26][N:27]1[C:31]([C:32](Cl)=[O:33])=[CH:30][C:29]([CH3:35])=[N:28]1>CN(C)C(=O)C>[Cl:24][C:5]1[C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]4[CH2:21][CH2:22]4)=[O:19])[N:16]=3)[N:13]=2)=[CH:23][C:2]([NH:1][C:32]([C:31]2[N:27]([CH3:26])[N:28]=[C:29]([CH3:35])[CH:30]=2)=[O:33])=[C:3]([F:25])[CH:4]=1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c(Cl)cc1F
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c(Cl)cc2F)n(C)n1
Yield: 40.6 %

Procedure:
Using N-[6-(5-amino-2-chloro-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.55 mmol), N,N-dimethylacetamide (4.0 mL) and 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (105 mg, 0.66 mmol), and in the same manner as in Example 120, the title compound (108 mg, 40%) was obtained as a white powder.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH:5]=[C:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[CH3:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13].Cl.[NH:23]1[CH2:33][CH2:32][CH2:31][CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:29]([O:28][C:26]([C@@H:25]1[CH2:31][CH2:32][CH2:33][N:23]([CH2:2][CH2:3][O:4][CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH3:21])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[CH2:24]1)=[O:27])[CH3:30]
Reactant: CCOC(=O)C1CCCNC1
Reactant: Cc1ccccc1C(=COCCBr)c1ccc(F)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)[C@@H]1CCCN(CCOC=C(c2ccccc2C)c2ccc(F)cc2C)C1

Procedure:
1-[2-(2-Bromethoxy)-1-(2-methylphenyl)ethenyl]-4-fluoro-2-methylbenzene (1.15 g, 0.0033 mol), the (R)-enantiomer of ethyl nipecotate hydrochloride (see example 1) (1.92 g, 0.0099 mol) and dried potassium carbonate (2.28 g, 0.0165 mol) were stirred in acetone (100 ml) at reflux temperature for 54 h.
Reaction SMILES: [CH3:1][C:2]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])=[O:5].O.[OH-].[Li+]>C1COCC1.O>[CH3:1][C:2]1[C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:5]
Reactant: COC(=O)CCCCCNC(=O)c1cccc(-c2ccccc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)NCCCCCC(=O)O)cccc1-c1ccccc1
Yield: 90.5 %

Procedure:
The procedure of the step 2 in Example 80 was repeated except that the methyl 6-(2-methyl-3-phenyl-benzamido)hexanoate (61 mg, 0.18 mmol) instead of methyl 6-(3-bromo-2-methylbenzamido)hexanoate, and 15 mg of lithium hydroxide monohydrate (0.36 mmol) were dissolved in 3 mL of THF/H2O (2:1) to obtain the title compound (53 mg, 90%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)/[C:7](/Cl)=[N:8]/[OH:9].[CH2:13]([Cl:16])[CH:14]=[CH2:15].Cl.O>CCOCC.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([C:7]2[CH2:15][CH:14]([CH2:13][Cl:16])[O:9][N:8]=2)[CH:11]=1
Reactant: C=CCCl
Reactant: O/N=C(\Cl)c1cc(Br)ccc1F
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1ccc(Br)cc1C1=NOC(CCl)C1
Temperature: 25 °C
Yield: 52.1 %

Procedure:
TEA (0.551 ml, 3.96 mmol, Aldrich) was added drop wise to a stirred solution of (Z)-5-bromo-2-fluoro-N-hydroxybenzimidoyl chloride (1c, 1 g, 3.96 mmol) at 0° C., followed by a solution of allyl chloride (0.968 ml, 11.88 mmol, Aldrich) in Et2O (20 mL). The reaction mixture was allowed to stir at RT for 4 hs. 2 M HCl (10 mL) was added, followed by water and EtOAc. The organic phase was separated and dried over MgSO4. The solvent was removed under reduced pressure. The crude material was absorbed onto a plug of silica gel and purified by chromatography eluting with a gradient of 3% to 35% EtOAc in hexane, to provide the title compound as colorless oil (0.604 g, 2.065 mmol, 52.1% yield). MS m/z=293.9 [M+H]+. Calculated for C10H8BrClFNO 292.53.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]1([C:47]([NH2:49])=[O:48])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.C(OCC)(=O)C.ClCCl>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:28][CH2:29][N:44]3[CH2:43][CH2:42][C:41]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=4)([C:47]([NH2:49])=[O:48])[CH2:46][CH2:45]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccn2)CCNCC1
Reactant: COc1cc(C(=O)N2CC[C@@](CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C(=O)N2CC[C@](CCN3CCC(C(N)=O)(c4ccccn4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 88.6 using (S)-2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (2.85 g, 5.2 mmol) and 4-(pyridin-2-yl)-piperidine-4-carboxylic acid amide (1.4 g, 6.8 mmol). Chromatograph on silica gel eluting sequentially with ethyl acetate, dichloromethane, 2% methanol/dichloromethane, 4% methanol/dichloromethane, and then 6% methanol/dichloromethane to give the title compound: Rf =0.24 (silica gel, 10% methanol/dichloromethane).