Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[F:43][C:44]1[CH:52]=[C:51]2[C:47]([C:48](=[CH:54][C:55]3[NH:56][CH:57]=[C:58]([CH2:60][N:61]4[CH2:66][CH2:65][O:64][CH2:63][CH2:62]4)[CH:59]=3)[C:49](=[O:53])[NH:50]2)=[CH:46][C:45]=1[CH2:67]O.N(C(OC(C)(C)C)=O)=NC([O-])=O>C1COCC1.CC#N>[F:43][C:44]1[CH:52]=[C:51]2[C:47]([C:48](=[CH:54][C:55]3[NH:56][CH:57]=[C:58]([CH2:60][N:61]4[CH2:62][CH2:63][O:64][CH2:65][CH2:66]4)[CH:59]=3)[C:49](=[O:53])[NH:50]2)=[CH:46][C:45]=1[CH2:67][N:3]1[C:4](=[O:6])[CH2:5][S:1][C:2]1=[O:7]
Reactant: O=C1CSC(=O)N1
Reactant: O=C1Nc2cc(F)c(CO)cc2C1=Cc1cc(CN2CCOCC2)c[nH]1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC#N
Product: O=C1Nc2cc(F)c(CN3C(=O)CSC3=O)cc2C1=Cc1cc(CN2CCOCC2)c[nH]1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Thiazolidine-2,4-dione (0.350 mmol) and triphenylphosphine on resin (1.66 mmol/g, 0.415 mmol) are stirred for 10 min. at ambient temperature in anhydrous THF (9 ml) under nitrogen. The mixture is cooled in an ice bath and di-tert-butyl azodicarboxylate (0.369 mmol) is added all at once. The mixture is stirred at 0° C. for 10 min, and then the compound obtained in Step D (0.238 mmol) is added all at once. The mixture is stirred at 0° C. for 1.5 hours, and then thiazolidine-2,4-dione (0.350 mmol), three portions of triphenylphosphine on resin (1.66 mmol/g; 0.166 mmol, 0.415 mmol and 0.166 mmol) and three portions of tert-butyl azodicarboxylate (each portion 0.369 mmol) are added over a period of 48 hours. Silica gel is added and the mixture is evaporated in vacuo. The residue obtained is purified by flash chromatography (DCM/MeOH 100:0 to 95:5) to yield a dark yellow solid which, after trituration in CH3CN, yields the title product in the form of a yellow solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]([CH:24]3[CH2:26][CH2:25]3)[C:16]2=[O:27])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCO.[Pd]>[CH:24]1([N:17]2[C:18]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[C:16]2=[O:27])[CH2:26][CH2:25]1
Reactant: O=c1n(-c2ccc(OCc3ccccc3)cc2)c2ncccc2n1C1CC1
Agent: [Pd]
Solvent: CCO
Product: O=c1n(-c2ccc(O)cc2)c2ncccc2n1C1CC1
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-1-cyclopropyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (120 mg) and 10% Pd—C (17.87 mg) in EtOH (10 mL) was hydrogenated under balloon pressure at room temperature for 2 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 1-cyclopropyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (89 mg) as a white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([Br:25])[CH:19]=3)[CH2:12][CH2:11]2)=[N:2]1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:33](=[O:35])[CH3:34])=[C:20]([Br:25])[CH:19]=3)[CH2:12][CH2:11]2)=[N:2]1
Reactant: CC(=O)Cl
Reactant: Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1Br
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A 2 dram vial was charged with 0.09 g (0.2 mmol) of 4-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-2-bromo-phenylamine and 0.87 mL CH2Cl2. This mixture was treated with 36 μL triethylamine (0.26 mmol) and 17 μL acetyl chloride and stirred at rt for 15 h. The reaction was quenched with aqueous 1M NaHCO3, the organic layer separated, dried, and concentrated in vacuo. This gave a quantitative yield of the desired product as a white solid. MS (APCI): 461 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=8 Hz, 1H), 7.77 (d, J=8 Hz, 1H), 7.43 (t, J=7.5 Hz, 1H), 7.32 (t, J=7.5 Hz, 1H), 7.26 (s, 1H), 6.95–6.93 (m, 1H), 6.7 (d, J=8 Hz, 1H), 3.98 (br s, 2H), 3.57–3.55 (m, 4H), 2.72–2.58 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[N:3](CC2C=CC(OC)=CC=2)[CH:4]=[C:5]2[N:10]3[C@H:11]4[CH2:16][CH2:15][CH2:14][C@H:12]4[N:13]=[C:9]3[N:8]([CH3:17])[C:7](=[O:18])[C:6]=12.C(O)(C(F)(F)F)=O.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[NH:3][CH:4]=[C:5]2[N:10]3[C@H:11]4[CH2:16][CH2:15][CH2:14][C@H:12]4[N:13]=[C:9]3[N:8]([CH3:17])[C:7](=[O:18])[C:6]=12
Reactant: COc1ccc(Cn2cc3c(c2Cl)C(=O)N(C)C2=N[C@@H]4CCC[C@@H]4N23)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)c2c(c[nH]c2Cl)N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 116.4 %

Procedure:
To a solution of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-chloro-5-methyl-2-(4-methoxy-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrrolo[4,3-e]pyrimidin-4(2H)-one (95 mg, 0.25 mmol) in CH2Cl2 is slowly added TFA and trifluoromethanesulfonic acid (TFMSA). The mixture is stirred at room temperature overnight. Solvents and TFA are removed under reduced pressure. The residue is neutralized and dissolved in DMF, and then purified by a semi-preparative HPLC to give 77 mg of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-chloro-5-methyl-cyclopent[4,5]imidazo[1,2-a]pyrrolo[4,3-e]pyrimidin-4(2H)-one. A suspension of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-chloro-5-methyl-cyclopent[4,5]imidazo[1,2-a]pyrrolo[4,3-e]pyrimidin-4(2H)-one (79 mg, 0.3 mmol), 2-(4-(chloromethyl)phenyl)pyridine (61 mg, 0.3 mmol) and cesium carbonate (192 mg, 0.6 mmol) in anhydrous DMF is stirred at room temperature for 4 h. The mixture is filtered through a 0.2 μL microfilter. The filtrate is purified by a semi-preparative HPLC to give pure product. MS (ESI) m/z 432.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:23]3[CH2:27][CH2:26][N:25]([C:28](OC(C)(C)C)=[O:29])[CH2:24]3)[N:9]=[C:10]([C:11]#[C:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=3)[C:3]=12.Cl.[CH3:36][N:37]([CH3:44])[CH2:38][CH:39]=[CH:40]C(O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:23]3[CH2:27][CH2:26][N:25]([C:28](=[O:29])[CH:40]=[CH:39][CH2:38][N:37]([CH3:44])[CH3:36])[CH2:24]3)[N:9]=[C:10]([C:11]#[C:12][C:13]3[CH:14]=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=3)[C:3]=12
Reactant: COc1cc(C#Cc2nn([C@H]3CCN(C(=O)OC(C)(C)C)C3)c3ncnc(N)c23)cc(OC)c1
Reactant: CN(C)CC=CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C#Cc2nn([C@H]3CCN(C(=O)C=CCN(C)C)C3)c3ncnc(N)c23)cc(OC)c1
Reaction time: 8 h

Procedure:
The crude product (5.6 mg) of (S)-3-((3,5-dimethoxyphenyl)ethynyl)-1-(pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine obtained in Example 2 as an intermediate, 4-(dimethylamino)but-2-enoic acid hydrochloride (6.3 mg), and HATU (15 mg) were dissolved in DMF (1.0 ml). DIPEA (50 μl) was added thereto, followed by stirring overnight. Chloroform and water were added to the reaction mixture to separate the organic layer. After being washed with a saturated sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by preparative reversed-phase HPLC purification (water/acetonitrile (0.1% formic acid)) to obtain the title compound as a colorless, amorphous substance (2.3 mg). Table 1 shows the physical properties thereof.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:25])[CH2:18][CH2:19][CH:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:26]([O:28]C)=[O:27].[I-].[Li+].Cl>N1C=CC=CC=1.O>[O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:25])[CH2:18][CH2:19][CH:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:26]([OH:28])=[O:27]
Reactant: COC(=O)c1cnc2c3cc(NC(=O)CCC4CCCC4)ccc3ncn2c1=O
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: c1ccncc1
Product: O=C(CCC1CCCC1)Nc1ccc2ncn3c(=O)c(C(=O)O)cnc3c2c1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 79.8 %

Procedure:
A mixture of methyl 4-oxo-10-(3-cyclopentylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (5.72 g) and anhydrous lithium iodide (14.3 g) in dry pyridine (59 ml) was stirred at 120° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure to give a crystalline residue, which was suspended in water (100 ml). The suspension was adjusted to pH 1.7 with conc. hydrochloric acid to yield yellow crystals, which were separated by filtration, washed with water and dried. Recrystallization from N,N-dimethylformamide gave crystalline 4-oxo-10-(3-cyclopentylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylic acid (4.4 g).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[N+:5]([CH2:8][CH2:9][C:10](Cl)=[O:11])([O-:7])=[O:6].C([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)CCCCCCC.Cl>C(Cl)Cl>[N+:5]([CH2:8][CH2:9][C:10]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:11])([O-:7])=[O:6]
Reactant: O=C(Cl)CC[N+](=O)[O-]
Reactant: CCCCCCCCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CC[N+](=O)[O-])c1ccccc1
Temperature: 2.5 °C
Yield: 76 %

Procedure:
AlCl3 (12.0 g, 89.0 mmol) was added to 15 ml of methylene chloride and cooled to 0-5° C., following by addition of 3-nitropropanoyl chloride (11 g, 80 mmol). Octylbenzene (17.10 g, 89.0 mmol) in 40 ml of CH2Cl2 was dropwise added and the solution was stirred at room temperature under TLC monitoring. After reaction completion, the mixture was poured onto ice, acidified by addition of 2 M HCl to pH 2, and extracted with CH2Cl2. The combined organic extracts were washed again with 2 M HCl and water, dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to yield a solid that was recrystallized (hexanes) to give 3-nitro-1-phenylpropan-1-one (76%); mp 59-62° C., ESIMS 292 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([C:15](=[O:32])[CH2:16][N:17]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:18]([CH3:24])[CH2:19][C:20]([O:22]C)=[O:21])[CH:11]=[CH:10][C:9]=2[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:5])C.CO.[OH-].[Na+].[ClH:45]>O1CCCC1>[ClH:45].[CH2:25]([N:17]([CH2:16][C:15]([C:12]1[CH:11]=[CH:10][C:9]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:8]2[C:13]=1[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]2)=[O:32])[CH:18]([CH3:24])[CH2:19][C:20]([OH:22])=[O:21])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cc2c(C(=O)CN(Cc3ccccc3)C(C)CC(=O)OC)ccc(OCc3ccccc3)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(CC(=O)O)N(CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(C(=O)O)cc12)Cc1ccccc1

Procedure:
38 g of 4-[N-benzyl-N-(2-methoxycarbonyl-1-methylethyl)aminoacetyl]-7-benzyloxyindole-2-carboxylic acid ethyl ester is stirred at room temperature for 4 hours in a mixture of 1 liter of tetrahydrofuran, 1 liter of methanol, and 350 ml of 2N sodium hydroxide solution. The reaction mixture is then acidified with 2N hydrochloric acid, concentrated until the onset of crystallization, cooled in an ice bath, and the resultant crystals are vacuum-filtered, thus producing 25.8 g of 4-[N-benzyl-N-(2-carboxy-1-methylethyl)aminoacetyl]-7-benzyloxyindole-2-carboxylic acid hydrochloride, decomposing from 150° C. on.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[C:8]1[C:9]([CH:14]2[CH2:17][N:16]([C:18]3[N:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[CH2:15]2)=[N:10][CH:11]=[CH:12][N:13]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>O1CCOCC1.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>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:8]2[C:9]([CH:14]3[CH2:17][N:16]([C:18]4[N:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:31][CH:30]=1
Reactant: Clc1nccnc1C1CN(c2ncc3ccccc3n2)C1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1ccc(-c2nccnc2C2CN(c3ncc4ccccc4n3)C2)cc1
Temperature: 80 °C
Reaction time: 17 h
Yield: 63.7 %

Procedure:
2M aqueous sodium carbonate (0.378 mL, 0.756 mmol, J. T. Baker) was added to a stirred mixture of 2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinazoline (0.075 g, 0.252 mmol, Preparation 1), trans-dichlorobis(triphenylphosphine)palladium (ii) (0.009 g, 0.013 mmol, Strem), and 4-chlorophenylboronic acid (0.047 g, 0.302 mmol, ASDI) in 1,4-dioxane (1 mL) in a sealed tube under an argon atmosphere. The reaction mixture was stirred at 80° C. for 17 h. The reaction mixture was concentrated in vacuo and diluted with DCM. The resulting suspension was filtered, and the filtrate was concentrated in vacuo. The resulting crude material was purified via reverse phase HPLC (Column: Xbridge 19×100 mm, 5 μm, 1771302301) eluting with 0.1% NH4OH in acetonitrile/water to give 0.060 g (64%) of a yellow amorphous solid.
Reaction SMILES: [CH3:1][NH2:2].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]1([C:18]([S:20]C)=S)[CH2:17][CH2:16][CH2:15][S:14]1.C>C(O)C>[CH3:1][NH:2][C:18]([C:13]1([C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:3]=2)[CH2:17][CH2:16][CH2:15][S:14]1)=[S:20]
Reactant: CN
Reactant: CSC(=S)C1(c2ccc3ccccc3n2)CCCS1
Solvent: CCO
Product: CNC(=S)C1(c2ccc3ccccc3n2)CCCS1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
A 33% (weight/volume) solution of methylamine in ethanol (13.5 cc) is added dropwise and in the course of 10 minutes to a suspension of methyl 2-(quinol-2-yl)-tetrahydrothiophen-2-carbodithioate (20 g) in ethanol (42 cc), kept at a temperature of about 20° C. The reaction mixture is then stirred for 15 hours at a temperature of about 20° C. The resulting crystals are filtered off, washed twice with ethanol (24 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. A crystalline crude product (12.1 g) is thus obtained. This product is redissolved in boiling ethanol (75 cc); decolourising charcoal (0.6 g) is added to the solution, which is filtered hot, and the filtrate is then cooled for 3 hours at a temperature of about 5° C. The resulting crystals are filtered off, washed twice with ethanol (24 cc in total) and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 60° C. N-Methyl-2-(quinol-2-yl)-tetrahydrothiophen-2-carbothioamide (11 g), melting at 124° C., is thus obtained.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][C@@H:13]([CH2:23][CH2:24][C:25]2[C:26]([NH:31][C:32](=[O:52])[C@H:33]([CH:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[NH:34][C:35]([O:37][CH3:38])=[O:36])=[N:27][CH:28]=[CH:29][CH:30]=2)[O:12][CH2:11]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O.[NH4+].[Cl-]>[OH:8][CH2:9][C@H:10]1[N:15]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:14][C@@H:13]([CH2:23][CH2:24][C:25]2[C:26]([NH:31][C:32](=[O:52])[C@H:33]([CH:39]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[NH:34][C:35]([O:37][CH3:38])=[O:36])=[N:27][CH:28]=[CH:29][CH:30]=2)[O:12][CH2:11]1
Reactant: COC(=O)N[C@H](C(=O)Nc1ncccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)CO1)C(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)Nc1ncccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)CO1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl (2R,5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}pyridin-3-yl)ethyl]morpholine-4-carboxylate in THF (0.1 M) at rt was added TBAF (1M in THF) (4 eq.). The mixture was stirred at rt for 2 hrs, diluted with EtOAc and saturated aqueous NH4Cl and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by automated SiO2 flash chromatography system using solvent gradient of 0-10% MeOH/CH2Cl2 to afford the desired compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:13])([CH3:3])[CH3:2].[OH-].[Na+].Br[CH2:17][Cl:18]>C1COCC1>[Cl:18][CH2:17][O:13][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:10]([CH3:12])[CH3:11]
Reactant: ClCBr
Reactant: CC(C)c1cccc(C(C)C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1cccc(C(C)C)c1OCCl
Temperature: 62.5 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A four-necked 500 mL round bottom flask was equipped with a mechanical stirrer, nitrogen inlet, condenser and thermometer. It was charged with 8.9 grams (0.05 moles) of 2,6-diisopropylphenol, 100 mL of THF and 4.0 grams (0.10 mole) of sodium hydroxide pellets. The resultant green suspension was heated to 60-65° C. and held for one hour. The reaction mixture was cooled to 30° C. and 100 mL (199 grams, 1.54 moles) bromochloromethane was added and heating was resumed. The reaction mixture was held at 64° C. for 2-3 hours until no more 2,6-diisopropylphenol was present as measured by GC. After cooling to 25° C., the suspension was filtered through Celite and the filter cake was washed with THF. The THF was removed by rotary evaporation and the resultant oil was distilled under vacuum (0-1 torr, b.p.=80° C.) to give 9.6 grams (0.042 moles, 85% yield) of O-chloromethyl 2,6-diisopropylphenol.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.O[CH:13]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)[CH:14]1[CH2:16][CH:15]1[C:17]#[N:18].[CH3:29][S:30]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:42]=1[NH:41][CH:40]=[CH:39]2)(=[O:32])=[O:31]>ClCCCl.ClCCl>[CH3:29][S:30]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:42]=1[NH:41][CH:40]=[C:39]2[CH:13]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)[CH:14]1[CH2:16][CH:15]1[C:17]#[N:18])(=[O:32])=[O:31]
Reactant: N#CC1CC1C(O)c1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)Cc1cccc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Cc1cccc2c(C(c3ccc(C(F)(F)F)cc3)C3CC3C#N)c[nH]c12

Procedure:
1.05 g (4.75 mmol) of indium(III) chloride and 0.55 ml (7.12 mmol) of trifluoroacetic acid were added to 954 mg (3.96 mmol) of the compound from Example 160A and 1.02 g (4.75 mmol) of the compound from Example 86A in 60 ml of 1,2-dichloroethane, and the mixture was heated under reflux overnight. It was diluted with dichloromethane and washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 197 mg (12% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-])=O)[O:8][Si:9]([CH3:12])([CH3:11])[CH3:10])[CH3:2]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19])[O:8][Si:9]([CH3:10])([CH3:11])[CH3:12])[CH3:2]
Reactant: CCOC(=O)CCC(O[Si](C)(C)C)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCC(O[Si](C)(C)C)c1ccccc1N
Yield: 73.3 %

Procedure:
A solution of 4-(2-nitro-phenyl)-4-trimethlysilanyloxy-butyric acid ethyl ester (200 mg, 0.6 mmol) in dry EtOAc (5 mL) was hydrogenated (1 atm) in the presence of Pd/C (20 mg) overnight Then the mixture was filtered and evaporated. The residue was dissolve in dry MeOH (5 mL) and was further hydrogenated (1 atm) in the presence of Pd/C (20 mg) for 1 h. The mixture was then filtered and the filtrate evaporated. Purification of this residue by filtration over silica gel, eluting with hexane: ethyl acetate (8:1) afforded the title compound (130 mg, 72%) as a colorless oil; m/z 295 (M).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:15]1[N:20]=[C:19]([N:21]2[CH2:30][CH2:29][C:24]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:23][CH2:22]2)[CH:18]=[C:17]([Cl:31])[N:16]=1.C(NC(C)C)(C)C>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:15]2[N:20]=[C:19]([N:21]3[CH2:30][CH2:29][C:24]4([O:25][CH2:26][CH2:27][O:28]4)[CH2:23][CH2:22]3)[CH:18]=[C:17]([Cl:31])[N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cc(N2CCC3(CC2)OCCO3)nc(Cl)n1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Clc1cc(N2CCC3(CC2)OCCO3)nc(N2CCN(Cc3ccccc3)CC2)n1
Yield: 83.6 %

Procedure:
1-Benzylpiperazine (7.59 g, 43.1 mmol) was added to a solution of 8-(2,6-dichloro-4-pyrimidinyl)-1,4-dioxa-8-azaspiro[4.5]decane (10.0 g, 34.5 mmol) in tetrahydrofuran (100 mL), followed by diisopropylamine (9.26 g, 71.7 mmol). The reaction mixture was then heated at reflux overnight. The crude product was concentrated under reduced pressure and the residue was re-dissolved in CH2C12 and then washed with aqueous citric acid (2×100 mL) and brine (2×200 mL). The organic layer was dried over -anhydrous Na2SO4 and filtered. Upon standing, crystallization occurred, giving the desired product (12.4 g, 84%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[S:9][C:10]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:5][CH:4]=1.Cl.[CH2:21]1[CH:25]2[CH2:26][NH:27][CH2:28][CH:24]2[CH2:23][N:22]1[C:29]([NH2:31])=[O:30].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([O:7][C:6]3[CH:18]=[CH:19][C:3]([CH2:2][N:27]4[CH2:26][CH:25]5[CH2:21][N:22]([C:29]([NH2:31])=[O:30])[CH2:23][CH:24]5[CH2:28]4)=[CH:4][CH:5]=3)[S:9][C:10]=2[CH:16]=1
Reactant: Fc1ccc2nc(Oc3ccc(CCl)cc3)sc2c1
Reactant: NC(=O)N1CC2CNCC2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)N1CC2CN(Cc3ccc(Oc4nc5ccc(F)cc5s4)cc3)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
To a suspension of 2-(4-chloromethyl-phenoxy)-6-fluoro-benzothiazole (152 mg, 0.52 mmol), hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid amide hydrochloride (110 mg, 0.57 mmol) and Cs2CO3 (676 mg, 2.08 mmol) in DMF (1 mL) was stirred at rt overnight. The resultant mixture was filtered and the residue purified via preparative reverse phase HPLC to afford the title compound (15 mg, 7%). MS (ESI): Mass calcd for C21H21N4O2SF, 412.1; m/z found, 413.1 [M+H]+; 1H NMR (400 MHz, CD3OD): 7.64 (dd, J=8.9, 4.7 Hz, 1H), 7.58 (dd, J=8.4, 2.6 Hz, 1H), 7.47 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 7.19 (dt, J=9.0, 8.9, 2.6 Hz, 1H), 3.66 (s, 2H), 3.59-3.40 (m, 2H), 3.29-3.27 (m, 2H), 2.97-2.83 (m, 2H), 2.77 (d, J=9.3, 6.8 Hz, 2H), 2.46 (d, J=9.3, 3.6 Hz, 2H).