Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:22]([OH:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.CO>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[OH:29])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Cl)c(Cl)c2)(C(O)c2ccccn2)CC1
Agent: Cl
Solvent: CO
Product: OC(c1ccccn1)C1(c2ccc(Cl)c(Cl)c2)CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 140C (390 mg, 0.866 mmol) in MeOH (2 mL) was added HCl/MeOH (2 M, 2 mL, 4 mmol) at room temperature. The reaction mixture was stirred at ambient temperature overnight. The solvent was removed in vacuo. The resulting residue was partitioned between EtOAc (20 mL) and saturated NaHCO3 (20 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated. Crude product was purified by Prep-HPLC (Column: Waters X-bridge ODS C18 21.2×250 mm, water (0.05% TFA): acetonitrile 45-85%) to give Example 140D. LCMS: 450[M+1]. 1H NMR (400 MHz, DMSO-d6): δ 12.81 (s, 1H), 7.76 (s, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.37-7.46 (m, 3H), 7.20 (d, J=16.0 Hz, 1H), 2.61 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:16])=[CH:8]1.[OH-].[Na+].CN([CH:22]=[O:23])C>O>[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:16])=[C:8]1[CH:22]=[O:23]
Reactant: CN(C)C=O
Reactant: Cc1cn(C)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1c(C=O)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a stirred solution of phosphorus oxychloride (7.0 mL, 75 mmole) in DMF (25 mL) was added dropwise a solution of 1,3-dimethylindole (12.0 g, 83 mmole) in dry DMF (6.0 mL). The reaction was stirred at RT for 2 hr then was poured onto ice. The mixture was basified with a solution of NaOH (13.2 g, 330 mmole) in H2O (44 mL), then was extracted with Et2O (2×50 mL). The combined organic layers were washed with brine, dried (MgSO4), and concentrated under vacuum. Flash chromatography on silica gel (10% ethyl acetate/hexanes) gave the title compound (13.03 g, 91%) as an off-white solid: LCMS (ES) m/e 174.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 10.16 (s, 1 H), 7.68 (d, J=8.1 Hz, 1 H), 7.42 (t, 1 H), 7.32 (d, J=8.5 Hz, 1 H), 7.15 (t, 1 H), 4.04 (s, 3 H), 2.63 (s, 3 H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([NH:23][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([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)[CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:2]1.C(N(CC)CC)C.[C:50](OC(=O)C)(=[O:52])[CH3:51]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([NH:23][C:24]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:12][N:13]([C:50](=[O:52])[CH3:51])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:2]1
Reactant: COc1ccccc1CNCC(Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1CN(CC(Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)=O
Reaction time: 4 h
Yield: 87 %

Procedure:
To a stirring solution of 3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)amino]-2-(N-triphenylmethylamino)propane (0.404 mole) in anhydrous tetrahydrofuran (1.2 liters) under a nitrogen atmosphere at 0° C. was added triethylamine (66.5 ml, 0.477 mole) and acetic anhydride (45.0 ml, 0.477 mole). After 4 hours, the mixture was concentrated on a rotary evaporator, redissolved in methylene chloride and ethyl acetate, washed with water (2×) and brine (2×), dried over anhydrous sodium sulfate, filtered, and concentrated to a solid on a rotary evaporator. The resulting solid was dissolved in chloroform and loaded onto silica gel 60 (230-400 mesh) and eluted with a 1:1 mixture of ethyl acetate and hexanes. The product was then crystallized from an ethyl acetate/hexanes mixture. The resulting product of 3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]-2-(N-triphenylmethylamino)propane was crystallized and isolated over three crops giving 208.97 grams (87% yield) of analytically pure material.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:12]([OH:18])[CH2:13][CH2:14][CH2:15][C:16]#[CH:17]>ClCCl.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([C:17]#[C:16][CH2:15][CH2:14][CH2:13][CH2:12][OH:18])[CH:3]=1
Reactant: C#CCCCCO
Reactant: Brc1cnc2ccccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCCCCC#Cc1cnc2ccccc2c1
Yield: 88.7 %

Procedure:
6-(3-Quinolinyl)-5-hexyn-1-ol was prepared in the manner described above in Example 105 starting with 15.0 g of 3-bromoquinoline, 8.5 g of 5-hexyn-1-ol, 1.05 g of bis(triphenylphosphine)palladium dichloride and 0.10 g of cuprous iodide in 115 ml of dichloromethane and 28.5 ml of triethylamine. The crude product was chromatographed on a preparative high pressure liquid chromatograph eluting with 2.5% methanol-dichloromethane to give 14.4 g (89%) of 6-(3-quinolinyl)-5-hexyn-1-ol as a colorless oil. A portion was purified further on a silica thick layer plate eluting with 10% methanol-dichloromethane and solidified on drying, mp 47°-48° C.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Br:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15]>CCOCC>[Br:11][C:12]1[CH:13]=[C:14]([NH:15][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCOCC
Product: O=C(Nc1cccc(Br)c1)Oc1ccccc1

Procedure:
A solution of 1.56 g. of phenyl chloroformate in 50 ml. of ether is added dropwise to a stirred solution of 3.44 g. of 3-bromoaniline in 35 ml. of ether and the mixture is stirred for one hour at room temperature and then filtered. The filtrate is evaporated and the residue is crystallized from hexane to yield phenyl N-(3-bromophenyl)carbamate, m.p. 88°-90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][NH:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36]>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][N:22]([C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1
Reactant: CC(C)C(=O)Cl
Reactant: Clc1ccc2c(c1Nc1ccnc3[nH]c4c(c13)CNCC4)OCO2
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)N1CCc2[nH]c3nccc(Nc4c(Cl)ccc5c4OCO5)c3c2C1
Temperature: 25 °C
Yield: 15.4 %

Procedure:
(5-Chloro-benzo[1,3]dioxol-4-yl)-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (75 mg, 0.22 mmol) and DIEA (0.11 mL, 0.66 mmol) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature. Isobutyryl chloride (0.03 mL, 0.26 mmol) was added dropwise, and the reaction was stirred for 1 h at room temperature. The reaction was concentrated. The crude material was dissolved in DMSO (3 mL) and filtered. The filtrate was purified directly via prep-LC-MS to provide 72 (14 mg, 15% yield) as a white fluffy solid. LC-MS (M+H=413, obsd.=413).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]([CH2:20][CH2:21][CH3:22])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=2)[CH2:4][C@H:3]1[O:23][CH3:24].[Cl:25][C:26]1[N:27]=[C:28]([C:33](O)=[O:34])[NH:29][C:30]=1[CH2:31][CH3:32].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[Cl:25][C:26]1[N:27]=[C:28]([C:33]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[O:9][C:10]([CH2:20][CH2:21][CH3:22])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=3)[CH2:4][C@H:3]2[O:23][CH3:24])=[O:34])[NH:29][C:30]=1[CH2:31][CH3:32]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OC)C2)oc1CCC
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)oc1CCC
Yield: 44.4 %

Procedure:
The same operation as in Example (106d) was performed using butyl cis(±)-2-(4-amino-3-methoxypiperidin-1-yl)-5-propyl-1,3-oxazole-4-carboxylate obtained in Example (116c) (0.69 g, 2.0 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 0.2 g, 1 mmol), WSC hydrochloride (0.5 g, 2.5 mmol), HOBt (0.2 g, 1.5 mmol), DMA (3 mL) and dichloromethane (3 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 3/2, 4/1) to obtain 0.22 g of the title compound as a colorless solid (44%).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[C:20]([CH2:21][OH:22])[C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5]>C(Cl)Cl.CO.O=[Mn]=O>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[C:20]([CH:21]=[O:22])[C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5]
Reactant: O=C(Nc1c[nH]nc1-c1nc2c(CO)cccc2[nH]1)c1c(F)cccc1F
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CO
Product: O=Cc1cccc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.1 %

Procedure:
A mixture of 2,6-difluoro-N-[3-(4-hydroxymethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (200 mg, 0.54 mmol) and MnO2 (500 mg) in CH2Cl2/MeOH (5:1, 12 ml) was stirred at ambient temperature for 18 h, then filtered through Celite and reduced in vacuo. The residue was purified by flash column chromatography [SiO2, EtOAc-hexane (1:3, 1:2)] to give 2,6-difluoro-N-[3-(4-formyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (30 mg) as a cream solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>CC(C)=O>[Cl:21][CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCCCCl)cc1
Temperature: 65 °C
Yield: 99 %

Procedure:
A mixture of 1-(4-hydroxyphenyl)ethanone (20.4 g, 150 mmol), K2CO3 (62.1 g, 3.0 eq.), and 3-bromo-1-chloropropane (29.6 mL, 2.0 eq.) in CH3COCH3 (200 mL) was heated to 65° C. overnight. The mixture was filtered, washed with acetone, and concentrated to dryness. The crude product was dissolved in 150 mL of CH2Cl2, and washed with saturated NaHCO3, NaCl solution and dried over Na2SO4. Concentration to dryness under vacuum afforded product (31.5 g, 99% yield): MS m/z 213 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>C(Cl)Cl>[C:21]([O:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1)(=[O:25])[C:22]([CH3:24])=[CH2:23]
Reactant: CCS(=O)(=O)Nc1cccc(O)c1
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Oc1cccc(NS(=O)(=O)CC)c1
Yield: 82.5 %

Procedure:
To 20.0 g (0.099 mol) of N-(3-hydroxyphenyl)ethanesulfonamide, 10.06 g (0.099 mol) of triethylamine and 150 ml of methylene chloride cooled to 0° C., was added a solution of 10.39 g (0.099 mol) of methacryloyl chloride in 100 ml of methylene chloride, dropwise. Stirring was continued at reduced temperature for 4 hours, after which the solution was washed once with 2 percent hydrochloric acid, twice with water and dried over magnesium sulfate. Concentration of the solution in vacuo gave 22.0 g (82.5 percent yield) of non-crystallizable oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:27][NH:28][S:29]([CH2:32][CH2:33]OS(C)(=O)=O)(=[O:31])=[O:30])[CH2:4][O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[I-:39].[Na+]>CC(C)=O>[I:39][CH2:33][CH2:32][S:29]([NH:28][CH2:27][CH:3]([O:2][CH3:1])[CH2:4][O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:31])=[O:30]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCOS(C)(=O)=O)OC
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCI)OC
Reaction time: 5 h
Yield: 89.2 %

Procedure:
To a solution of 200 mg (0.341 mM) of 2-methoxy-1-octadecylcarbamoyloxy-3-(2-methanesulfonyloxyethylsulfonylamino)propane VIa4' in 5 ml of acetone is added 200 mg (1.33 mM) of sodium iodide and the mixture is refluxed with stirring for 5 hours. After the solvent is evaporated, the residue is purified by the column chromatography on silica gel with a n-hexane-ethyl acetate (2:1) mixture as an eluent to give 188 mg (0.296 mM) of 3-(2-iodoethylsulfonylamino)-2-methoxy-1-octadecylcarbamoyloxypropane IIa4 in 87% yield.
Reaction SMILES: [S:1]1[C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=[CH:2]1.[C:16](Cl)(=[O:20])[CH2:17][CH2:18][CH3:19].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[C:16]([C:2]1[S:1][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1)(=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: O=C1Nc2ccccc2Oc2sccc21
Reactant: CCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCC(=O)c1cc2c(s1)Oc1ccccc1NC2=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 60.5 %

Procedure:
Thieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.5 g) was suspended in 1,2-dichloroethane (20 ml) and butyryl chloride (880 mg) was added. To this reaction system was added portionwise aluminium chloride (4.6 g) under ice-cooling. The mixture was stirred at room temperature for 45 minutes. Insoluble matter was filtrated and the filtrate was poured into ice water, and chloroform was added. The organic layer was washed with water and dried over sodium sulfate. The solvent was evaporated under reduced pressure and water-ethanol was added. The precipitated crystals were collected by filtration. The obtained crystals were washed with chloroform-diisopropyl ether to give 2-butyrylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.2 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[CH2:15][N:14]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[OH:33])[N:17]=2)[CH2:13][CH2:12][N:11]1C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@@H:10]1[NH:11][CH2:12][CH2:13][N:14]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[OH:33])[N:17]=2)[CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(N3CCN(C(=O)OC(C)(C)C)[C@@H](COCc4ccccc4)C3)nc(-c3ccccc3O)nc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(N3CCN[C@@H](COCc4ccccc4)C3)nc(-c3ccccc3O)nc2c1
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a solution of (R)-tert-butyl 2-((benzyloxy)methyl)-4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate (760 mg, 1.72 mmol) in 15 mL CH2Cl2 was added 10 mL of TFA. The reaction was stirred for 1 hour. TFA was removed under vacuum and the reaction was neutralized using a 1 M NaOH solution. The aqueous layer was extracted twice with CH2Cl2, dried over Na2SO4, filtered, and concentrated to obtain 2-(4-((R)-3-((benzyloxy)methyl)piperazin-1-yl)-7-methylquinazolin-2-yl)phenol (570 mg, 92%). This material was used in the next step without further purification. LC/MS: m/z 441.5 (M+H)+ at 2.44 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:31]=[C:32]=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:25]=[C:26]([NH:31][C:32]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(Cl)c(Cl)c4)cc3)c2cc1OC
Yield: 85.2 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (51 mg) was dissolved in toluene (5 ml) with heat, 3,4-dichlorophenyl isocyanate (102 mg) was added, and the admixture was refluxed with heat for 8 minutes. The separated crystals were filtered and then washed with toluene to obtain 71 mg of the title compound (yield: 84%).
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.ON1C2C=CC=CC=2N=N1.N=C=N.C(N(CC)C(C)C)(C)C.[CH3:51][O:52][CH2:53][CH2:54][O:55][CH2:56][C:57](O)=[O:58]>CN(C)C=O>[S:4]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][N:26]([C:57](=[O:58])[CH2:56][O:55][CH2:54][CH2:53][O:52][CH3:51])[CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1
Reactant: C1=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CCNC1
Reactant: COCCOCC(=O)O
Agent: Cl
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCOCC(=O)N1CC=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a suspension of benzothiazol-6-yl-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine tris-hydrochloride (138.0 mg, 0.2984 mmol), 1-hydroxybenzotriazole (40.8 mg, 0.302 mmol), and PS-Carbodiimide (1.37 mmol/g loading; 873 mg, 1.20 mmol) in anhydrous N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (260 μL, 1.5 mmol) was added. A small amount of sonication was used to get majority of solid into solution. 2-(2-Methoxyethoxy)acetic acid (45.7 mg, 0.334 mmol) in anhydrous DMF (1 mL) was added, and the reaction was vigorously shaken at rt for 5.5 h. An additional 0.2 eq of 2-(2-methoxyethoxy)acetic acid (8.1 mg, 0.060 mmol) in anhydrous N,N-dimethylformamide (0.5 mL) was added (after 7 h), and the reaction was shaken overnight at rt. The resin was filtered off (M-size frit) and rinsed several times with DMF. The filtrate was concentrated in vacuo at medium temp (bath temp: max 43° C.), redissolved in MeOH and DCM, and concentrated again under reduced pressure. The crude material was adsorbed onto Hydromatrix, dry loaded, and purified by chromatography on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with MeOH:DCM 2%→5%→10%]. Fractions containing product were combined and concentrated in vacuo, affording the title compound, as an off-white solid. The material was further purified by trituration in MeOH/sonication, affording the title compound, as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ=2.36-2.56 (s, br, rotamers, 2H), 3.19 (s, 3H), 2.38-2.45 (m, 2H), 3.49-3.55 (m, 2H), 3.58 & 3.64 (t, J=5.2 Hz, rotamers, 2H), 4.08 & 4.10 (s, br, rotamers, 2H), 4.14 & 4.18 (s, rotamers, 2H), 6.37 (s, br, 1H), 6.77 & 6.78 (s, rotamers, 1H), 7.80 (dd, J=8.8, 2.0 Hz, 1H), 7.97 (d, J=8.8 Hz, 1H), 8.28 (s, 1H), 8.85 (s, 1H), 9.17 (s, 1H), 9.54 (s, —NH), 11.95 (d, J=9.2 Hz, —NH). MS (ES+): m/z 465.01 (100) [MH+]. HPLC: tR=2.24 min (ZQ2000, polar—5 min).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[CH:17][N:18]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].[B:30](OC(C)C)([O:35]C(C)C)[O:31]C(C)C.Cl>C1COCC1>[C:26]([O:25][C:23]([N:18]1[C:19]2[C:15](=[C:14]([F:13])[CH:22]=[CH:21][CH:20]=2)[CH:16]=[C:17]1[B:30]([OH:35])[OH:31])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)OC(=O)n1ccc2c(F)cccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)n1c(B(O)O)cc2c(F)cccc21
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 76.7 %

Procedure:
To a solution of diisopropylamine (7.5 mL, 0.11 mol) in THF (35 mL) at 0° C. was added n-BuLi (21 mL, 0.055 mol) dropwise. The mixture was stirred at 0° C. for 40 minutes. Then the mixture was cooled to −78° C. Tert-butyl 4-fluoro-1H-indole-1-carboxylate (5 g, 0.02 mol) in THF (13 mL) was added dropwise slowly. After addition, the mixture was stirred at −78° C. for 2 hours. Then triisopropyl borate (3.29 g, 0.03 mol) was added. The mixture was stirred at −78° C. for another 40 minutes. The reaction was monitored using TLC. When the reaction was completed, the mixture was adjusted to pH=6 with 1 N HCl. After extracted with EtOAc (25 mL×3), the combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The obtained solid was recrystallized with EtOAc and petroleum ether to provide (1-(tert-butoxycarbonyl)-4-fluoro-1H-indol-2-yl)boronic acid (4.5 g, yield: 76.7%, which might be unstable at high temp. work up, store in fridge). 1H-NMR (CDCl3, 400 MHz) δ 7.77 (d, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.44 (s, 2H), 7.24 (m, 1H), 6.90 (m, 1H), 1.66 (s, 9H). MS (M+H)+: 280.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([BH3-])#N.[Na+]>>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:1][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([O:9][CH3:10])=[O:8])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)c1sccc1N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COC(=O)c1sccc1NC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
3-Amino-2-methoxycarbonylthiophene is reductively alkylated with 1-tert-butyloxycarbonylpiperidin-4-one and sodium cyanoborohydride to give 3-(1-tert-butyloxycarbonylpiperidin-4-ylamino)-2-methoxycarbonylthiophene.
Reaction SMILES: [C:1]1([C:7](=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N:21]([Si](C)(C)C)[C:22]1[CH:27]=[CH:26][NH:25][C:24](=[O:28])[N:23]=1)(C)C>C1C=CC=CC=1>[C:1]1([C:7](=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][N:25]2[CH:26]=[CH:27][C:22]([NH2:21])=[N:23][C:24]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)N(c1cc[nH]c(=O)n1)[Si](C)(C)C
Reactant: ClCC(=Cc1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: Nc1ccn(CC(=Cc2ccccc2)c2ccccc2)c(=O)n1

Procedure:
A solution of 10 parts of 2,3-diphenylallyl chloride in 43.9 parts of benzene is treated with 20 parts of bis-trimethylsilylcytosine under a nitrogen atmosphere and then the reaction container is sealed and maintained at a temperature of 65° for 120 hours. The solid which forms is collected by filtration, washed with benzene and recrystallized from a 1:1 acetic acid-water mixture to yield 1-(2,3 -diphenylallyl)-4-amino-2-oxo-1,2-dihydro-pyrimidine. That product displays nuclear magnetic resonance maxima at about 293, 405, 425, 437, 453 and 461 Hertz and is represented structurally by the following formula ##STR8##