Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@:2]([C:13]1[C:18]([F:19])=[CH:17][CH:16]=[C:15]([Br:20])[N:14]=1)([CH:10]([F:12])[F:11])[CH2:3][C@H:4]([OH:9])[C:5]([F:8])([F:7])[F:6].[C:21]([N:29]=[C:30]=S)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C1COCC1.O>[Br:20][C:15]1[N:14]=[C:13]([C@@:2]2([CH:10]([F:12])[F:11])[CH2:3][C@@H:4]([C:5]([F:6])([F:7])[F:8])[O:9][C:30]([NH:29][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:1]2)[C:18]([F:19])=[CH:17][CH:16]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: N[C@](C[C@H](O)C(F)(F)F)(c1nc(Br)ccc1F)C(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1=N[C@](c2nc(Br)ccc2F)(C(F)F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.3 %

Procedure:
To a 50-mL round-bottomed flask was added (2S,4R)-4-amino-4-(6-bromo-3-fluoropyridin-2-yl)-1,1,1,5,5-pentafluoropentan-2-ol (22 mg, 0.060 mmol) and benzoyl isothiocyanate (8.87 μl, 0.066 mmol) in THF (599 μl). The reaction mixture was stirred at RT for 16 h. To the reaction mixture was added triethylamine (10.00 μl, 0.072 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12.64 mg, 0.066 mmol). The mixture was heated at 75° C. for 1.5 h. The reaction mixture was allowed to cool to RT and was diluted with water and extracted with EtOAc. The organic extract was washed with satd NaCl (10 mL) and dried over MgSO4. The solution was filtered and concentrated in vacuo. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 30% EtOAc in hexane, to provide N-((4R,6S)-4-(6-bromo-3-fluoropyridin-2-yl)-4-(difluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (22 mg, 0.044 mmol, 74.0% yield) as off-white solid. MS m/z=496, 498 M+, Calculated for C18H12BrF6N3O2: 496.20.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].O.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>C(Cl)Cl>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 89.4 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.00 g) obtained from Referential Example 7 and potassium carbonate (1.10 g) were suspended in a mixed solvent of methylene chloride (30 ml) and water (20 ml). A solution of benzyl chloroformate (1.35 g) in methylene chloride (10 ml) was added thereto under ice-cooling, and the mixture was stirred for 2 hours at same temperature and then stirred overnight at room temperature. The reaction mixture was separated into organic layer and aqueous layer, the organic layer was successively washed with aqueous 10% oxalic acid solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure, to thereby obtain the 2.61 g of titled compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([NH:10][C:11](=[O:15])OCC)=[N:2]1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([OH:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][C:18]=1[C:30]([F:33])([F:32])[F:31]>CS(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([NH:10][C:11]([N:26]2[CH2:27][CH2:28][C:23]([C:20]3[CH:21]=[CH:22][C:17]([Cl:16])=[C:18]([C:30]([F:32])([F:31])[F:33])[CH:19]=3)([OH:29])[CH2:24][CH2:25]2)=[O:15])=[N:2]1
Reactant: CCOC(=O)Nc1n[nH]c2ccccc12
Reactant: OC1(c2ccc(Cl)c(C(F)(F)F)c2)CCNCC1
Solvent: CS(C)=O
Product: O=C(Nc1n[nH]c2ccccc12)N1CCC(O)(c2ccc(Cl)c(C(F)(F)F)c2)CC1
Temperature: 100 °C
Yield: 66 %

Procedure:
Ethyl 1H-indazol-3-ylcarbamate (synthesized according to the method described in Tetrahedron, 1976, 32(4), 493)(200 mg) and 4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxypiperidine (ACROS CO., 272 mg) were dissolved in dimethyl sulfoxide (2 ml). Potassium fluoride-alumina (Aldrich Co., 40 wt %, 200 mg) was added to the solution, and the mixture was stirred with heating at 100° C. for 2 hr. After completion of the reaction, the solid was collected by filtration and washed with methanol. The filtrate was concentrated, and 1N aqueous hydrochloric acid was added. The precipitated solid was collected by filtration and vacuum dried. The obtained solid was washed with diethyl ether and dried to give 4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide (280 mg, yield 66%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:46])[CH:5]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[C:19]([C:21]2[C:22](=[O:30])[N:23]([CH3:29])[C:24](=[O:28])[N:25]([CH3:27])[CH:26]=2)[CH:18]=[C:17](Br)[CH:16]=1)[CH3:7])[CH3:2].[CH3:47][O:48][C:49]1[CH:54]=[CH:53][C:52](B(O)O)=[CH:51][CH:50]=1>>[CH2:1]([O:3][C:4](=[O:46])[CH:5]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:52]2[CH:53]=[CH:54][C:49]([O:48][CH3:47])=[CH:50][CH:51]=2)[CH:18]=[C:19]([C:21]2[C:22](=[O:30])[N:23]([CH3:29])[C:24](=[O:28])[N:25]([CH3:27])[CH:26]=2)[CH:20]=1)[CH3:7])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)CCc1ccccc1OC(C(=O)OCC)C(C)CCCCCCOc1cc(Br)cc(-c2cn(C)c(=O)n(C)c2=O)c1
Product: CCOC(=O)CCc1ccccc1OC(C(=O)OCC)C(C)CCCCCCOc1cc(-c2ccc(OC)cc2)cc(-c2cn(C)c(=O)n(C)c2=O)c1
Yield: 45 %

Procedure:
A similar procedure as described in Example 1, step 2 was used, starting from 4-[3-{6-[3-bromo-5-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl) -phenoxy]-hexyl}-(2-(2-ethoxycarbonyl-ethyl)-phenoxy)-butyric acid ethyl ester (130 mg, 0.18 mmol) and 4-methoxyphenylboronic acid (85 mg, 0.56 mmol) to obtain 4-[3-{6-[5-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-4′-methoxy-biphenyl-3-yloxy]-hexyl}-(2-(2-ethoxycarbonyl-ethyl)-phenoxy)-butyric acid ethyl ester (59 mg, 44%) as a light yellow oil: ES(+)-HRMS m/e calculated for C42H52N2O9 (M+H)+ 729.3746, found 729.3742.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:15][C:14](=[O:16])[CH2:13][C:12](=[O:17])[O:11]2)[CH:5]=[CH:4][C:3]=1[C:23]([CH3:27])([CH3:26])[C:24]#[N:25].ClC1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=C(CC)C=1OC.[CH3:54][N:55]1[C:59]([CH:60]=O)=[N:58][C:57]([CH3:62])=[N:56]1.CC1C=C(C)N2N=C(C=O)N=C2N=1>O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[CH2:15][C:14]([OH:16])=[C:13]([CH2:60][C:59]3[N:55]([CH3:54])[N:56]=[C:57]([CH3:62])[N:58]=3)[C:12](=[O:17])[O:11]2)[CH:5]=[CH:4][C:3]=1[C:23]([CH3:27])([CH3:26])[C:24]#[N:25]
Reactant: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: Cc1nc(C=O)n(C)n1
Agent: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(Cl)c1OC
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Solvent: O
Product: Cc1nc(CC2=C(O)CC(CCc3ccc(C(C)(C)C#N)c(Cl)c3)(C3CCCC3)OC2=O)n(C)n1

Procedure:
The title compound was prepared analogously to example A(1): where 2-{2-chloro-4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-2-methyl-propionitrile.from step 5 below, was substituted in place of 6-[2-(3-chloro-5-ethyl-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione and 2,5-dimethyl-2H-[1,2,4]triazole-3-carbaldehyde was substituted instead of 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde in that example. 1H NMR (300 MHz, DMSO-d6): δ 1.47–1.74 (m, 8 H), 1.79 (s, 6 H), 2.01–2.11 (m, 8 H), 2.36–2.42 (m, 1 H), 2.56 (d, J=16 Hz, 1 H), 2.60–2.66 (m, 2 H), 2.77 (d, J=16 Hz, 1 H), 3.53 (d, J=16 Hz, 1 H), 3.62 (d, J=16 Hz, 1 H), 7.25 (dd, J=8.2, 1.8 Hz, 1 H), 7.4 (d, J=1.8 Hz, 1 H), 7.45 (d, J=8.2 Hz, 1 H). Anal. Calcd. For C27H33ClN4O3.0.25 H2O: C, 64.66; H, 6.73; N, 11.17. Found: C, 64.88; H, 6.74; N, 10.86. ESIMS (MH+): 498.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[N:14]([CH:15]=2)[N:13]=[CH:12][N:11]=[C:10]3O)[CH:2]=1.O=P(Cl)(Cl)[Cl:19].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:19][C:10]1[C:9]2=[CH:8][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:15][N:14]2[N:13]=[CH:12][N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnn2cc(-c3cccnc3)cc12
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncnn2cc(-c3cccnc3)cc12
Temperature: 100 °C
Yield: 33.2 %

Procedure:
To a suspension of 6-(pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol (100 mg, 0.30 mmol) in 10 mL of toluene were added POCl3 (0.18 mL, 1.88 mmol) and DIEA (0.09 mL, 0.5 mmol). The suspension was heated at 100° C. for 7 h. After cooling down, the excess POCl3 was removed under reduced pressure. The residue was suspended in EtOAc, and then neutralized with sat. NaHCO3. The organic layer was then washed with brine and dried over MgSO4. After filtration and concentration, the residue was purified by flash column chromatography to afford the title compound (23 mg, 33%). MS(ESI+) m/z 231.2/233.2 (M+H)+.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH2:1]([N:15]1[CH2:14][CH2:13][N:12]([C:10]([O:9][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:11])[CH2:17][CH2:16]1)[C:2]#[CH:3]
Reactant: C#CCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C#CCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
A solution of propargyl bromide (0.766 g, 6.44 mmol) in acetonitrile (25 mL) was added with 1-tert-butoxycarbonylpiperazine (1.00 g, 5.37 mmol) and potassium carbonate (1.11 g, 8.03 mmol), and the mixture was stirred at 60° C. for 4 hours. The reaction mixture was added with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-(prop-2-ynyl)piperazine-1-carboxylate (1.01 g, 83%).
Reaction SMILES: [CH3:1][N:2]1[O:9][CH2:8][CH:7]2[CH:3]1[CH:4]([CH3:15])[N:5](C(OCC)=O)[CH2:6]2>O>[CH3:1][N:2]1[O:9][CH2:8][CH:7]2[CH:3]1[CH:4]([CH3:15])[NH:5][CH2:6]2
Reactant: CCOC(=O)N1CC2CON(C)C2C1C
Solvent: O
Product: CC1NCC2CON(C)C21

Procedure:
9.2 g (42.9 mmol) of ethyl 2,8-dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane-7-carboxylate are heated under reflux with 23.5 g of Ba(OH)2.8H2O in 235 ml of water overnight. The BaCO3 is filtered off with suction, K2CO3 is added to the filtrate and the solid is filtered off with suction again. The filtrate is extracted ten times with 50 ml of CHCl3 each time, the extracts are dried over K2CO3 and concentrated and the residue is distilled.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[N:6][CH:7]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:9]=1)[CH3:2].[CH2:29]([O:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:47](=[O:58])[CH2:48][C:49]2[C:54]([F:55])=[CH:53][C:52](Br)=[CH:51][C:50]=2[F:57])=[CH:42][C:41]=1[C:59]([F:62])([F:61])[F:60])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH2:29]([O:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:47](=[O:58])[CH2:48][C:49]2[C:50]([F:57])=[CH:51][C:52]([C:8]3[CH:7]=[N:6][C:5]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=3)=[CH:53][C:54]=2[F:55])=[CH:42][C:41]=1[C:59]([F:61])([F:60])[F:62])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)cnc1OCc1ccc(OC)cc1
Reactant: O=C(Cc1c(F)cc(Br)cc1F)Nc1ccc(OCCOCc2ccccc2)c(C(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCOc1cc(-c2cc(F)c(CC(=O)Nc3ccc(OCCOCc4ccccc4)c(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Yield: 35.1 %

Procedure:
A solution of 3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (78 mg, 0.202 mmol), N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2,6-difluorophenyl)acetamide (110 mg, 0.202 mmol), PdCl2(dppf)-DCM adduct (16.50 mg, 0.020 mmol) and Cs2CO3 (132 mg, 0.404 mmol) in 1,4-dioxane (6 mL) and H2O (2 mL) was stirred at 110° C. for 15 min. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. The residue was dissolved in DCM (60 mL) and washed with H2O (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (DCM/MeOH=10/1) to yield N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2,6-difluorophenyl)acetamide (70 mg, 0.071 mmol, 35.1% yield): 1H NMR (400 MHz, CD3OD) δ 7.97 (d, J=2.0 Hz, 1H), 7.84 (s, 1H), 7.71 (d, J=11.2 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.39 (d, J=8.6 Hz, 2H), 7.37-7.13 (m, 8H), 6.90 (d, J=8.6 Hz, 2H), 5.39-5.34 (m, 2H), 4.61 (s, 2H), 4.27-4.20 (m, 2H), 4.18-4.10 (m, 2H), 3.86-3.82 (m, 2H), 3.78 (s, 3H), 1.42 (t, J=6.9 Hz, 3H), 1.19 (s, 2H); ES-LCMS m/z 723.2 (M+H).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Br:10]Br.C(=O)([O-])O.[Na+]>ClCCl.[Fe]>[Br:10][C:7]1[CH:8]=[CH:9][C:2]2[S:1][CH2:5][CH2:4][C:3]=2[CH:6]=1
Reactant: c1ccc2c(c1)CCS2
Reactant: BrBr
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Brc1ccc2c(c1)CCS2
Yield: 62.6 %

Procedure:
Iron powder (10.4 mg, 1.47 mmol) was added to a solution of 2,3-dihydrobenzo[b]thiophene 112 (400 mg, 2.94 mmol) in dichloromethane (5.9 mL). Bromine (0.15 mL, 2.94 mmol) was added dropwise to the mixture with stirring under ice-cooling. This mixture was stirred at the same temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution was added to the mixture and this was extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to provide the desired product 113 (396 mg, 63%).
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]([F:20])=[C:11]([C:16](=O)[CH2:17][CH3:18])[CH:12]=[C:13]([F:15])[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si]([CH2:25][C:26]([O:28][CH3:29])=[O:27])(C)C>>[Si:1]([O:8][C:9]1[C:10]([F:20])=[C:11]([C:16]([CH2:17][CH3:18])=[CH:25][C:26]([O:28][CH3:29])=[O:27])[CH:12]=[C:13]([F:15])[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)C[Si](C)(C)C
Reactant: CCC(=O)c1cc(F)cc(O[Si](C)(C)C(C)(C)C)c1F
Product: CCC(=CC(=O)OC)c1cc(F)cc(O[Si](C)(C)C(C)(C)C)c1F

Procedure:
Compound 90.E (mixture of geometric isomers) was prepared from 90.D and methyl (trimethylsilyl)acetate (available from Aldrich) according to the analogous method described in Example 84.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:12][C:10](=O)[NH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.[CH3:13][N:14]([CH3:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH-].[Na+]>O1CCCC1>[CH3:13][N:14]([CH3:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:10][NH:9][C:7](=[O:8])[C:5]1[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=1)[OH:12]
Reactant: CN(C)CCCCCCO
Reactant: O=c1[nH]c(=O)c2ccccc2o1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)CCCCCCNC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 47.4 %

Procedure:
A slurry of 18.02 g (110 mmol) of carsalam, 18.0 mL (15.84 g, 109 mmol) of 6-dimethylamino-1-hexanol, 29.12g (111 mmol) of triphenylphosphine,. and 150 mL of tetrahydrofuran was treated with a solution of 21.8 mL (22.39 g, 111 mmol) of diisopropyl azodicarboxylate and 40 mL of tetrahydrofuran, added dropwise over 20 minutes, causing the temperature of the slurry to rise to about 67° C. The reaction mixture was allowed to cool back to about 25° C. and stir for about 20 hours. The solution was treated with 150 mL (300 mmol) of aqueous 2N sodium hydroxide and warmed to about 60° C. for about 90 minutes. The reaction mixture was washed with ethyl acetate (2×60 mL). The aqueous phase was acidified with 4% aqueous hydrochloric acid to a pH slightly less than about 0 and washed with ethyl acetate (2×60 mL). The pH of the aqueous phase was raised to about 4.5 with 50% aqueous potassium carbonate and washed with ethyl acetate (2×60 mL). The aqueous phase was treated with solid sodium bicarbonate and extracted with ethyl acetate (14×60 mL). The combined 14 ethyl acetate extracts were dried over sodium sulfate and concentrated to a viscous liquid. The liquid was taken up into a minimum amount of ethyl acetate, diluted with 100 ml of hexanes and treated in an ice bath with 150 mL of hexanes, causing a white solid to develop. A total of 13.65 g of N-(6-dimethylaminohexyl)salicylamide was isolated by filtration.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)[CH:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[N:3]=1.[I:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1>>[F:15][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[N:3]=[C:2]([N:24]3[CH:25]=[C:21]([I:20])[N:22]=[CH:23]3)[N:7]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1F
Reactant: Ic1c[nH]cn1
Product: Fc1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)cc1F

Procedure:
The title compound was prepared from 2-chloro-4-(3,4-difluoro-phenyl)-6-trifluoromethyl-pyrimidine (example A.46) (1.50 g, 5.1 mmol) and commercially available 4-iodo-imidazole (1.48 g, 7.63 mmol) according to the general procedure IVa. Obtained as a light red solid (2.23 g, 97%). MS (ISP) 452.9 [(M+H)+]; mp 206° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([NH2:11])=[O:10])=[CH:5][CH:4]=1.[Cl:16][CH2:17][C:18]([CH2:20]Cl)=O.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Cl:16][CH2:17][C:18]1[N:11]=[C:9](/[CH:8]=[CH:7]/[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:14])([F:15])[F:1])=[CH:13][CH:12]=2)[O:10][CH:20]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)C=Cc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(/C=C/c2nc(CCl)co2)cc1
Temperature: 25 °C
Yield: 54.8 %

Procedure:
4-(Trifluoromethyl)cinnamamide (1 g, 4.65 mmol) and 1,3-dichloroacetone (1.1 g, 8.66 mmol) were added to toluene (5 ml) and the mixture was refluxed under heating for 8 hours. Ethyl acetate (20 ml) was added and the mixture was washed with water (20 ml) twice, and then concentrated under reduced pressure. To the residue was added methanol (4 ml) and the mixture was stirred at room temperature. The crystals were filtrated and dried under reduced pressure to give 4-(chloromethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole (733 mg, yield 55%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C@@H:11]2[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]3[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=3)=[O:17])[CH2:12]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH3:32][C:33]([O:36][C:37]([NH:39][CH2:40][C@H:41]1[CH2:46][CH2:45][C@H:44]([C:47](O)=[O:48])[CH2:43][CH2:42]1)=[O:38])([CH3:35])[CH3:34]>>[CH3:35][C:33]([O:36][C:37]([NH:39][CH2:40][C@H:41]1[CH2:46][CH2:45][C@H:44]([C:47]([N:14]2[CH2:15][C@@H:11]([N:8]3[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]3)[CH2:12][C@H:13]2[C:16]([NH:18][C:19]2[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])=[CH:21][CH:20]=2)=[O:17])=[O:48])[CH2:43][CH2:42]1)=[O:38])([CH3:32])[CH3:34]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCN(S(C)(=O)=O)CC3)CN2)cc1
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)N2C[C@@H](N3CCN(S(C)(=O)=O)CC3)C[C@H]2C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)CC1

Procedure:
Following the procedure described in Example 8, the compound prepared in Example 6 was treated with trans-4-[({[(2-methyl-2-propanyl)oxy]carbonyl}amino)methyl]cyclohexanecarboxylic acid to give the title compound as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]([OH:10])[CH2:7][C:8]#[N:9])[C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2.B.O1CCCC1.B.[ClH:22]>CO>[ClH:22].[NH2:9][CH2:8][CH2:7][CH:6]([C:4]1[C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=2[S:1][CH:5]=1)[OH:10]
Reactant: N#CCC(O)c1csc2ccccc12
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: NCCC(O)c1csc2ccccc12
Temperature: 75 °C
Yield: 58 %

Procedure:
3-Benzo[b]thiophen-3-yl-3-hydroxy-propionitrile (1.2 g, 5.90 mmol) was slowly treated with a solution of borane-tetrahydrofuran complex (13 mL, 12.98 mmol, 1M in tetrahydrofuran) at 0° C. After bubbling ceased, the reaction mixture was heated to 75° C. for 2 hours and 6.0 eq of additional borane was added to drive the reaction to completion. The reaction mixture was concentrated. The white solid obtained was treated with methanol (14 mL), followed by hydrogen chloride (2M in diethyl ether, 43 mL). The resulting mixture was heated to reflux for 2 hours, allowed to cool to ambient temperature and then concentrated at reduced pressure. To the residue was added aqueous hydrochloric acid (10 mL, 1 N) followed by diethyl ether (20 mL). The aqueous layers were separated and concentrated at reduced pressure to give the product as a yellow solid (840 mg, 58%).
Reaction SMILES: [C:1]([C:3](=[CH:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[N+:15]([O-])=O)[C:4]([NH2:6])=[O:5])#[N:2]>[Fe]>[Cl:14][C:12]1[CH:13]=[C:8]2[C:9](=[CH:10][CH:11]=1)[N:15]=[C:1]([NH2:2])[C:3]([C:4]([NH2:6])=[O:5])=[CH:7]2
Reactant: N#CC(=Cc1cc(Cl)ccc1[N+](=O)[O-])C(N)=O
Agent: [Fe]
Product: NC(=O)c1cc2cc(Cl)ccc2nc1N

Procedure:
Following the procedure of Example IV-B, α-cyano-β-(2-nitro-5-chlorophenyl)acrylamide (51.0 g., 0.2 mole) is treated with iron powder (56 g., 1.0 mole) to provide 19 g. (43%) of the title carboxamide derivative. M.P. 250°-251° C. when recrystallized from ethanol.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)C(C)C)C.[CH2:35]([NH:39][NH2:40])[CH:36]([CH3:38])[CH3:37].C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>CN(C=O)C>[CH2:35]([N:39]1[C:2]2[C:3](=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)[C:4](=[O:6])[NH:40]1)[CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)CNN
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Cn1[nH]c(=O)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 2-fluoro-5-nitrobenzoic acid (1.5 g) in DMF (50 mL) was added EDCI.HCl (1.71 g) followed by N-ethyldiisopropylamine (5.51 mL). After 10 minutes isobutylhydrazine.p-toluenesulfonicacid salt (2.32 g) was added. The reaction mixture was stirred at ambient temperature for 22 hours and the reaction was poured onto aqueous 1N HCl solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. Purification via ISCO combiflash chromatography afforded pure desired 1-isobutyl-5-nitro-1,2-dihydro-indazol-3-one (0.9 g) as a yellow solid. MS (ESI−):234.1 ([M−H]−).