Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[S:12][CH:13]=2)O1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].Br[C:43]1[CH:44]=[N:45][C:46]2[N:47]([N:49]=[CH:50][C:51]=2[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:48]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O1CCOCC1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl.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>[C:52]1([C:51]2[CH:50]=[N:49][N:47]3[CH:48]=[C:43]([C:9]4[CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[S:12][CH:13]=4)[CH:44]=[N:45][C:46]=23)[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: Brc1cnc2c(-c3ccccc3)cnn2c1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2cnc3c(-c4ccccc4)cnn3c2)cs1
Temperature: 80 °C

Procedure:
A mixture of methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (5-1, 3.00 g, 13.6 mmol, 1 equiv), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (3.80 g, 15.0 mmol, 1.10 equiv), potassium acetate (4.10 g, 41.8 mmol, 3.07 equiv), and 1,1′-bis(diphenylphophino)-ferrocene)dichloropalladium (360 mg, 0.44 mmol, 0.032 equiv) in DMF (50 mL) was heated at 80° C. for 4 hours. The reaction mixture was concentrated and the residue was partitioned between aqueous half-saturated sodium bicarbonate solution and ethyl acetate (150 mL). The organic layer was dried over sodium sulfate and concentrated. A solution of this residue, 6-bromo-3-phenylpyrazolo[1,5-a]pyrimidine (1-3, 1.90 g, 6.93 mmol, 0.510 equiv), and tetrakis(triphenylphosphine)palladium (400 mg, 0.350 mmol, 0.025 equiv) in a mixture of dioxane and aqueous sodium carbonate solution (2M, 7 mL, 14 mmol, 1.0 equiv) was heated at reflux for 20 hours. The reaction mixture was partitioned between aqueous saturated sodium bicarbonate solution and ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The residue was suspended in methanol and filtered to give methyl 4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)thiophene-2-carboxylate (5-2) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.86 (d, 1H, J=2.4 Hz), 8.80 (d, 1H, J=2.2 Hz), 8.46 (s, 1H), 8.07 (d, 1H, J=1.6 Hz), 8.05 (br d, 2H, J=7.8 Hz), 7.75 (d, 1H, J=1.6 Hz), 7.47 (br t, 2H, J=7.7 Hz), 7.30 (t, 1H, J=7.5 Hz), 3.95 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[C:7]([Cl:14])=[N:8][C:9]([Cl:13])=[N:10][C:11]=1Cl)[CH3:2].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>C(#N)C.CC(N(C)C)=O>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:11]2[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])=[C:7]([Cl:14])[N:8]=[C:9]([Cl:13])[N:10]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCOC(=O)Cc1c(Cl)nc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: CCOC(=O)Cc1c(Cl)nc(Cl)nc1NC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A solution of (2,4,6-trichloro-pyrimidin-5-yl)-acetic acid ethyl ester (1.00 g, 3.71 mmol, 1.0 equiv; commercially available from Tyger Scientific Inc, USA), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.26 g, 6.31 mmol, 1.7 equiv) and triethylamine (0.77 mL, 0.56 g, 5.57 mmol, 1.5 equiv) in acetonitrile (9 mL) and DMAc (2 mL) was heated by microwave irradiation to 120° C. for 30 min. The reaction mixture was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 0.87 g (54%) of the title compound. 1H NMR (400 MHz, DMSO): δ1.19 (t, J=8.0 Hz, 3H), 1.35-1.44 (m, 2H), 1.40 (s, 9H), 1.76-1.79 (m, 2H), 2.84 (br s, 2H), 3.73 (s, 2H), 3.93-3.96 (m, 2H), 4.11 (q, J=8.0 Hz, 2H), 4.08-4.13 (m, 1H), 7.52 (d, J=8.0 Hz, 1H). MS (ISP): 433.3 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:13]1[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=1)[C:11]#[N:12].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([O:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[N:14]=1)[C:11]#[N:12]
Reactant: N#CC(c1ccnc(Cl)n1)c1nc2ccccc2s1
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COc1ccc(Oc2nccc(C(C#N)c3nc4ccccc4s3)n2)cc1
Temperature: 100 °C
Reaction time: 192 h
Yield: 51.4 %

Procedure:
To a solution of 1 (0.300 g, 1.05 mmol) in DMSO (7 ml) were added 4-methoxyphenol (0.261 g, 2.1 mmol) and cesium carbonate (1.7 g, 5.25 mmol) and the suspension was shaken at 100° C. for 8 days. After cooling to r.t., the suspension was poured onto ice/water and the product was extracted with AcOEt. The organic phases were washed with water then brine, dried over MgSO4 and concentrated to dryness. The residue was triturated in hot EtOH then filtered off and dried under vacuum at 50° C. overnight, affording 202 mg (51%) of the title compound.
Reaction SMILES: C1(C)C=CC=CC=1.[O:8]=[C:9]1[CH2:14][CH2:13][CH:12]([CH:15]2[CH2:20][CH2:19][CH:18]([CH:21]=[O:22])[CH2:17][CH2:16]2)[CH2:11][CH2:10]1.[CH2:23]([CH:27]([CH2:30]O)[CH2:28][OH:29])[CH2:24][CH2:25][CH3:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[O:8]=[C:9]1[CH2:10][CH2:11][CH:12]([CH:15]2[CH2:20][CH2:19][CH:18]([CH:21]3[O:29][CH2:28][CH:27]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:30][O:22]3)[CH2:17][CH2:16]2)[CH2:13][CH2:14]1
Reactant: O=CC1CCC(C2CCC(=O)CC2)CC1
Reactant: CCCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCC1COC(C2CCC(C3CCC(=O)CC3)CC2)OC1
Yield: 10.2 %

Procedure:
To 300 ml of toluene were added 20.2 g (97.0 mmol) of the 4-(4-oxocyclohexyl)cyclohexanecarbaldehyde described above, 12.8 g (96.8 mmol) of 2-n-butyl-1,3-propanediol, and 1 g of p-toluenesulfonic acid, and the mixture was refluxed by using a Dean-Stark for 2 hours. Water in an amount of 200 ml was added to the reaction solution, the product thus formed was extracted with toluene, the extract was washed with saturated aqueous bicarbonate solution and water in this turn, and then the solvent was distilled off. After the residue was purified by column chromatography on silica gel (eluent: heptane/ethyl acetate=5/1), the solvent was distilled off. The residue was Silo recrystallized from ethanol to give 3.2 g (9.9 mmol) of 2-(4-(4-oxocyclohexyl)-cyclohexyl)-5-n-butyl-1,3-dioxane. Yield of this compound based on 4-(4-oxocyclohexyl)cyclohexanecarbaldehyde was 10%.
Reaction SMILES: C([N:8]([C@H:20]([CH2:34][OH:35])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][CH2:32][CH3:33])=[O:30])=[CH:24][CH:23]=1)[CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[CH2:32]([NH:31][C:29]([NH:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C@H:20]([NH:8][CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:34][OH:35])=[CH:27][CH:26]=1)=[O:30])[CH3:33]
Reactant: CCNC(=O)Nc1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CCNC(=O)Nc1ccc(C[C@@H](CO)NC[C@H](O)COc2ccccc2)cc1
Yield: 64.2 %

Procedure:
A solution of N-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]phenyl]-N′-ethylurea (73 mg) in methanol (1.5 ml) was hydrogenated (1 atm) over 10% palladium on carbon (11 mg) at room temperature for 12 hours. After the catalyst was filtered off, the filtrate was concentrated and the residue was purified by column chromatography (silica gel, chloroform/methanol) followed by recrystallization from ehtanol/hexane to give N-ethyl-N′-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]-propyl]phenyl]urea (38 mg) as a white powder.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH:15]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][N:21]=2)[CH2:16]1)(C)(C)C>ClCCl>[NH2:14][CH:15]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][N:21]=2)[CH2:16]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(C#N)cn2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(N2CCC(N)C2)nc1
Reaction time: 2 h
Yield: 101.1 %

Procedure:
Add trifluoroacetic acid (30 mL) to [1-(5-cyanopyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (7.95 g, 27.6 mmol) in dichloromethane (200 mL) and stir for 2 h. Concentrate, add toluene (100 mL) and reconcentrate to give a residue. Partition the residue between dichloromethane and an saturated aqueous solution of sodium bicarbonate and separate the layers. Extract the aqueous layer 5 times with 15:85 isopropyl alcohol:chloroform, combine the organic layers, dry (sodium sulfate), filter, and concentrate to give the title compound as a yellow oil (5.25 g). 1H NMR (400 MHz, CDCl3) δ 8.34 (d, 1H, J=2.5 Hz), 7.53-7.50 (m, 1H), 6.29 (d, 1H, J=8.8 Hz), 3.80-3.10 (m, 5H), 2.25-2.15 (m, 1H), 1.90-1.75 (m, 3H); MS (ES): m/z=189 [M+H]+.
Reaction SMILES: Cl.[Br:2][C:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:12]([OH:14])=O)[CH:11]=[C:6]2[NH:5][CH:4]=1.Cl.[C:16]([N:20]1[CH:33]=[C:32]2[C:22]([C:23](=[O:34])[CH2:24][C:25]3([CH2:31]2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:21]1)([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.C(OCC)(=O)C.CN(C)C=O>[Br:2][C:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:12]([N:28]3[CH2:27][CH2:26][C:25]4([CH2:24][C:23](=[O:34])[C:22]5[C:32](=[CH:33][N:20]([C:16]([CH3:19])([CH3:18])[CH3:17])[N:21]=5)[CH2:31]4)[CH2:30][CH2:29]3)=[O:14])[CH:11]=[C:6]2[NH:5][CH:4]=1
Reactant: O=C(O)c1cnc2c(Br)c[nH]c2c1
Reactant: CC(C)(C)n1cc2c(n1)C(=O)CC1(CCNCC1)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)n1cc2c(n1)C(=O)CC1(CCN(C(=O)c3cnc4c(Br)c[nH]c4c3)CC1)C2
Temperature: 25 °C
Reaction time: 60 h
Yield: 70.6 %

Procedure:
To a suspension of 3-bromo-1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid hydrochloride (2.75 g, 9.91 mmol) and 2-tert-butyl-4,6-dihydrospiro[indazole-5,4′-piperidin]-7(2H)-one hydrochloride salt (2.95 g, 9.91 mmol) in dichloromethane (30 mL) was added triethylamine (5.52 mL, 39.6 mmol). N,N-dimethylformamide (5 mL) was then added, followed by 1-hydroxybenzotriazole (1.61 g, 11.9 mmol) and 1, (3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (2.28 g, 11.9 mmol). The reaction was allowed to stir at room temperature for 60 hours. The reaction was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organics were dried over magnesium sulfate, filtered, and concentrated. Purification by flash column chromatography (0-10% methanol/ethyl acetate) gave the title compound (3.39 g, 71%) as a pale brown solid. +ESI (M+1+H) 486.2; 1H NMR (400 MHz, CDCl3, δ): 10.05 (br. s., 1 H), 8.57 (d, J=1.8 Hz, 1 H), 7.87 (d, J=1.8 Hz, 1 H), 7.61 (d, J=2.7 Hz, 1 H), 7.44 (s, 1 H), 3.78 (br. s., 2 H), 3.51 (br. s., 2 H), 2.81 (s, 2 H), 2.65 (s, 2 H), 1.63 (s, 13 H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[CH2:13]O)[CH2:2][CH:3]=[CH2:4].S(Cl)([Cl:17])=O>>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[CH2:13][Cl:17])[CH2:2][CH:3]=[CH2:4]
Reactant: O=S(Cl)Cl
Reactant: C=CCCOc1ccc(F)cc1CO
Product: C=CCCOc1ccc(F)cc1CCl
Temperature: 25 °C
Yield: 91 %

Procedure:
(2-(But-3-en-1-yloxy)-5-fluorophenyl)methanol (6.3 g, 32.1 mmol, 1 equiv) was taken up in thionyl chloride (107 mL) and heated to reflux for 1 h. Upon cooling to ambient temperature, the solution was concentrated in vacuo. The residue was concentrated in vacuo with benzene (×3) to remove residual thionyl chloride and provide the benzyl chloride (6.3 g, 91%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.12 (dd, J=8.7, 3.1 Hz, 1H), 6.98 (ddd, J=8.9, 8.0, 3.1 Hz, 1H), 6.82 (dd, J=9.0, 4.3 Hz, 1H), 5.93 (ddt, J=17.1, 10.3, 6.8 Hz, 1H), 5.25-5.09 (m, 2H), 4.62 (s, 2H), 4.05 (t, J=6.5 Hz, 2H), 2.58 (qt, J=6.6, 1.3 Hz, 2H).
Reaction SMILES: [CH2:1]([N:9]1[C:17]([CH2:18]Br)=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:20])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Na].[OH:22][CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27]>CN(C=O)C>[CH2:1]([N:9]1[C:17]([CH2:18][O:22][CH2:23][P:24]([O:28][CH2:29][CH3:30])([O:25][CH2:26][CH3:27])=[O:31])=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:20])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1ncnc2c1nc(CBr)n2CCc1ccccc1
Reactant: CCOP(=O)(CO)OCC
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOP(=O)(COCc1nc2c(N)ncnc2n1CCc1ccccc1)OCC

Procedure:
A solution of N9-phenethyl-8-bromomethyladenine (1 mmol) in DMF was treated with a solution of diethyl hydroxymethylphosphonate sodium salt (1 mmol) in DMF at 25° C. for 1 h. Extraction and chromatography gave N9-phenethyl-8-diethylphosphonomethoxymethyladenine as a white solid. TLC: Rf=0.31,10% MeOH—CH2Cl2.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:53]([CH3:56])[CH2:54][CH3:55])[C@H:26]([O:51][CH3:52])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:49][CH3:50])[C@@H:36]([CH3:48])[C:37](=[O:47])[NH:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12].O=[CH:58][CH2:59][CH2:60][C:61]([OH:63])=[O:62].C([BH3-])#N.[Na+]>>[C:61]([CH2:60][CH2:59][CH2:58][N:9]([CH3:8])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:53]([CH3:56])[CH2:54][CH3:55])[C@H:26]([O:51][CH3:52])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:49][CH3:50])[C@@H:36]([CH3:48])[C:37](=[O:47])[NH:38][CH2:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH:11]([CH3:13])[CH3:12])([OH:63])=[O:62]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Reactant: O=CCCC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C

Procedure:
The title compound was synthesized by analogy with the synthesis process of Example 1 by reacting 57 mg (71 μmol) N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-[(2-phenylethyl)amino]propyl}pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetic acid salt (intermediate 25) with a 15% aqueous solution of 4-oxobutanoic acid in the presence of sodium cyanoborohydride.
Reaction SMILES: CN(C)CCNC.C([Li])CCC.[CH:13]([Si:16]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[C:17]1[O:18][C:19]([CH:22]=[O:23])=[CH:20][N:21]=1)([CH3:15])[CH3:14].[Br:30]C(F)(F)C(F)(F)Br.[Cl-].[NH4+]>C(OCC)(=O)C.CCCCCC.C1COCC1>[Br:30][C:20]1[N:21]=[C:17]([Si:16]([CH:13]([CH3:15])[CH3:14])([CH:24]([CH3:26])[CH3:25])[CH:27]([CH3:29])[CH3:28])[O:18][C:19]=1[CH:22]=[O:23]
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: CC(C)[Si](c1ncc(C=O)o1)(C(C)C)C(C)C
Agent: CNCCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)[Si](c1nc(Br)c(C=O)o1)(C(C)C)C(C)C
Temperature: -20 °C
Reaction time: 3 h

Procedure:
To a mixture of N,N,N′-trimethylethylenediamine (2.86 g) and THF (80 mL) there were added dropwise a 2.6 M hexane solution of n-butyllithium (8.46 mL), and 2-triisopropylsilanyloxazole-5-carboaldehyde [CAS No. 869542-45-0] (5.08 g), in that order at −20° C. under a nitrogen atmosphere. After stirring the mixture at −20° C. for 3 hours, the 2.6 M hexane solution of n-butyllithium (8.46 mL) was again added dropwise, stirring was continued at −20° C. for 3 hours, and then the mixture was cooled to −75° C. and 1,2-dibromotetrafluoroethane (7.12 mL) was added. The mixture was returned to room temperature, and then ethyl acetate (300 mL) and an aqueous ammonium chloride solution (300 mL) were added. After sufficiently shaking the mixture, the organic layer was separated off and dried over anhydrous magnesium sulfate. The mixture was filtered to obtain a filtrate, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane mixture) to obtain the target compound (1.94 g) as a brown liquid.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4](C(OC)=O)[CH2:5][CH2:6][CH2:7][Si:8]([CH3:20])([CH3:19])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[K+]>CO>[CH3:20][Si:8]([CH3:19])([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:25])=[O:2]
Reactant: CCCCCCCCCC[Si](C)(C)CCCC(C(=O)OC)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCC[Si](C)(C)CCCCC(=O)O

Procedure:
A mixture of 6.7 g (18 mmole) of methyl-2-methoxycarbonyl-6,6-dimethyl-6-sila-n-hexadecanoate (from step C) in 50 ml of methanol and 3.0 g (about 48 mmole) of potassium hydroxide (powder) in 50 ml of methanol is refluxed for 45 min. The resulting mixture is then concentrated to a solid. Dilute hydrochloric acid (2N) is then added to the solid (in excess, to acid pH) and the mixture extracted with methylene chloride. The extract is dried, then concentrated to a residue. The residue is heated to 160°-170° under reduced pressure (approx. 15 mm Hg), for 1 hour, then distilled under high vacuum through a jacketed Vigreux column to obtain refined title product of this step (as the main fraction) at 145°-140° at 0.101-0.090 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:5]([Cl:16])=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=[O:19].[Na].[CH2:22](I)[CH3:23].O>CC1OC(C)=C(C)C=1C>[CH2:22]([O:19][C:18](=[O:20])[CH2:17][C:3]1[CH:4]=[C:5]([Cl:16])[CH:6]=[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:2]=1[NH2:1])[CH3:23]
Reactant: CCI
Reactant: Nc1c(CC(=O)O)cc(Cl)cc1C(=O)c1ccccc1
Agent: Cc1oc(C)c(C)c1C
Agent: [Na]
Solvent: O
Product: CCOC(=O)Cc1cc(Cl)cc(C(=O)c2ccccc2)c1N
Reaction time: 2 h

Procedure:
A solution of 3.12 g (0.1 mole) of 2-amino-3-benzoyl-5-chlorobenzeneacetic acid, sodium salt in 250 ml of dry tetramethylfuran was treated with 44 g of ethyl iodide (0.3 mole) under nitrogen and stirred for 2 hours. The resulting solution was then added to 1 liter of water and extracted several times with ethyl ether. The combined ether layers were washed with water, dried over sodium sulfate, filtered and stripped to yield a solid yellow residue. This material was recrystallized from absolute ethyl alcohol to give 1.5 g, yellow needles, m.p. 80°-82° C.
Reaction SMILES: NC1C=CC=CC=1C1C([C:14]([C:16]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH2:28])=[CH:20][CH:19]=[CH:18][N:17]=2)=O)=NC=CC=1.[NH2:29][C:30](N)=[O:31]>C(O)(=O)C>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:14][C:16]=1[C:21]1[C:22]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:28][C:30](=[O:31])[N:29]=1
Reactant: NC(N)=O
Reactant: Nc1ccccc1-c1cccnc1C(=O)c1ncccc1-c1ccccc1N
Solvent: CC(=O)O
Product: O=c1nc(-c2ccccn2)c2ccccc2[nH]1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
A solution of 2-aminophenyl-2-pyridyl ketone (0.95 g, 4.8 mmol), urea (500 mg, 8.3 mmol) and acetic acid (10 mL) was stirred at 110° C. for 18 h. The reaction mixture was cooled to rt and filtered. The solid was washed with water and dried under reduced pressure to give 4-(pyridin-2-yl)quinazolin-2(1H)-one as a yellow solid (0.83 g, 78%), which was dissolved in phosphorous oxychloride (3 mL) and the mixture was stirred at reflux for 30 min. The reaction mixture was cooled to rt and slowly poured over an ice/water mixture. The mixture was filtered and the solid was dried under reduced pressure to give 2-chloro-4-(pyridin-2-yl)quinazoline as an off-white solid (56 mg, 6%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[O:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=3)=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[OH-].[Li+]>>[N+:20]([C:16]1[CH:15]=[C:14]([C:11]2[O:12][C:13]3[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=[CH:8][C:9]=3[N:10]=2)[CH:19]=[CH:18][CH:17]=1)([O-:22])=[O:21]
Reactant: COC(=O)c1cccc2nc(-c3cccc([N+](=O)[O-])c3)oc12
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1cccc2nc(-c3cccc([N+](=O)[O-])c3)oc12

Procedure:
Prepared by the method of Example 76c), from 2-(3-nitrophenyl)benzoxazole-7-carboxylic acid methyl ester (600 mg, 2.01 mmol) and lithium hydroxide (240 mg, 10.06 mmol) the subtitle compound was obtained, (442 mg, 77%). The product was used directly in next step without purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[N:9]=[CH:8][CH:7]=[C:6]2[O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[O:31])=[C:25]([F:40])[CH:24]=1)#[N:2].O>CO>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[N:9]=[CH:8][CH:7]=[C:6]2[O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)=[O:31])=[C:25]([F:40])[CH:24]=1)#[N:2]
Reactant: CCOC(=O)CCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)c2cc1C#N
Solvent: O
Solvent: CO
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1OCCCC(=O)O
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 30.3 %

Procedure:
N-(4-(6-Cyano-7-(3-(ethoxycarbonyl)propoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(4-fluorophenyl)urea (800 mg) was dissolved in methanol (45 ml), 2N Noah water (15 ml) was added, and the mixture was heated and stirred for 40 minutes at 80° C. After completion of the reaction, the reaction solution was poured into ice water and neutralized with 1N Hal, and the precipitated solid was filtered out. The obtained solid was washed with water and dried to obtain 230 mg of the title compound.
Reaction SMILES: BrBr.[Br:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].P(Br)(Br)[Br:12]>>[Br:12][CH:7]([CH2:6][CH2:5][CH2:4][Br:3])[C:8]([OH:10])=[O:9]
Reactant: O=C(O)CCCCBr
Reactant: BrP(Br)Br
Agent: BrBr
Product: O=C(O)C(Br)CCCBr
Reaction time: 0.5 h

Procedure:
39 ml of bromine is added to a mixture of 106 g of 5-bromo pentanoic acid and 1 ml of phosphorus tribromide. The reaction mixture is taken to 70˜80° C. for 16 hours 30 minutes. The reaction medium is taken to 100° C. for 15 minutes, then allowed to return to ambient temperature. 147 g of sought product is obtained.