Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[CH:28]([NH2:30])=[O:29]>>[CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([NH:30][CH:28]=[O:29])=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(c1ccc(I)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: NC=O
Product: O=CNc1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)cc1

Procedure:
Using [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (710 mg) described in Preparation Example 186 and formamide (89 μL) and by the reaction and treatment in the same manner as in Example 262, the title compound (213 mg) was obtained.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1)[C:10]([NH2:12])=O.[C:21]([O-])([O-])=[O:22].[Na+].[Na+]>CN(C=O)C>[CH:21]([C:17]1[N:16]([C:15]2[CH:14]=[CH:13][C:9]([C:10]#[N:12])=[CH:8][C:7]=2[CH3:6])[CH:20]=[CH:19][CH:18]=1)=[O:22]
Reactant: Cc1cc(C(N)=O)ccc1-n1cccc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C#N)ccc1-n1cccc1C=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68 %

Procedure:
POCl3 (65 g, 427 mmol) was added to DMF (34 mL) at 0° C. for 30 min. After addition, the mixture was stirred at room temperature for 1.5 h, and then cooled to 0° C. A solution of 3-methyl-4-(1H-pyrrol-1-yl)benzamide (6A) (42.7 g, 213.5 mmol) in DMF (150 mL) was added at 0° C. and the resultant mixture was stirred at room temperature for 20 min, and then heated to 80° C. for 1 h. The solution was cooled to room temperature and then sat. Na2CO3 was added at 0° C. until pH=8. The mixture was extracted with ethyl acetate three times. The combined organic layers were washed with sat. NaHCO3 and brine, dried over Na2SO4, concentrated and purified by silica gel column chromatography (PE:EA=10:1) to afford 4-(2-formyl-1H-pyrrol-1-yl)-3-methylbenzonitrile as a yellow solid (30.5 g, yield 68%).
Reaction SMILES: [N:1]([CH2:4][C:5]([NH:7][C@H:8]([CH2:14][S:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C2CCCCO2)[CH:18]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6])=[N+:2]=[N-:3].Cl>CO>[N:1]([CH2:4][C:5]([NH:7][C@H:8]([CH2:14][S:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6])=[N+:2]=[N-:3]
Reactant: CCOC(=O)[C@@H](CSCc1cccc(OC2CCCCO2)c1)NC(=O)CN=[N+]=[N-]
Agent: Cl
Solvent: CO
Product: CCOC(=O)[C@@H](CSCc1cccc(O)c1)NC(=O)CN=[N+]=[N-]
Yield: 92.1 %

Procedure:
To a 250 mL round bottom flask containing 132 (6.5 g, 15.4 mmol) in MeOH (150 mL) at RT, was added Cone. HCl (1 mL) and stirred for 2.5 h. The reaction was concentrated on silica and purified over silica gel using EtOAc:Hexanes (1:1) as an eluent to afford 133 (4.8 g, 92%) as a colorless oil.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([N:7]([CH2:35][CH3:36])[C:8]1[CH:34]=[CH:33][C:11]([CH:12]=[N:13][N:14](CC2C=CC(C)=CC=2)[C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[CH3:6].CO>C(Cl)Cl>[CH2:35]([N:7]([CH2:5][CH3:6])[C:8]1[CH:9]=[CH:10][C:11]([CH:12]=[N:13][NH:14][C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:33][CH:34]=1)[CH3:36]
Reactant: CCN(CC)c1ccc(C=NN(Cc2ccc(C)cc2)C(=O)c2ccc(OC)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)c1ccc(C=NNC(=O)c2ccc(O)cc2)cc1
Temperature: 0 °C
Yield: 54.2 %

Procedure:
BBr3 (2 mL, 1.0 M solution in dichloromethane) was added dropwise to a cooled (0° C.) solution of 4-Methoxy-benzoic acid N′-(4-diethylamino-benzylidene)-N-(4-methyl-benzyl)-hydrazide (compound 2) (0.33 g, 0.00077 mol) in dried CH2Cl2 (5 mL) at −78° C. under Ar. After stirring for an additional hour at 0° C., the reaction mixture was warmed to room temperature and treated with 1:1 CH3OH:CH2Cl2 (10 mL) with cooling and stirred 2 hr at ambient temperature. Concentration of the mixture gave oil, which was purified by flash chromatography 9:1 CH2Cl2/MeOH to give the desired product as a solid 0.13 g in 41% yield, mp: 228.4° C. 1H NMR (CD3OD) δ 8.16 (s, 1H), 7.81 (d, 2H), 7.63 (d, 2H), 6.88 (d, 2H), 6.72 (d, 2H), 3.87 (d, 1H), 3.46 (q, 4H), 1.19 (t, 6H). 13C NMR (CD3OD) δ 162.2, 158.2, 147.1, 146.7, 126.3, 126.2, 120.7, 117.7, 111.9, 110.6, 108.0, 41.1, 8.6. Anal. Calcd for C18H21N3O2.¼H2O: C, 68.43; H, 6.70; N, 13.31. Found: C, 68.36; H, 6.99; N, 13.58.
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6](=S)[NH:7][NH2:8])([CH3:4])[CH3:3].Cl[CH:11]([C:17]([CH3:19])=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].[S]>Cl>[CH3:1][C:2]([NH:5][C:6]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:17]([CH3:19])[NH:8][N:7]=1)([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CC(C)(C)NC(=S)NN
Agent: Cl
Agent: [S]
Product: CCOC(=O)c1c(NC(C)(C)C)n[nH]c1C
Temperature: 25 °C
Yield: 101.8 %

Procedure:
A solution of 25 g (0.17 mole) of 4-(1,1-dimethylethyl)-3-thiosemicarbazide in 85 mL of 2N ethanolic hydrogen chloride was cooled to 0° C. with an ice bath and while stirring under nitrogen atmosphere, 28 g (0.17 mole) of ethyl 2-chloroacetoacetate was added dropwise. The reaction mixture was allowed to come to room temperature while stirring for 16 hr. The pale yellow solution was then refluxed for 2 hr during which a film of sulfur deposited on the sides of the flask. The reaction mixture was cooled to room temperature and the sulfur removed by filtration. The filtrate was concentrated in vacuo to give 39 g of pale yellow oil which was dissolved in ligroin and, after standing at ~7-10° C. for ~60 hr, yielded 20.5 g of large crystals, mp 118°-119° C. An additional 6.1 g of crude material was obtained by reworking the residues.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7](I)([CH3:9])[CH3:8].CS(C)=O.Br.[Br:16][C:17]1[CH:18]=[N:19][C:20]([OH:23])=[N:21][CH:22]=1>O>[Br:16][C:17]1[CH:18]=[N:19][C:20](=[O:23])[N:21]([CH:7]([CH3:9])[CH3:8])[CH:22]=1
Reactant: Oc1ncc(Br)cn1
Reactant: CC(C)I
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)n1cc(Br)cnc1=O
Temperature: 15 °C
Reaction time: 16 h
Yield: 30.6 %

Procedure:
With cooling with ice, potassium carbonate (17 g, 123 mmol) and isopropyl iodide (4.56 mL, 45.7 mmol) were added to a dimethyl sulfoxide (150 mL) solution of 5-bromo-2-hydroxypyrimidine hydrobromide (9.0 g, 35.2 mmol), and stirred at 15° C. for 16 hours. Water was added to the reaction mixture, and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (C-300, hexane/ethyl acetate=3/2) to obtain the entitled compound (2.34 g, 31%) as a colorless solid.
Reaction SMILES: [Cl:1]C1C=CC(O)=C(C(C2C=C(F)C=CC=2O)(C)C)C=1.[C:20]([C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[C:36]([N+:41]([O-:43])=[O:42])[C:35]=1[OH:44])([C:23]1[CH:28]=[C:27](F)[CH:26]=[C:25]([N+:30]([O-:32])=[O:31])[C:24]=1[OH:33])([CH3:22])[CH3:21]>>[Cl:1][C:27]1[CH:26]=[C:25]([N+:30]([O-:32])=[O:31])[C:24]([OH:33])=[C:23]([C:20]([C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[C:36]([N+:41]([O-:43])=[O:42])[C:35]=2[OH:44])([CH3:22])[CH3:21])[CH:28]=1
Reactant: CC(C)(c1cc(F)ccc1O)c1cc(Cl)ccc1O
Reactant: CC(C)(c1cc(F)cc([N+](=O)[O-])c1O)c1cc(F)cc([N+](=O)[O-])c1O
Product: CC(C)(c1cc(F)cc([N+](=O)[O-])c1O)c1cc(Cl)cc([N+](=O)[O-])c1O

Procedure:
2-(5-chloro-2-hydroxy-3-nitrophenyl)-2-(5-fluoro-2-hydroxy-3-nitrophenyl)propane (m.p. 160° C.) was prepared from 2-(5-chloro-2-hydroxyphenyl)-2-(5-fluoro-2-hydroxyphenyl)propane following the method described in Example 3 for the preparation of 2,2'-isopropylidene bis(4-fluoro-6-nitrophenol).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([OH:24])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:41][C:42]#[C:43][C:44]([O:47][Si:48]([CH2:53][CH3:54])([CH2:51][CH3:52])[CH2:49][CH3:50])([CH3:46])[CH3:45].[H-].[Na+].C1OCCOCCOCCOCCOC1>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:24][CH2:41][C:42]#[C:43][C:44]([O:47][Si:48]([CH2:49][CH3:50])([CH2:51][CH3:52])[CH2:53][CH3:54])([CH3:45])[CH3:46])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC[Si](CC)(CC)OC(C)(C)C#CCBr
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)C#CCOC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 62 %

Procedure:
1α,3β-Bis(tert-Butyldimethylsilyloxy)-20-hydroxy-20-methylpregna-5,7,16-triene (100 mg, 0.175 mmol), 1-bromo-4-triethylsilyloxy-4-methyl-2-pentyne (203 mg, 0.697 mmol), sodium hydride (60% in oil, 42 mg, 1.05 mmol), 15-crown-5 (38 mg, 0.173 mmol) and tetrahydrofuran (3 ml) were reacted using a procedure similar to that of Example 5 (1) (reflux under heating for 17 hours), worked-up and purified by column chromatography (hexane:toluene=2:1) to give the titled compound (85 mg, 62%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:9])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>CC(O)C.C(N(C(C)C)CC)(C)C>[Br:1][C:2]1[C:3]([OH:9])=[N:4][C:5]([N:13]2[CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]2)=[N:6][CH:7]=1
Reactant: Oc1nc(Cl)ncc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)c(O)n2)CC1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
A solution of 5-bromo-2-chloropyrimidin-4-ol (6.5 g, 31 mmol), tert-butyl piperazine-1-carboxylate (6.5 g, 35 mmol) in propan-2-ol (200 mL) and diisopropylethylamine (10 mL) was stirred at 80° C. overnight. The mixture was cooled to RT and then concentrated. The residue was purified by silica gel chromatography eluting with ethyl acetate:petroleum ether (100:1) to give tert-butyl 4-(5-bromo-4-hydroxypyrimidin-2-yl)piperazine-1-carboxylate (9 g, 80%) as a yellow solid. MS (ES+) C13H19BrN4O3 requires: 358, 360, found: 303, 305 [M+H-56]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:20])[CH3:19])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: COc1cc(F)ccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(F)ccc1NC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-fluoro-2-(methyloxy)aniline (Heterocycles 1992, 34, 2301-2311) (5.6 g, 40 mmol) and triethylamine (6.9 ml, 50 mmol) in dichloromethane (200 ml) at 0° C. was treated with acetyl chloride (2.85 ml, 40 mmol). After stirring at room temperature for 1 hour the solution was washed with 2N hydrochloric acid. The organic phase was separated, washed with water and brine then dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (1:5 to 1:2 ethyl acetate in dichloromethane) to afford the title compound. MS (ES+) m/e 184 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])O[C:10]=1[C:17]([OH:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1>CO>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[N:23]([CH:20]2[CH2:22][CH2:21]2)[C:10]=1[C:17]([OH:19])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1
Reactant: NC1CC1
Solvent: CO
Product: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)O)n1C1CC1

Procedure:
To a suspension of 3-(benzyloxy)-6-methyl-4-oxo-4H-pyran-2-carboxylic acid (70 g, 0.27 mol) in MeOH (350 mL) in a 3-necked RBF (round bottom flask) fitted with a mechanical stirrer was added cyclopropylamine (120 mL, 1.72 mol). A clear light yellow solution resulted. The reaction mixture was refluxed for ca. 19 h. Volatiles were removed in vacuo and the residue was dissolved in water (700 mL) with stirring. The aqueous mixture was filtered through a pad of Celite®. The filtrate was placed in a 3-necked RBF fitted with a mechanical stirrer, and cooled in an ice bath. Conc. HCl was added until the pH was ca. 1-2, and voluminous “orange” solid precipitated out. Acetone (200 mL) was added to the suspension. The solid was then collected by suction filtration, thoroughly washed with acetone, and air-dried. The title compound was obtained as an off-white solid (71.0 g, 88%). Mp: 139.0-139.5° C.; 1H-NMR (300 MHz, DMSO-D6) δ (ppm): 0.98-1.15 (m, 4H, 2 c-CH2), [2.37 (s)+2.40 (s), rotamers, 3/2 ratio, 3H, CH3)], 3.30-3.50 (m, 1H, c-CH), 5.00-5.05 (m, 2H, CH2Ph), 6.20-6.25 (m, 1H, C═CH), 7.28-7.50 (m, 5H, Ph); MS (m/z): 300.2 (M++1), 256.2, 192.2, 164.4, 91.0 (100%); Anal. Calcd. for C17H17NO4: C, 68.21; H, 5.72; N, 4.68%. Found: C, 67.76; H, 5.76; N, 4.61%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7](S)[N:6]3[N:13]=[C:14]([C:16]4[O:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[C:5]3[C:4]=2[CH:3]=1>NC1C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[N:8][C:9]3[CH:10]=[CH:11][CH:2]=[CH:3][CH:4]=3)[N:6]3[N:13]=[C:14]([C:16]4[O:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[C:5]3[C:4]=2[CH:3]=1
Reactant: Sc1nc2ccc(Cl)cc2c2nc(-c3ccco3)nn12
Solvent: Nc1ccccc1
Product: Clc1ccc2[nH]c(=Nc3ccccc3)n3nc(-c4ccco4)nc3c2c1
Reaction time: 66 h

Procedure:
A mixture of 9-chloro-2-(2-furyl)-5-mercapto[1,2,4]triazolo[1,5-c]quinazoline (5.6 g) and aniline (40 ml) is stirred at 150° for 66 hours under nitrogen. The mixture is heated on a rotary evaporator under water pump vacuum to remove residual aniline and recrystallized from aqueous ethanol to afford pure 9-chloro-2-(2-furyl)-5-phenylimino-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazoline, mp 231°-233°.
Reaction SMILES: O=C1N2C[C@@H](CC[C@H]2C([NH:12][O:13][C@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)=O)N1OS(O)(=O)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:12][O:13][C@@H:14]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](ON)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
To a mixture of tert-butyl (3S)-3-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate 10 (0.11 g, 0.24 mmol) in DCM (4.0 mL) was added trifluoroacetic acid (0.20 mL) at 0° C. The mixture was stirred at 0° C. for 1 h, concentrated and washed with ether. The white solid was collected by centrifugation. The crude product was purified by preparative HPLC to provide Compound 2 (Table 1)(30.4 mg, 36%) as a white solid.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:17][C:18]([O:20]C)=[O:19]>C1COCC1>[O:13]=[C:11]1[CH2:10][CH2:9][CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:12]1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: COC(=O)CBr
Reactant: O=C1CCCC(c2ccccc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CN1C(=O)CCCC1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (±)-6-phenylpiperidin-2-one (155 mg, 0.885 mmol) in THF (10 mL), cooled to 0° C., was added NaH (30.0 mg, 1.24 mmol). The ice bath was removed and the reaction was allowed to warm to ambient temperature. After 1 h at ambient temperature, the reaction was cooled to 0° C. prior to the introduction of methyl bromoacetate (149 mg, 0.973 mmol). After 40 minutes, the ice bath was removed and the reaction was stirred under nitrogen for 12 h. Additional quantities of NaH and methyl bromoacetate were then added in parts to nearly consume the lactam, as judged by LCMS analysis. After sufficient lactam was consumed, 1 M aqueous sodium hydroxide was added (1 mL, 1 mmol). After a majority of the methyl ester was saponified (˜3 h), the reaction was quenched with 1 M hydrochloric acid (5 mL), and EtOAc (50 mL). The organics were washed with saturated brine (twice), dried over sodium sulfate, filtered and concentrated in vacuo, to yield a residue which was used without further purification. MS: m/z=234 (M+1).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.[CH2:28]1[O:30][C@@H:29]1[CH2:31][OH:32]>>[NH2:14][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([CH2:28][C@H:29]([OH:30])[CH2:31][OH:32])[CH2:4]3)[N:6]=[C:7]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[C:8]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Reactant: OC[C@@H]1CO1
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CN(C[C@H](O)CO)C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 37.9 %

Procedure:
To a solution of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.05 g, 0.00014 mol) was added (R)-(+)-glycidol (0.05 M in isopropanol, 2.8 mL, 0.00014 mol) at room temperature under an atmosphere of nitrogen. The mixture was stirred at 80° C. for three hours. The solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel using ammonium hydroxide/methanol/dichloromethane (2:7:91) followed by ammonium hydroxide/methanol/dichloromethane (2:10:88) as mobile phase to yield (2S)-3-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}propane-1,2-diol (0.023 g, 0.000053 mol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([N:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]2)=[CH:21][C:20]=1[O:34][CH3:35]>>[Cl:17][C:5]1[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[N:7][C:2]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][CH:28]([N:31]([CH3:32])[CH3:33])[CH2:27][CH2:26]3)=[CH:21][C:20]=2[O:34][CH3:35])=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reactant: COc1cc(N2CCC(N(C)C)CC2)ccc1N
Product: COc1cc(N2CCC(N(C)C)CC2)ccc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 2) and 1-(4-amino-3-methoxyphenyl)-N,N-dimethylpiperidin-4-amine (INTERMEDIATE 28).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C@H:23]3[C:32]4[C:27](=[C:28]([O:33][Si](C(C)(C)C)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:69]([O:72][CH2:73][CH3:74])(=[O:71])[CH3:70]>C1COCC1>[C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C@H:23]3[C:32]4[C:27](=[C:28]([O:33][CH2:70][C:69]([O:72][CH2:73][CH3:74])=[O:71])[CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC[C@H]2N1CCC[C@@H]1c1nc(-c2ccccc2)c(-c2ccccc2)o1)(c1ccccc1)c1ccccc1
Reactant: CCOC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)COc1cccc2c1CCC[C@H]2N1CCC[C@@H]1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1R)-1-[(2R)-2-(4,5-diphenyloxazol-2-yl)pyrrolidin-1-yl]-5-tert-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (1.22 g) in THF (20 ml) was added tetrabutylammonium fluoride (2.7 ml, 1M solution in THF) at 0° C. After being stirred for 2 hours at the room temperature, the mixture was diluted with ethyl acetate and washed with water and brine. The dried solvent was evaporated in vacuo. The obtained oil was dissolved into DMF (10 ml) and then K2CO3 (2.0 g) and ethyl bromoacetate (0.3 ml) were added at room temperature. The mixture was stirred for 2 hours at the same temperature and then partitioned between ethyl acetate and water. The organic layer was washed with water, sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give (1R)-1-[(2R)-2-(4,5-diphenyloxazol-2-yl)pyrrolidin-1-yl]-5-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphthalene (800 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1.C(N(CC)CC)C.[NH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCNC(=O)OC(C)(C)C)c1C
Temperature: 60 °C
Yield: 77.4 %

Procedure:
A solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (60 g, 271 mmol) in anhydrous N,N-dimethylfornamide (600 mL) was cooled to 0° C. Triethylamine (44.8 mL, 326 mmol) was added drop wise followed by tert-butyl 2-aminoethylcarbamate (52.2 g, 326 mmol). After 30 minutes the ice bath was removed and the reaction mixture was heated to 60° C. The reaction was heated at 60° C. overnight and then it was concentrated under reduced pressure to provide an orange oil. The oil was dissolved in ethyl acetate (1 L), washed with water (3×500 mL), dried over magnesium sulfate and then concentrated under reduced pressure to provide a yellow oil. The oil was triturated with methanol (˜100 mL). The resulting solid was isolated by filtration and washed with cold methanol to provide 72.3 g of tert-butyl 2-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]ethylcarbamate as a solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>C(O)C>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCN(Cc3ccccc3)C2)cc1
Reactant: C1CCNC1
Solvent: CCO
Product: c1ccc(CN2CC[C@H](N3CCCC3)C2)cc1
Temperature: 140 °C
Reaction time: 20 h
Yield: 69.8 %

Procedure:
2.00 g of (R)-1-benzyl-3-(p-toluenesulfonyloxy)pyrrolidine (J. Med. Chem., 1992, 35, 4205-4208) was dissolved in 12 ml of ethanol, 1.63 g of pyrrolidine was added, and then the mixture was stirred at 140° C. for 20 hours in a sealed tube. The reaction solution was concentrated under reduced pressure, mixed with water, followed by extraction with ethyl acetate, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.97 g of the objective compound as a brown oily product.