Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:29]=[CH:28][C:20]([O:21][CH2:22][C:23]([O:25]CC)=[O:24])=[C:19]([CH3:30])[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:31].O.O[Li].O>C1COCC1>[CH3:34][C:2]([CH3:1])([CH3:33])[C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:29]=[CH:28][C:20]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[C:19]([CH3:30])[CH:18]=2)([CH2:13][CH3:14])[CH2:15][CH3:16])=[CH:8][C:7]=1[CH3:31]
Reactant: CCOC(=O)COc1ccc(C(CC)(CC)c2ccc(OCC(=O)C(C)(C)C)c(C)c2)cc1C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(=O)O)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Reaction time: 2 h
Yield: 66.9 %

Procedure:
Compound 5 (50.0 mg, 0.1066 mmol) was dissolved in THF (1.0 mL) and H2O (0.5 mL) and LiOH.H2O (9.0 mg, 0.2133 mmol, 2.0 equiv.) was added. After stirring for 2 h, the reaction was quenched by the addition of sat. aq. NH4Cl solution and diluted with H2O. The resulting mixture was extracted with EtOAc (×3), and the combined organic phases were dried over MgSO4 and concentrated in vacuo. The crude residue was purified by preparative tlc (1:5:94 AcOH/MeOH/CH2Cl2) to afford the title acid 6 (31.4 mg, 67%)
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]=[C:12]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:13](OC)=[O:14].C(OCC)(=O)C.CCCCCC>C(Cl)Cl>[CH2:11]=[C:12]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:13][OH:14]
Reactant: C=C(CCCCCCCCCCCCCC)C(=O)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: C=C(CO)CCCCCCCCCCCCCC
Reaction time: 0.5 h

Procedure:
A solution of diisobutylaluminum hydride in CH2Cl2 (47 ml of a 1M solution, 0.047 mole, Aldrich Chem. Co.) was stirred under nitrogen in a round-bottom flask and cooled in an ice-water bath. To this was added dropwise over a period of 4 minutes a solution of 2-methylenehexadecanoic acid, methyl ester (2.82 g, 20 mmole) in CH2Cl2 (20 ml). The reaction was complete within 30 minutes as determined by TLC (20% ethyl acetate-hexane) of a sample quenched in brine-ether. The reaction was worked up after one hour by diluting with methylene chloride (300 ml) and adding several milliliters each of methanol and water. A gelatinous mass formed which broke up upon vigorous swirling. The mixture was filtered through Celite and the filtrate dried over MgSO4. Following filtration and concentration, an oily residue was obtained. The residue crystallized and was recrystallized by dissolving in hexane at room temperature then cooling in the freezer. Crystals were collected from the cold hexane by rapid filtration. 2-Methylenehexadecan-1-ol (22) was obtained in a first crop (1.718 g) of colorless crystals, mp 33°-34° C., and a second crop (0.081 g, total 1.799 g, 0.0071 mole, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:14]1[NH:15][C:16]([CH2:23][CH2:24][C:25](O)=O)=[C:17]2[C:22]=1[CH2:21][CH2:20][CH2:19][CH2:18]2.ClC1C=CC([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:25][CH2:24][CH2:23][C:16]3[N:15]([C:37]4[CH:36]=[CH:35][CH:40]=[CH:39][N:38]=4)[N:14]=[C:22]4[C:17]=3[CH2:18][CH2:19][CH2:20][CH2:21]4)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1[nH]nc2c1CCCC2
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: Clc1ccc(N2CCNCC2)cc1
Product: Clc1ccc(N2CCN(CCCc3c4c(nn3-c3ccccn3)CCCC4)CC2)cc1

Procedure:
In the same manner as in Example 102 except that 3-(4,5,6,7-tetrahydro-2-(2-pyridyl)-2H-indazol-3-yl)propionic acid obtained in Staring Material Synthesis Example 10 and 1-(4-chlorophenyl)piperazine were used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine, 3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2-(2-pyridyl)-2H-indazole was obtained, m.p. 101-103° C.
Reaction SMILES: [I-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:17][C:18]1[CH:19]=[C:20]([OH:39])[CH:21]=[CH:22][C:23]=1[CH:24]([CH3:38])[C:25]([OH:37])([C:30]1[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=1)[C:26]([F:29])([F:28])[F:27]>CC(C)=O>[CH2:9]([O:39][C:20]1[CH:21]=[CH:22][C:23]([CH:24]([CH3:38])[C:25]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=2)([OH:37])[C:26]([F:27])([F:28])[F:29])=[C:18]([Cl:17])[CH:19]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)ccn1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(C(O)(C(C)c2ccc(OCc3ccccc3)cc2Cl)C(F)(F)F)ccn1
Yield: 22.9 %

Procedure:
Potassium iodide (4 mg, 0.02 mmol), potassium carbonate (45 mg, 0.33 mmol), and benzyl chloride (41 mg, 0.33 mmol) were added to a solution of 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(2-methyl-pyridin-4-yl)-propyl]-phenol (Example 73, 50 mg, 0.14 mmol) in acetone (3 mL), and the mixture was refluxed for 3.5 h. The green suspension was filtered, the solvent evaporated, and the title compound (14 mg) was isolated from the residue by reversed-phase, preparative HPLC (Agilent Zorbax XdB-C18 column, solvent gradient 5-95% CH3CN in 0.1% TFA[aq]). MS (m/e)=436.1 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH3:25])[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.Cl[S:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[C:32]([OH:39])[CH:31]=1)(=[O:29])=[O:28]>>[Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[C:21]([CH3:23])[C:20]([O:24][S:27]([C:30]3[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[C:32]([OH:39])[CH:31]=3)(=[O:29])=[O:28])=[C:19]([CH3:25])[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1O
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)O)c(O)c1

Procedure:
Using 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenol (0.302 g, 0.744 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (1.09 g, 4.61 mmol) the title compound was prepared according to the procedure in Example 1, step 9. Purification on Dynamax C18 eluting with 85% CH3CN/H2O (0.1% TFA added) gave 0.20 g (44%) of the title compound as a yellow solid, mp >225° C.; 1H NMR (DMSO-d6) δ 1.59 (s, 3 H), 2.16 (s, 6 H), 2.45 (s, 3 H), 7.19 (S, 2 H), 7.46-7.52 (m, 4 H), 7.65-7.69 (m, 1 H), 8.07 (d, 1 H), 8.21 (d, 1 H). IR (KBr) 3450, 2900, 1675, 1385 and 1185 cm-1. mass spectrum (-ESI), m/z 609/611 (M-H). Anal. Calcd. for C29H23BrO6S2.0.7H2O: C, 55.81; H, 3.94 N, 0.00. Found: C, 55.93; H, 4.23 N, 0.12.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6](=[O:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[BH4-].[Na+]>>[CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Agent: [BH4-]
Agent: [Na+]
Product: CC1(C)CC(O)CC(C)(C)N1
Yield: 99 %

Procedure:
2,2,6,6-tetramethyl-4-piperidinol was prepared by the reduction of 2,2,6,6-tetramethyl-4-piperidone (Aldrich) with sodium borohydride. It was purified by recrystallization from ligroin (bp 65-90). It formed colorless needles with mp 130-131; the reported mp is 128-131 (Lutz et al 1962).
Reaction SMILES: [N:1]1([C@:4]23[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:5]2[C@@H:6]2[C@@:19]([CH3:22])([CH2:20][CH2:21]3)[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:37])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH:27]=3)=[CH:12][CH2:11]4)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.C([N:47]([CH2:51][CH3:52])[CH:48]([CH3:50])[CH3:49])(C)C.C1C[O:56]CC1>CO.O1CCOCC1>[CH:52]12[CH2:49][CH:48]([N:47]([CH2:2][CH2:3][NH:1][C@:4]34[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:5]3[C@@H:6]3[C@@:19]([CH3:22])([CH2:20][CH2:21]4)[C@@:18]4([CH3:23])[C@@H:9]([C@:10]5([CH3:37])[C@@H:15]([CH2:16][CH2:17]4)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]4[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH:27]=4)=[CH:12][CH2:11]5)[CH2:8][CH2:7]3)[CH2:51]1)[CH2:50][O:56]2
Reactant: C=C(C)[C@@H]1CC[C@]2(N3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CCN(C(C)C)C(C)C
Reactant: C1CCOC1
Solvent: CO
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CC4CC3CO4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 100 °C
Yield: 26 %

Procedure:
To a vial containing a suspension of ethyl 4-((1R,3 aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (0.05 g, 0.085 mmol) in THF (1 mL) was added N,N-diisopropylethylamine (0.089 mL, 0.510 mmol) followed by 2-oxa-5-azabicyclo[2.2.1]heptane, HCl (0.035 g, 0.255 mmol). The vial was sealed and the mixture was heated to 100° C. After 16 h of heating, the mixture was cooled to rt, was diluted with methanol and 1,4-dioxane and was purified by prep HPLC (method 8). The fractions containing the expected product were concentrated under reduced pressure to give ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (0.0152 g, 0.022 mmol, 26.0% yield) as an off-white foam. LCMS: m/e 687.7 (M+H)+, 1.96 min (method 5).
Reaction SMILES: [C:1]([NH:10][NH2:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:12](O)(=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].N1C=CC=CC=1.S(Cl)(Cl)=O>ClC1C=CC=CC=1>[C:1]([NH:10][NH:11][C:12](=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: NNC(=O)c1ccccc1O
Reactant: CCCCCCCCCCCC(=O)O
Solvent: O=S(Cl)Cl
Solvent: Clc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCCCCC(=O)NNC(=O)c1ccccc1O
Reaction time: 1 h
Yield: 53 %

Procedure:
15.2 g (0.1 mol) of salicylic acid hydrazide and 20.0 g (0.1 mol) of lauric acid are suspended in 200 ml of chlorobenzene, 2.0 g (0.025 mol) of pyridine are added and the mixture is heated to the boil. 13.1 g (0.11 mol) of thionyl chloride are added dropwise at this temperature. The product separates out initially as a turbidity and then as a flocculent precipitate. After boiling for 1 hour the mixture is cooled and the product is filtered off and washed with a little benzene and then with petroleum ether. N-Salicyloyl-N'-lauroyl-hydrazine of melting point 158° C is thus obtained in a yield of 53%. The product can be recrystallised from ethylene glycol monomethyl ether.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[N:7][N:6]=[C:5]1[C:9]1[S:10][C:11]2[CH2:12][CH2:13][O:14][C:15]3[CH:22]=[C:21]([C:23](O)=[O:24])[CH:20]=[CH:19][C:16]=3[C:17]=2[N:18]=1)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:32][C:33]1[CH:37]=[CH:36][O:35][N:34]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C=O)C>[O:35]1[CH:36]=[CH:37][C:33]([NH:32][C:23]([C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:18]=[C:9]([C:5]5[N:4]([CH:1]([CH3:3])[CH3:2])[CH:8]=[N:7][N:6]=5)[S:10][C:11]=4[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)=[O:24])=[N:34]1
Reactant: CC(C)n1cnnc1-c1nc2c(s1)CCOc1cc(C(=O)O)ccc1-2
Reactant: Nc1ccon1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)n1cnnc1-c1nc2c(s1)CCOc1cc(C(=O)Nc3ccon3)ccc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.3 %

Procedure:
To a suspension of 2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylic acid (226 mg, 0.63 mmol) in DCM (5 mL) at 0° C. was added DMF (4 drops, catalytic) then oxalyl chloride (115 μL, 1.32 mmol) dropwise. The reaction mixture was stirred at room temperature for 18 hours. 3-Amino-isoxazole (233 μL, 3.15 mmol) was added followed by triethylamine (176 μL, 1.26 mmol) and the reaction mixture was stirred for 4 hours. Aqueous saturated sodium bicarbonate solution was added and then ether and the mixture was filtered. The filtrate was concentrated in vacuo to remove the organics and the resulting aqueous phase was extracted with DCM (×3). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 0-5% MeOH in EtOAc) then trituration with EtOAc to give 140 as an off-white solid (126 mg, 47%). LCMS: RT=9.86 min, [M+H]+=423. 1H NMR δ (ppm) (DMSO-d6): 11.39 (1 H, s), 8.94 (1 H, s), 8.81 (1 H, d, J=1.76 Hz), 8.39 (1 H, d, J=8.33 Hz), 7.79 (1 H, dd, J=8.34, 1.90 Hz), 7.70 (1 H, d, J=1.87 Hz), 7.00 (1 H, d, J=1.76 Hz), 5.51-5.41 (1 H, m), 4.41-4.35 (2 H, m), 3.47-3.41 (2 H, m), 1.54 (6 H, d, J=6.70 Hz)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[C:19]1([NH:25][C:26]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:4][CH:3]=2)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C=Nc1ccccc1
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Solvent: CC#N
Product: CN1CCN(c2cccc3ccc(NC(=O)Nc4ccccc4)cc23)CC1
Yield: 62.5 %

Procedure:
7-Amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.216 g, 0.896 mmol) and phenyl isocyanate (0.222 g, 1.86 mmol) were combined in acetonitrile (14 mL) and refluxed overnight. Phenyl isocyanate (0.106 g, 0.896 mmol) was added and the reaction was refluxed 2 hours more. Upon cooling a tan solid precipitated which was collected and recrystallized from methanol/ethyl acetate to give 0.202 g (62%) of the title product; mp 213°-214° C. Analysis calculated for C22H24N4O: C, 73.31; H, 6.71; N, 15.54. Found: C0 73.03; H, 6.55; N, 15.22.
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10].[CH:14]([C:16]([CH3:18])=O)=[CH2:15]>O1CCOCC1>[Br:6][C:7]1[CH:8]=[C:9]2[C:11]([C:16]([CH3:18])=[CH:14][CH:15]=[N:10]2)=[CH:12][CH:13]=1
Reactant: C=CC(C)=O
Reactant: Nc1cccc(Br)c1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Cc1ccnc2cc(Br)ccc12
Reaction time: 1 h

Procedure:
H2SO4 (14.4 mL, 270 mmol) is added to a solution of 3-bromoaniline (Aldrich, 30.0 g, 174 mmol) in 1,4-dioxane (1 L) at RT. The mixture is heated to reflux and treated with methyl vinyl ketone (Aldrich, 19.5 mL, 270 mmol) in 1,4-dioxane (50 mL) dropwise over 3 h. Heating is continued for 1 h after the addition, followed by removal of the solvent in vacuo. The residue is dissolved in water (100 mL), neutralized with Na2CO3 and extracted with CH2Cl2. The combined organic extracts are washed with water and brine, dried (Na2SO4) and filtered. The filtrate is concentrated, and the residue chromatographed on silica gel (Biotage, eluting with 20% EtOAc/Hexanes) to give the title compound, 15.0 g (43%), as a brownish solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=O)[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:14][C:15]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:16]=1[NH2:17]>>[Cl:14][C:15]1[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][C:16]=1[NH:17][C:9](=[O:11])[C:8]1[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[OH:13]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Product: O=C(Nc1cc(C(F)(F)F)ccc1Cl)c1cc([N+](=O)[O-])ccc1O
Yield: 31.1 %

Procedure:
Using 5-nitrosalicylic acid and 2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH:3](Cl)[CH2:4][C:5](=[O:9])[CH2:6][CH2:7][CH3:8].[SH:11][CH2:12][CH2:13]O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:6]([C:5]1[O:9][CH2:13][CH2:12][S:11][C:4]=1[CH2:3][CH2:2][Cl:1])[CH2:7][CH3:8]
Reactant: CCCC(=O)CC(Cl)CCl
Reactant: OCCS
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCC1=C(CCCl)SCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
A mixture of 0.056 mole (10 g.) of 1,2-dichloro-4-heptanone and 0.06 mole (5 g.) 2-mercaptoethanol was stirred in 200 ml toluene; 0.06 mole (6 g.) triethylamine was added dropwise. The mixture was stirred at room temperature overnight, then washed with dilute hydrochloric acid and refluxed with 0.5 mole PTS, using a Dean-Stark trap to remove water for 7 hours. The PTSA solution was washed with 5% sodium bicarbonate, dried, filtered and the solvent was removed. The product was distilled; bp 80°-85°/0.05 mm. Yield 23%.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][N:17]([C:13]1[CH:12]=[C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:16]=[CH:15][N:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH3:35]
Reactant: c1ccc(COc2ccnc(Nc3ccccn3)c2)cc1
Reactant: CCOC(=O)CCCCCCBr
Agent: O=S([O-])([O-])=S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(OCc2ccccc2)ccn1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 47.8 %

Procedure:
NaH (245 mg, 6.38 mmol) was added to II (1.77 g, 6.38 mmol) in DMF (25 mL) at rt. After 15 min, KI (1.588 g, 9.57 mmol) and ethyl 7-bromoheptanoate (1.86 mL, 9.57 mmol) were added, and the reaction mixture was stirred at 90° C. for 17 h. Aqueous 0.1 M Na2S2O3 (100 mL) and EtOAc (100 mL) were added and the phases were separated. The organic phase was washed with brine (100 mL), dried over MgSO4, filtered, and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with hexane/EtOAc (90:10 to 70:30) to furnish III as a yellow oil (1.321 g, 48%).
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[C:5]1([NH2:12])[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>O>[C:13]([NH:11][C:7]1[CH:6]=[C:5]([NH:12][C:1](=[O:4])[CH3:2])[CH:10]=[CH:9][CH:8]=1)(=[O:15])[CH3:14]
Reactant: Nc1cccc(N)c1
Reactant: CC(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1cccc(NC(C)=O)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Into a 1-liter reaction flask cooled with an ice bath was introduced 35 ml of acetic acid. Thereto was gradually added 15 g (138.7 mmol) of m-phenylenediamine. Thereto was dropwise added 2 ml (307.4 mmol) of acetic anhydride at room temperature to 30° C. After completion of the addition, the mixture was stirred at 60° C. for 1 hour and then poured into 150 ml of water. The resultant precipitate was taken out by filtration, sufficiently washed with water, and then dried to obtain 18.4 g of diacetyl-m-phenylenediamine as the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]#[N:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>FC(F)(F)C(O)C(F)(F)F>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:13][CH2:14][N:15]([C:18]([NH:26][CH2:25][C:24]4[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=4)=[NH:19])[CH2:16][CH2:17]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#CN1CCN(c2ccnc3cc(Cl)ccc23)CC1
Reactant: NCc1ccc(F)cc1
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: N=C(NCc1ccc(F)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
7-Chloro-4-(4-cyanopiperazin-1-yl)quinoline (219 mg, 0.8 mmol) and 4-fluorobenzylamine (114 μL, 1.0 mmol) in 1,1,1,3,3,3-hexafluoro-2-propanol (5 mL) are heated at 130° C. in a sealed tube for 44 h. The reaction mixture is concentrated, and the residue is purified by column chromatography with CH2Cl2—NH3-MeOH to give the title product as a yellow foam.
Reaction SMILES: [C:1]1([CH2:7]/[CH:8]=[CH:9]/[CH2:10][O:11][N:12]2C(=O)C3=CC=CC=C3C2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(CN)O.[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29]>C(OCC)(=O)C>[C:27]([O-:32])(=[O:31])[C:28]([O-:30])=[O:29].[C:1]1([CH2:7]/[CH:8]=[CH:9]/[CH2:10][O:11][NH3+:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([CH2:7]/[CH:8]=[CH:9]/[CH2:10][O:11][NH3+:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C(=O)O
Reactant: O=C1c2ccccc2C(=O)N1OC/C=C/Cc1ccccc1
Solvent: NCCO
Solvent: CCOC(C)=O
Product: O=C([O-])C(=O)[O-]
Product: [NH3+]OC/C=C/Cc1ccccc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
55.5 g of compound (1) (0.19 mol) were admixed in 190 ml of ethyl acetate with 11.6 g (0.19 mol) of ethanolamine, and the mixture was stirred at 60° C. for 5 hours. After cooling the solution, precipitated N-(hydroxyethyl)phthalimide was filtered off, and a solution of 18.8 g of oxalic acid (0.21 mol) in 30 ml of ethyl acetate was added to the filtrate. The product crystallized out as oxalate.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[NH:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[N:14][N:15]=2)=[CH:6][CH:5]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:36]1[CH:41]=[C:40]([NH2:42])[N:39]=[C:38]([NH2:43])[N:37]=1.[C:44]([O-])([O-:46])=[O:45].[K+].[K+]>CN(C=O)C.CO>[F:24][C:2]([F:1])([F:23])[C:44]([OH:46])=[O:45].[F:24][C:2]([F:1])([F:23])[O:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[NH:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:36]4[N:37]=[C:38]([NH2:43])[N:39]=[C:40]([NH2:42])[CH:41]=4)=[CH:18][CH:17]=3)=[N:14][N:15]=2)=[CH:8][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: Oc1ccc(-c2nnc(Nc3ccc(OC(F)(F)F)cc3)[nH]2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1cc(Oc2ccc(-c3nnc(Nc4ccc(OC(F)(F)F)cc4)[nH]3)cc2)nc(N)n1
Product: O=C(O)C(F)(F)F
Temperature: 80 °C
Yield: 55.5 %

Procedure:
4-[5-(4-trifluoromethoxy-phenylamino)-4H[1,2,4]triazol-3-yl]-phenol (112.0 mg, 0.33 mmol) was dissolved in 2 mL of anhydrous DMF in a 5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (132.8 mg, 0.66 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 15 min, then 4-chloro-2,6-diamino-pyrimidine (53.0 mg, 0.366 mmol) was added, followed by anhydrous K2CO3 (46.0 mg, 0.33 mmol). Then the vial was capped and microwaved at 250° C. for 15 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. The product was isolated as a TFA salt (51.1 mg of beige solid).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[C:4]([F:18])[CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1B(O)O>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:22]3[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:21]=3[O:20][CH3:19])=[CH:3][C:4]=2[F:18])(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(Br)cc1F
Reactant: COc1ccc(C)cc1B(O)O
Product: COc1ccc(C)cc1-c1ccc(S(=O)(=O)c2ccc(F)cc2)c(F)c1

Procedure:
The subtitle compound was prepared by the method of example 2 step (ii) using the product of example 4 step (i) and (2-methoxy-5-methylphenyl)boronic acid.