Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:28])=[C:8]([C:10]2[NH:14][C:13](=[O:15])[N:12]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([O:26][CH3:27])[CH:17]=3)[N:11]=2)[CH:9]=1.CCN(C(C)C)C(C)C.[CH:38]1([C:41](Cl)=[O:42])[CH2:40][CH2:39]1>C1COCC1>[Cl:28][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:41]([CH:38]2[CH2:40][CH2:39]2)=[O:42])=[CH:9][C:8]=1[C:10]1[NH:14][C:13](=[O:15])[N:12]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([O:26][CH3:27])[CH:17]=2)[N:11]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)cc1OC
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
A solution of methyl 4-(3-(5-(aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate hydrochloride (0.500 g, 1.29 mmol) in THF (20 mL) was added DIPEA (2 mL) and cyclopropyl carbonyl chloride (0.201 g, 1.9 mmol) under nitrogen atmosphere. The reaction mass was stirred at RT for 2-4 h. The reaction mass was quenched in water, extracted with DCM and concentrated to afford 0.400 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.69 (m, 4H), 1.60 (s, 1H), 3.79 (s, 3H), 3.86 (s, 3H), 4.33 (d, J=5.4 Hz, 2H), 7.41-7.54 (m, 3H), 7.61 (d, J=8.4 Hz, 1H), 7.73 (s, 1H), 7.79 (d, 1H), 8.71 (m, H); MS (m/z): 456.97 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1>[Pd].C1COCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C=Cc1cccc(O)c1)c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(CCc1cccc(O)c1)c1ccccc1

Procedure:
The title compound was prepared as described in General Method 3 from 3-(3-hydroxy-phenyl)-1-phenyl-prop-2-en-1-one (8.0 g, 35.7 mmol), 5% Pd on BaSO4 (0.4 g), and THF (100 mL) at a reaction time of 2 hours. The crude product was purified by silica gel chromatography, eluting with EtOAc:hexane (10:90 to 25:75) to give the title compound, m.p. 81-83° C.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH:8]([C:11]([O:13]CC)=O)[C:6](=[O:7])[N:5]([CH3:16])[C:3]1=[O:4].[F:17][C:18]([F:34])([F:33])[C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)=[N:23][CH:24]=1.C(O)C>C1(C)C=CC=CC=1>[CH3:16][N:5]1[C:6](=[O:7])[CH:8]([C:11](=[O:13])[NH:30][C:29]2[CH:31]=[CH:32][C:26]([O:25][C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:34])([F:17])[F:33])=[CH:24][N:23]=3)=[CH:27][CH:28]=2)[C:9](=[O:10])[N:2]([CH3:1])[C:3]1=[O:4]
Reactant: Nc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CCOC(=O)C1C(=O)N(C)C(=O)N(C)C1=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN1C(=O)C(C(=O)Nc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)C(=O)N(C)C1=O

Procedure:
1.60 g (0.007 mol) of 1,3-dimethyl-5-ethoxycarbonylbarbituric acid and 1.78 g (0.007 mol) of 4-(5-trifluoromethylpyrid-2-yloxy)aniline are suspended in 20 ml of toluene. The suspension is heated to reflux for 16 hours, during which time ethanol escapes. After cooling, the precipitate is isolated by filtration, washed with toluene and dried, affording 1,3-dimethyl-5-[4-(5-trifluoromethylpyrid-2-yloxy)phenylcarbamoyl]barbituric acid of the formula ##STR24## with a melting point of 180°-181° C.
Reaction SMILES: CC[N:3](C(C)C)C(C)C.[I:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13](Cl)=[O:14]>C(Cl)Cl>[I:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13]([NH2:3])=[O:14]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1I
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC(=O)c1cc([N+](=O)[O-])ccc1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The deprotected Rink amide polymer is suspended in 20 ml of DCM and 2.00 g (1.55 mmol, 2 equivalents) of DIEA, and then 1.93 g (6.18 mmol, 2 equivalents) of 2-iodo-5-nitrobenzoyl chloride (Example 2A) are added. The mixture is shaken at room temperature overnight. This is followed by washing three times each with DMF, methanol and DCM. The resulting polymer 1 is dried in vacuo.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:29](O)=[O:30])[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH:32][N:33]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.NO>CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:29]([NH:33][OH:32])=[O:30])[CH2:16][CH2:17][N:18]([C:21]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])[CH2:19][CH2:20]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C(=O)c3cccnc3)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)NO)CCN(C(=O)c3cccnc3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(3-pyridinylcarbonyl)-4-piperidinecarboxamide was prepared following the procedure Example 64 (step 6). Starting from 4-(4-But-2-ynyloxybenzenesulfonyl)-1-(3-pyridinylcarbonyl)-4-piperidinecarboxylic acid (195 mg, 0.44 mmol) in dimethylformamide (4 ml), 1-hydroxybenzotriazole(72 mg, 0.53 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(119 mg, 0.62 mmol), N-methylmorpholine (0.072 ml, 0.66 mmol), and hydroxylamine (0.135 ml, 2.2 mmol), 65 mg (32%) of the product was isolated as a solid. HR-MS: m/z Calculated for C22H23N3O6S 458.1380; Found 458.1373.
Reaction SMILES: C[C:2]([CH3:4])=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.OCCCCCC[CH2:21][CH:22]1[CH:26]([OH:27])[CH:25]([CH3:28])[CH:24]([CH:29]=[CH:30][C:31](=[O:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:23]1.[OH2:38]>CC(C)=O.[Cr]>[CH3:21][CH:22]1[CH2:23][CH:24]([CH:29]=[CH:30][C:31](=[O:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:25]([CH2:28][CH2:21][CH2:22][CH2:23][CH2:24][CH2:4][C:2]([OH:38])=[O:3])[C:26]1=[O:27]
Reactant: CCCCCC(=O)C=CC1CC(CCCCCCCO)C(O)C1C
Reactant: O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: [Cr]
Agent: O=S(=O)(O)O
Product: CCCCCC(=O)C=CC1CC(C)C(=O)C1CCCCCCC(=O)O
Reaction time: 1 h
Yield: 19 %

Procedure:
8N Jones' reagent (11.6ml.) was added to a stirred solution of a mixture of 2-(7-hydroxyhoptyl)-5-methyl-3-(3-oxo-1-octenyl)cyclopentanol and 5-(7-hydroxyheptyl)-2-methyl-3-(3-oxo-1-octenyl)cyclopentanol (5.2 g., 0.0154 mole) in acetone (35 ml.) at 15°-25°C., at a rate such that the deep red coloration caused by the addition of one drop of reagent had changed to green before addition of the next drop. The reaction mixture was diluted with sufficient water to dissolve the precipitated chromium salts, and was then extracted three times with diethyl ether. The combined ether extracts were washed with 2N aqueous sulphuric acid and then added to 10% aqueous sodium carbonate (200 ml.) and stirred for 1 hour. The aqueous layer (containing the desired acid as the sodium salt) was separated and washed with diethyl ether. The solution was then covered with a layer of diethyl ether cooled to below 20°C. and acidified to pH 1 by the dropwise addition of concentrated hydrochloric acid. The ether layer was separated and the aqueous layer was again extracted with diethyl ether. The combined extracts were dried over magnesium sulphate, and the ether was removed in vacuo to give the crude acid (3.45 g.). This was purified by preparative thin layer chromatography on silica gel using a 65:15:1 mixture of benzene, dioxane and acetic acid as solvent. Evaporation gave pure 7-[3-methyl-2-oxo-5-(3-oxo-1-octenyl)cyclopentyl]heptanoic acid (1.03 g., 19%) λmax 228 mμ, ε 12,100 (ethanol), νmax 1730 cm-1, 1700 cm-1, 1670 cm-1 and 1625 cm-1 (liquid film). N.M.R. (approximately 10% solution in deuterochloroform) 0.89 δ (triplet J=51/2c/s, terminal CH3), 1.06 and 1.11 δ (two doublets J=6c/s, ring methyl), 1.35 δ (multiplet, chain CH2), ~2.1 δ (multiplet, CH--C=C), 2-2.7 δ (multiplet, CH2CO), 6.17 and 6.75 δ (doublet J=16c/s and doublet of doublets J=16c/s and 8c/s, CH=CHCO), 10.22 δ (singlet COOH). (Found: C, 72.3; H, 9.8. C21H34O4 requires C, 72.0; H, 9.8%).
Reaction SMILES: [CH:1]([C:3]([CH3:14])([CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)=O.[CH3:15][O:16][C:17]([CH2:19]P(=O)(OCC)OCC)=[O:18]>>[CH3:15][O:16][C:17](/[CH:19]=[CH:1]/[C:3]([CH3:14])([CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)=[O:18]
Reactant: CC(C)(C=O)CCCCn1ccnc1
Reactant: CCOP(=O)(CC(=O)OC)OCC
Product: COC(=O)/C=C/C(C)(C)CCCCn1ccnc1

Procedure:
By the proceeding as described in Example 1 but utilizing 1-(5-formyl-5-methylhexyl)imidazole and diethyl methoxycarbonylmethylphosphonate, there was obtained the title compound having the following physical characteristic in 66% yields:
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:10]([C:11](=[O:14])[CH2:12]Br)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([OH:22])(=[O:21])[CH2:18][CH2:19][CH3:20]>>[C:17]([O:22][CH2:12][C:11]([C:10]1[CH:15]=[CH:16][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][CH:9]=1)=[O:14])(=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: O=C(CBr)c1ccc(-c2ccccc2)cc1
Reactant: CCCC(=O)O
Product: CCCC(=O)OCC(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the procedure of Example 1, 5 grams of 4-phenylphenacyl bromide are reacted with 5 grams of butyric acid to obtain 4-phenylphenacyl butyrate, m.p. 82° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)[CH3:2].[Cl:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][NH2:21])[CH:16]=[CH:17][CH:18]=1.[BH4-].[Na+]>C(O)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][NH:21][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: NCCc1cccc(Cl)c1
Reactant: CCOc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cccc(CNCCc2cccc(Cl)c2)c1
Reaction time: 15 h

Procedure:
Combine 3-ethoxybenzaldehyde (3.38 g, 22.5 mmol), 2-(3-chlorophenyl)ethylamine (2.33 g, 15.0 mol), and 3 Å molecular sieves (2.88 g) in ethanol (230 ml). Stir the reaction mixture at reflux for 4 hours. Filter to remove the molecular sieves and then slowly add sodium borohydride (1.70 g, 45.0 mmol) to the filtrate and stir at ambient temperature. After 15 hours, concentrate the reaction mixture to a residue, dissolve the residue in 1N NaOH, and extract with dichloromethane. Combine organic extracts, wash with brine, dry over Na2SO4, and concentrate to a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give the title compound. The HCl salt was prepared in ethyl acetate to give the title compound: mp 178–180° C.; MS (ACPI): m/e 290.1 (M+1); Analysis for C17H21Cl2NO: Calcd: C, 62.58; H, 6.49; N, 4.29; Found: C, 62.65; H, 6.53; N, 4.32.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[Mg].[CH:13]1([C:16](=[O:24])[CH2:17][CH2:18][N:19]([CH3:23])[C:20](=[O:22])[CH3:21])[CH2:15][CH2:14]1.[Cl-].[NH4+]>O.CCOCC.CC(=O)C>[CH:13]1([C:16]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=2)([OH:24])[CH2:17][CH2:18][N:19]([CH3:23])[C:20](=[O:22])[CH3:21])[CH2:15][CH2:14]1
Reactant: CC(=O)N(C)CCC(=O)C1CC1
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)N(C)CCC(O)(c1cccc(C(F)(F)F)c1)C1CC1
Temperature: 25 °C

Procedure:
An ether solution of a Grignard reagent prepared from 50.0 g. (0.35 mole) of 3-bromobenzotrifluoride, 400 ml. of ether and 8.6 g. (0.354 mole) of magnesium was treated at -20°C. to -30°C. with 12.5 g. (0.059 mole) of crude 1-cyclopropyl-3-(N-methyl-acetamido)-1-propanone (calculated to contain 80% of the propanone by the nuclear magnetic resonance spectrum) in 100 ml. of ether. The reaction mixture was warmed to room temperature and treated with 7.4 g. (0.14 mole) ammonium chloride followed by 20 ml. of water. The ether layer was separated, concentrated to a dark oil and distilled under reduced pressure. The yield was 6.2 g.; b.p. 110°-114°C./0.1 mm.
Reaction SMILES: C(O[N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]C)=[O:21])=[C:15]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:14]=2)[CH2:8][C:7]1=C=O)(C)(C)C.[OH-:32].[Na+].[CH3:34][OH:35]>>[C:16]([O:32][C:34]([N:6]1[CH2:7][CH2:8][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[C:15]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:14]=2)[CH2:10][CH2:11]1)=[O:35])([CH3:19])([CH3:17])[CH3:15]
Reactant: CO
Reactant: COC(=O)Cc1ccc(OC2CCN(OC(C)(C)C)C(=C=O)C2)cc1OCC(F)(F)F
Reactant: [OH-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CC(=O)O)c(OCC(F)(F)F)c2)CC1
Temperature: 25 °C

Procedure:
To a stirred solution of methyl 4-(N-tert-butyloxy-carbonyl-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetate (3.0 g, MW=435, 6.90 mmol) from Step 7 above in MeOH (25 mL) was added a solution of aqueous NaOH (6.9 mL of a 2.0 N solution, 13.8 mmol). The mixture was refluxed for 3 h and then cooled to ambient temperature. The solvents were removed under reduced pressure and the residue was partitioned between EtOAc (100 mL) and 0.25 M aqueous citric acid (75 mL). The organic phase was separated and washed with H2O (25 mL) and brine (25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. 4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetic acid was obtained as an amorphous solid (HPLC retention time=9.4 min (method A)).
Reaction SMILES: C([C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][N:10]([CH3:24])[S:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:5][CH2:4]1)=O.C1(P(=[CH:44][C:45]([O:47][CH3:48])=[O:46])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:49]1(C)C=CC=CC=1>>[CH3:48][O:47][C:45](=[O:46])[CH:44]=[CH:49][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][N:10]([CH3:24])[S:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)(=[O:13])=[O:12])[CH2:5][CH2:4]1
Reactant: CN(C[C@H]1CC[C@H](C=O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1
Product: COC(=O)C=C[C@H]1CC[C@H](CN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Yield: 91 %

Procedure:
2 g (5.5 mmol) of trans-N-(4-formyl-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide and 2.2 g (6.6 mmol, 1.2 eq) of methyl (triphenyl-phosphoranylidene)acetate in 25 mL of toluene were stirred at 90° C. for 1 h. The solution was concentrated and chromatographed on silicagel with CH2Cl2:Et2O 95:5 as eluent, giving 2.09 g (91%) of trans-3-(4-{[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-methyl}-cyclohexyl)-acrylic acid methyl ester as an off white solid which was a mixture of E and Z isomers (98:2), MS: 437 (M+NH4+).
Reaction SMILES: O[CH2:2][C:3]1[CH:15]=[C:14]([I:16])[CH:13]=[CH:12][C:4]=1[O:5][C:6]([CH3:11])(C)[C:7](=[O:9])[CH3:8].[BrH:17].[C:18]1([P:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[Br-:17].[CH3:11][CH:6]([O:5][C:4]1[CH:12]=[CH:13][C:14]([I:16])=[CH:15][C:3]=1[CH2:2][P+:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:7](=[O:9])[CH3:8]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)C(C)(C)Oc1ccc(I)cc1CO
Reactant: Br
Solvent: CC#N
Product: CC(=O)C(C)Oc1ccc(I)cc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 90 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
A mixture containing crude 3-(2-hydroxymethyl-4-iodophenoxy)-3-methyl-2-butanone (0.84 g, 0.00252 mol) and triphenylphosphine hydrobromide (0.86 g, 0.00252 mol) in acetonitrile (5 ml) was heated at 90° C. for 2.5 hours. After evaporation of the solvent, the crude solid product was washed with ether and dissolved in ethanol (3 ml). Hot isopropyl ether (8 ml) was added until a light precipitate formed, and the solution was left at room temperature overnight. The crystalline product was recovered by filtration to yield 0.77 g (50%) of 2-(1-methyl-2-oxo-propyloxy)-5-iodobenzyltriphenylphosphonium bromide, m.p. 230° C.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][N:41]5[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCN1CCN(C)CC1
Temperature: 60 °C
Yield: 8.3 %

Procedure:
To a solution of 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea from Example 35B (225 mg, 0.439 mmol) in DMF (3 mL) was added N-methyl piperazine (0.146 mL, 1.317 mmol) followed by diisopropyl ethylamine (0.229 mL, 1.317 mmol) and tetrabutyl ammonium iodide (162.15 mg, 0.439 mmol). The reaction mixture was heated at 60° C. for 2 days. Formation of the product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (phenomenex phenylhexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4-yloxy)phenyl)urea (21 mg, 8%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.32 (s, 1H), 8.55 (s, 1H), 7.55 (d, 2H), 7.40 (m, 2H), 7.25 (s, 1H), 6.98 (m, 1H), 6.48 (s, 1H), 4.30 (m, 2H), 4.00 (s, 3H), 2.82-2.25 (m, 10H), 2.15 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 576 (M+H)+.
Reaction SMILES: [NH2:1]/[C:2](/[CH:9]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][N:10]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:29](=O)[C:30]#[CH:31]>C1(C)C=CC=CC=1>[C:25]([O:24][C:22]([N:10]1[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:14][CH:9]1[C:2]1[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:31][CH:30]=[CH:29][N:1]=1)=[O:23])([CH3:27])([CH3:26])[CH3:28]
Reactant: C#CC=O
Reactant: CCOC(=O)/C=C(\N)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccnc1C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of bis(1,1-Dimethylethyl) 2-[(1Z)-1-amino-3-(ethyloxy)-3-oxo-1-propen-1-yl]-1,4-piperazinedicarboxylate (may be prepared as described in Intermediate 4; 500 mg) in toluene (100 mL), propiolaldehyde (1.0 eq) was added at room temperature. After completion of addition, the reaction mixture was stirred for 2 h at room temperature and then heated to 90° C. Completion of reaction was followed by TLC. TLC showed disappearance of starting material in 5 h. Toluene was removed by vacuo then the residue was diluted with ethyl acetate (100 mL) and washed with water (2×50 mL) followed by brine solution (50 mL) and dried over anhydrous sodium sulphate, concentrated under vacuum to get 600 mg of crude product. The crude product was purified by column chromatography over 100-200 mesh silica gel by using 10%-30% ethyl acetate in pet ether as solvent, which yielded the title compound (200 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH3:10][O:11][C:12]1[CH:32]=[CH:31][C:15]([C:16]([NH:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]=2[C:28](O)=[O:29])=[O:17])=[CH:14][CH:13]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]=2[C:28]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:29])=[O:17])=[CH:31][CH:32]=1
Reactant: COc1ccc(C(=O)Nc2c(C(=O)O)[nH]c3ccccc23)cc1
Reactant: COc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2[nH]c3ccccc3c2NC(=O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 14.2 %

Procedure:
To a solution p-anisidine (79 mg, 0.645 mmol) in methylene chloride (5 mL) was added 3-(4-methoxybenzoyl)amino-2-indolecarboxylic acid (200 mg, 0.645 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (247 mg, 1.29 mmol), and 4-dimethylaminopyridine (8.0 mg, 0.065 mmol). The resulting solution was stirred at room temperature for 6 h. The resulting precipitate was collected via vacuum filtration to provide 38 mg (14%) of the title compound as a white solid.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:25])([CH3:24])[C:8]1[CH:9]=[C:10]([C:14]2[N:22]3[C:17]([CH:18]=[N:19][C:20](O)=[N:21]3)=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[N:26]1[C:30]2[CH:31]=[CH:32][C:33]([NH2:35])=[CH:34][C:29]=2[NH:28][CH:27]=1>>[N:26]1[C:30]2[CH:31]=[CH:32][C:33]([NH:35][C:20]3[N:19]=[CH:18][C:17]4=[CH:16][CH:15]=[C:14]([C:10]5[CH:11]=[CH:12][CH:13]=[C:8]([C:7]([CH3:25])([CH3:24])[O:6][SiH2:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=5)[N:22]4[N:21]=3)=[CH:34][C:29]=2[NH:28][CH:27]=1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cccc(-c2ccc3cnc(O)nn23)c1
Product: CC(C)(C)[SiH2]OC(C)(C)c1cccc(-c2ccc3cnc(Nc4ccc5nc[nH]c5c4)nn23)c1

Procedure:
(3H-Benzoimidazol-5-yl)-{7-[3-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-yl}-amine was prepared from 7-[3-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 3H-benzimidazol-5-ylamine in an analogous manner to Example 1052a. Product isolated as an orange solid (129 mg, 81%). m.p.=70-75° C.; LCMS (m/e) 471 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.20-10.10 (m, 1H), 8.73 (s, 1H), 8.67-8.39 (m, 2H), 7.97 (s, 1H), 7.86-7.62 (m, 2H), 7.51-7.42 (m, 1H), 7.32 (d, 1H, J=7.5 Hz), 7.09-6.92 (m, 3H), 6.86 (d, 1H, J=4.7 Hz), 4.97 (s, 2H), 0.96 (s, 9H), 0.16 (s, 6H).
Reaction SMILES: [CH3:1][Si:2]([CH3:50])([CH3:49])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][N:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:21]=3)=[C:12]2[N:11]=[C:10]([CH:28]2[CH2:33][CH2:32][C:31]([CH2:39][OH:40])([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]2)[CH:9]=1.C1C(=O)N([Br:58])C(=O)C1>CC#N.C(Cl)Cl>[CH3:50][Si:2]([CH3:49])([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][N:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:21]=3)=[C:12]2[N:11]=[C:10]([CH:28]2[CH2:29][CH2:30][C:31]([CH2:39][OH:40])([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:32][CH2:33]2)[C:9]=1[Br:58]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1(CO)CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnn(-c5ccccc5)c4)c3n2)CC1
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)C1(CO)CCC(c2nc3c(-c4cnn(-c5ccccc5)c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a solution of ethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(hydroxymethyl)cyclohexanecarboxylate (200 mg, 0.277 mmol) in CH3CN/DCM (5/3 mL) was added NBS (54.3 mg, 0.305 mmol) and stirred at rt for 30 min. TLC showed complete conversion. All the volatiles were removed under reduced pressure and the residue was purified by a SiO2 column (0-35% EtOAc/Hexanes, Rf=0.7 in 50% EtOAc) to afford ethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(hydroxymethyl)cyclohexanecarboxylate as a pale yellow oil (201 mg).