Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[S:33])=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:12]=[CH:13][C:8]4[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=4[N:10]=3)[CH2:15][CH2:16]2)=[S:33])=[CH:27][CH:26]=1
Reactant: COc1ccc(N=C=S)cc1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4ccc(OC)cc4)CC3)nc21

Procedure:
Pipemidic acid (30 mg, 0.0989 mmol) and 4-methoxyphenyl isothiocyanate (13.7 μL, 0.0989 mmol) were used. Purification on silica yielded compound 24 in Table 1, below (37 mg, 80%). 1H NMR (300 MHz, CDCl3) δ 9.33 (s, 1H), 8.67 (s, 1H), 7.30 (s, 1H), 7.15 (d, J=8.76 Hz, 2H), 6.90 (d, J=8.82 Hz, 2H), 4.34 (q, J=7.10 Hz, 2H), 4.25-3.92 (m, 8H), 3.81 (s, 3H), 1.49 (t, J=7.12 Hz, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]2[CH2:5][C:6]3[C:10]([C@H:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:47][CH2:48][C:49]1[CH:59]=[CH:58][C:52]([O:53][CH2:54][CH:55]([OH:57])[CH3:56])=[CH:51][C:50]=1[O:60][CH3:61]>CN(C=O)C>[OH:57][CH:55]([CH3:56])[CH2:54][O:53][C:52]1[CH:58]=[CH:59][C:49]([CH2:48][NH:47][C:12]([C:7]2[S:8][C:9]([CH3:11])=[C:10]3[C:6]=2[CH2:5][C@H:4]2[C:2]([CH3:1])([CH3:15])[C@H:3]23)=[O:14])=[C:50]([O:60][CH3:61])[CH:51]=1
Reactant: COc1cc(OCC(C)O)ccc1CN
Reactant: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(OCC(C)O)ccc1CNC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Reaction time: 0.5 h
Yield: 42.5 %

Procedure:
A solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (9.6 mg, 0.043 mmol), TBTU (13.8 mg, 0.043 mmol) and ethyl-diisopropylamine (22 μL, 0.129 mmol) in DMF (1 mL) is allowed to stand at rt for 30 min. The solution is added to (rac)-1-(4-aminomethyl-3-methoxy-phenoxy)-propan-2-ol (9.1 mg, 0.043 mmol) and the mixture is allowed to stand at rt for 1 h. The mixture is separated by prep. HPLC to afford (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-((R/S)-2-hydroxy-propoxy)-2-methoxy-benzylamide (7.6 mg) as a colourless oil. LC-MS: tR=0.98 min, [M+1]+=402.16; 1H NMR (CDCl3): δ 7.20 (d, J=8.2 Hz, 1H), 6.50 (d, J=2.3 Hz, 1H), 6.44 (d, J=8.2 Hz, 1H), 6.16 (t br, J=5.3 Hz, 1H), 4.47 (d, J=5.9 Hz, 2H), 3.93 (dd, J=2.9, 11.1 Hz, 1H), 3.87 (s, 3H), 3.82-3.72 (m, 1H), 2.90 (dd, J=5.3, 17.6 Hz, 1H), 2.69 (d, J=18.1 Hz, 1H), 2.35 (s, 3H), 1.92-1.85 (m, 2H), 1.30 (d, J=6.4 Hz, 3H), 1.11 (s, 3H), 0.72 (s, 3H).
Reaction SMILES: [NH2:1][C:2](=[O:16])[CH:3]([CH3:15])[O:4][C:5]1[C:9]([Br:10])=[CH:8][S:7][C:6]=1[C:11]([O:13]C)=[O:12].CO.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:1][C:2](=[O:16])[CH:3]([CH3:15])[O:4][C:5]1[C:9]([Br:10])=[CH:8][S:7][C:6]=1[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1scc(Br)c1OC(C)C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(Oc1c(Br)csc1C(=O)O)C(N)=O
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 73.4 %

Procedure:
To a mixture of methyl 3-(2-amino-1-methyl-2-oxoethoxy)-4-bromothiophene-2-carboxylate (634 mg), MeOH (20 mL) and water (0.074 ml) was added potassium carbonate (853 mg), and the mixture was stirred at 65° C. for 1.5 hr. The reaction mixture was concentrated under reduced pressure, the residue was acidified (pH 1) with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of Et2O and hexane to give the title compound (444 mg, 73%) as colorless crystals.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[NH:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH2:14]>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[N:14][NH:13][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: O=Cc1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCO
Product: CC(C)(C)OC(=O)NN=Cc1ccc2ccccc2n1

Procedure:
A solution of 10.70 g 2-quinolinecarboxaldehyde and 9.00 g tert-butyl hydrazinecarboxylate in 200 ml of ethanol is refluxed for 2 h with stirring. Then the solution is evaporated to dryness and the residue is triturated with diisopropylether, separated off and dried at 50° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CO[C:9]1[C:10]2[C:11](=[N:15][O:16][N+:17]=2[O-:18])[N:12]=[CH:13][N:14]=1>C(O)C>[O:4]1[CH2:5][CH2:6][N:1]([C:9]2[C:10]3[C:11](=[N:15][O:16][N+:17]=3[O-:18])[N:12]=[CH:13][N:14]=2)[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: COc1ncnc2no[n+]([O-])c12
Solvent: CCO
Product: [O-][n+]1onc2ncnc(N3CCOCC3)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
A solution of 1.6 g (18 mmol) of morpholine in 20 ml of ethanol is added to a mixture of 3.0 g (18 mmol) of 7-methoxy-[1,2,5]oxadiazolo[3,4-d]pyrimidine-1-oxide (Arzneim.-Forsch. 33 (1983) 803) and 100 ml of ethanol. After stirring at room temperature for 4 hours, the solvent is removed by distillation in vacuo and the residue is recrystallised from isopropanol. 3.6 g (90%) of 7-morpholino-[1,2,5]oxadiazolo[3,4-d]pyrimidine-1-oxide are obtained.
Reaction SMILES: N1CCOCC1.[CH3:7][C:8]1([O:11][CH2:10]1)[CH3:9].[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2([C:25]#[N:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:17][CH:18]=1.C(=O)(O)[O-].[Na+]>O>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2([C:25]#[N:26])[CH2:20][CH2:21][N:22]([CH2:10][C:8]([OH:11])([CH3:9])[CH3:7])[CH2:23][CH2:24]2)=[N:17][CH:18]=1
Reactant: CC1(C)CO1
Reactant: N#CC1(c2ccc(Br)cn2)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCN1
Solvent: O
Product: CC(C)(O)CN1CCC(C#N)(c2ccc(Br)cn2)CC1
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 91.4 %

Procedure:
Morpholine (catalytic amount) and isobutylene oxide (2.84 g) were added to 4-(5-bromopyridin-2-yl)piperidine-4-carbonitrile (3.4 g) of Reference Example 88(2) and water (35 ml), and the mixture was stirred at 100° C. for 4.5 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine dried over anhydrous sodium sulfate and concentrated in vacuo. Water was added to the residue and the precipitated solid was washed with water to give 4-(5-bromopyridin-2-yl)-1-(2-hydroxy-2-methylpropyl)piperidine-4-carbonitrile (3.95 g) as a light brown solid.
Reaction SMILES: [CH:1]([C:4]1[O:8][C:7]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[N:6][N:5]=1)([CH3:3])[CH3:2].OO.C([O-])([O-])=[O:20].[K+].[K+]>>[CH:1]([C:4]1[O:8][C:7]([C:9]2[CH:16]=[CH:15][C:12]([C:13]([NH2:14])=[O:20])=[CH:11][CH:10]=2)=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nnc(-c2ccc(C#N)cc2)o1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Product: CC(C)c1nnc(-c2ccc(C(N)=O)cc2)o1
Yield: 1544.4 %

Procedure:
The title compound was prepared according to the procedure described in step 1 of Intermediate-59 by using 4-(5-isopropyl-1,3,4-oxadiazol-2-yl)benzonitrile (0.500 g, 2.34 mmol), 50% H2O2 (5.0 mL), K2CO3 (0.097 g, 0.070 mmol) to afford 0.250 g of desired product. 1H NMR (400 MHz, DMSO d6): δ 1.3 (s, 3H), 1.35 (s, 3H), 3.33 (m, 1H), 7.56 (br s, 1H), 8.06 (s, 4H), 8.16 (br s, 1H); MS (m/z): 232.30 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=1.[CH2:14]([O:16]CC)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:7]([CH3:8])=[C:6]([C:5]([OH:9])=[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=1)[CH:14]=[O:16]
Reactant: CCOCC
Reactant: Cc1cc(O)c(C(C)(C)C)cc1Br
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1c(Br)cc(C(C)(C)C)c(O)c1C=O
Temperature: 25 °C
Yield: 61 %

Procedure:
A stirred, cooled (ice bath) solution of 4-bromo-2-tert-butyl-5-methyl-phenol (Intermediate 139, 0.85 g, 3.5 mmol) in anhydrous dichloromethane (7 mL) was treated with titanium tetrachloride (0.64 mL, 5.8 mmol) followed by α,α-dichloro methyl ether (0.3 g, 3.5 mmol). The reaction mixture was allowed to warm to ambient temperature for 4 h. The reaction mixture was diluted with diethyl ether, washed with brine (×1) and dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which was subjected to flash column chromatography over silica gel (230-400 mesh) using 1% ethyl acetate in hexane to afford the title compound as a yellow solid (0.58 g, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C:14](=[O:15])[CH:13]=[C:12]([OH:16])[CH:11]2[CH:17]([CH3:19])[CH3:18])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(O)(=O)C.[BH4-].[Na+].O>C(#N)C>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C:14](=[O:15])[CH2:13][C@H:12]([OH:16])[C@@H:11]2[CH:17]([CH3:19])[CH3:18])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(C)C1C(O)=CC(=O)N1c1ccc(C#N)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: CC(C)[C@H]1[C@@H](O)CC(=O)N1c1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
To a mixture of 2-chloro-4-[3-hydroxy-2-(1-methylethyl)-5-oxo-2,5-dihydro-1H-pyrrol-1-yl]benzonitrile (300 mg) and acetic acid (0.68 mL) in acetonitrile (10 mL) was added sodium borohydride (103 mg) at 0° C. in small portions. The mixture was warmed to room temperature and stirred for 1 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent: hexane:ethyl acetate=4:1→-ethyl acetate), and recrystallized from hexane-ethyl acetate to give the title compound as colorless crystals (yield: 76 mg, 25%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH2:12])[C@H:10]2[CH2:13][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=2)[C@H:10]2[CH2:13][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N
Reactant: O=Cc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Reaction time: 3 h
Yield: 95.1 %

Procedure:
To a solution of (1S,2R,3S,4R)-3-amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (1.15 g, 6.28 mmol) in ethanol (30 mL) was added 4-fluorobenzaldehyde (0.68 mL, 6.31 mmol), glacial acetic acid (0.4 mL, 6.99 mmol), and sodium cyanoborohydride (1.04 g, 15.7 mmol) at 25° C. After stirring for 3 h, the mixture was diluted with ethyl acetate (50 mL) and quenched with saturated aqueous sodium bicarbonate (50 mL) for 0.5 h. The mixture was filtered through Celite. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50 mL×2). When all solvent was removed, a solid was formed. The solid was filtered, washed with water, and dried under vacuum to afford (1S,2R,3S,4R)-3-(4-fluorobenzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (1.74 g, 5.97 mmol, 95% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ: 1.05-1.16 (2H, m), 1.21 (1H, dt, J1=8.0 Hz, J2=1.6 Hz), 1.27 (3H, t, J=7.4 Hz), 1.45-1.61 (2H, m), 1.94 (1H, dt, J1=10.1 Hz, J2=1.9 Hz), 2.28 (1H, d, J=3.9 Hz), 2.43 (1H, d, J=3.3 Hz), 2.60 (1H, dd, J1=8.8 Hz, J2=1.5 Hz), 2.94 (1H, d, J=7.8 Hz), 3.66 (1H, d, J=13.2 Hz), 3.80 (1H, d, J=13.5 Hz), 4.13 (2H, q, J=7.0 Hz), 6.97 (2H, t, J=8.5 Hz), 7.26 (2H, t, J=7.1 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][C:5]([CH2:6][C@@H:7]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([OH:30])[CH:27]=4)[NH:22][C:21]3=[O:31])[CH2:16][CH2:15]2)=[O:13])[C:8](O)=[O:9])=[CH:4][C:3]=1[Cl:38].[O:39]1[CH2:44][CH2:43][CH:42]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1>>[NH2:1][C:2]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][C:5]([CH2:6][C@@H:7]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([OH:30])[CH:27]=4)[NH:22][C:21]3=[O:31])[CH2:16][CH2:15]2)=[O:13])[C:8]([N:48]2[CH2:47][CH2:46][N:45]([CH:42]3[CH2:43][CH2:44][O:39][CH2:40][CH2:41]3)[CH2:50][CH2:49]2)=[O:9])=[CH:4][C:3]=1[Cl:38]
Reactant: Nc1c(Cl)cc(C[C@@H](CC(=O)N2CCC(N3Cc4cc(O)ccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Reactant: C1CN(C2CCOCC2)CCN1
Product: Nc1c(Cl)cc(C[C@@H](CC(=O)N2CCC(N3Cc4cc(O)ccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc1C(F)(F)F

Procedure:
Prepared analogously to Example 81 from 80.0 mg (0.14 mmol) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(6-hydroxy-2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-4-oxo-butanoic acid and 24.5 mg (0.14 mmol) 1-(tetrahydropyran-4-yl)-piperazine.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1.[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br>O.C(#N)C>[F:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@:11]([CH2:20][C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[CH3:23])([OH:12])[CH2:10]1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Reactant: Cc1ccccc1CBr
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Cc1ccccc1C[C@]1(O)C[C@H](n2cc(F)c(=O)[nH]c2=O)O[C@@H]1CO
Yield: 20.4 %

Procedure:
A 1.14 g quantity of potassium hydroxide was dissolved in a mixture of 33 ml of water and 16 ml of acetonitrile. To the solution were added 1.00 g of 2'-deoxy-5-fluorouridine and 1.50 g of 2-methylbenzyl bromide at room temperature with stirring. Then the same subsequent procedures as in Examples 4 and 5 were conducted, giving 0.29 g of the title compound in a yield of 20%.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C@H:8]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)[O:7]2)([O-:3])=[O:2].CN1CCCC1=O.Cl[CH:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=2)=[CH:39][CH:38]=1)[CH3:36].C(N(C(C)C)CC)(C)C>O>[N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C@H:8]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([CH:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([C:51]([F:52])([F:53])[F:54])=[CH:47][CH:46]=5)=[CH:39][CH:38]=4)[CH3:36])[CH2:23][CH2:22]3)=[CH:17][CH:16]=1)[O:7]2)([O-:3])=[O:2]
Reactant: CC(Cl)c1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Reactant: O=[N+]([O-])c1cn2c(n1)O[C@@H](COc1ccc(N3CCNCC3)cc1)CC2
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1ccc(OCc2ccc(C(F)(F)F)cc2)cc1)N1CCN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(R)-2-Nitro-7-(4-piperazin-1-ylphenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (0.56 g) was added to an N-methylpyrrolidone solution (5 ml) of 1-(1-chloroethyl)-4-(4-trifluoromethylbenzyloxy)benzene (0.54 g). Subsequently, diisopropylethylamine (0.54 ml) was added thereto, and the mixture was stirred at room temperature for 12 hours. Thereafter, the mixture was heated to 60° C. and stirred for 7 hours. Water was added to the reaction mixture and the precipitated solid was collected by filtration. The solid thus obtained was purified by basic silica gel column chromatography (methylene chloride) and recrystallized from acetone-water to afford the title compound as a slightly yellow powder (0.15 g).
Reaction SMILES: [Br:1][C:2]1[N:12]=[CH:11][C:10]([C:13](Br)(Br)Br)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:17][CH2:18][OH:19].[OH2:20]>[N+]([O-])([O-])=O.[Ag+]>[Br:1][C:2]1[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:9][C:10]([C:13]([O:19][CH2:18][CH3:17])=[O:20])=[CH:11][N:12]=1
Reactant: O
Reactant: CCOC(=O)c1cc(C(Br)(Br)Br)cnc1Br
Reactant: CCO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Product: CCOC(=O)c1cnc(Br)c(C(=O)OCC)c1
Reaction time: 1 h
Yield: 78 %

Procedure:
A mixture of 7 (2.3 g, 0.005 mol), AgNO3 (2.5 g, 0.015 mol) and EtOH (25 mL) was heated on a steam bath. After 1 hour, H2O (25 mL) was added and the yellow solid filtered off. The solution was concentrated to dryness and the residue treated with H2O and extracted with CHCl3 (3X). The CHCl3 layers were washed with NaHSO3 solution, dried, filtered and concentrated to dryness to yield 0.8 g (78%) of 8; 1H NMR (CDCl3) 1.4δ(6H, t, J=7), 4.45 (4H, q, J=7), 8.6 (1H, d, J=3) and 9.0 (1H, d, J=3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1.CCN(C(C)C)C(C)C.Cl[C:26](OC1C=CC=CC=1)=[O:27].[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38][NH2:39]>ClCCl>[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38][NH:39][C:26]([NH:15][C:11]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:14]=[CH:13][N:12]=1)=[O:27]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccccc1-c1cc(N)ncn1
Reactant: CN(C)CCN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1cc(NC(=O)NCCN(C)C)ncn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-(2-methoxy-phenyl)-pyrimidin-4-ylamine (XXIV) (0.400 g, 1.98 mmol) and DIPEA (0.300 g, 2.38 mmol) in dry dichloromethane (10 ml) was added phenyl chloroformate (0.370 g, 1.98 mmol) dropwise at −78° C. The reaction mixture was then allowed to stir for 16 hours at room temperature. Dichloromethane was evaporated and the residue was dissolved in 1,4-dioxane (15 ml). N,N-dimethylethylenediamine (L) (0.160 g, 1.98 mmol) was added and the mixture was refluxed for 14 hours. The solvent was evaporated and the crude product was re-dissolved in ethyl acetate, washed with water (2×50 ml) and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude solid product was further purified by silica gel column chromatography (15% methanol/dichloromethane) yielding 1-(2-dimethylamino-ethyl)-3-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-urea. Yield: 293 mg, 47%.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH:11]1([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[Si](C#N)(C)(C)C.[N:31]1([C:36](N2C=CN=C2)=[O:37])C=CN=[CH:32]1>[Pd]>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:21]([C:20]4[CH:23]=[CH:24][C:17]([CH:11]5[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]5)=[CH:18][CH:19]=4)[CH2:32][NH:31][C:36]3=[O:37])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: O=Cc1ccc(C2CCCCC2)cc1
Agent: [Pd]
Agent: C[Si](C)(C)C#N
Product: O=C1NCC(c2ccc(C3CCCCC3)cc2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 1H-benzo[d]imidazol-5-amine (0.400 g, 3 mmol), 4-cyclohexylbenzaldehyde (0.565 g, 3 mmol), TMSCN (0.375 mL, 3 mmol), Pd/C (10%, 0.02 g), TEA 1.05 mL, 7.5 mmol), di-(imidazol-1-yl)methanone (0.730 g, 4.5 mmol) as described in method 2.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:7]([Br:11])[CH2:8][CH2:9][CH3:10]>CCC(C)=O>[Br-:11].[CH3:1][N+:2]1([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CN1CCCC1
Reactant: CCCCBr
Solvent: CCC(C)=O
Product: CCCC[N+]1(C)CCCC1
Product: [Br-]
Temperature: 80 °C

Procedure:
A flask equipped with a thermometer, nitrogen gas inlet tube, reflux condenser, stirrer and dropping funnel was charged with 85 g (1.0 mol) of methylpyrrolidine and 400 g of 2-butanone (hereinafter referred to as MEK) and, while maintaining the temperature at 50° C. under a nitrogen stream, 205.5 g′ (1.5 mol) of n-butyl bromide was added dropwise over 2 hours and, then, the temperature was maintained at 80° C. for 2 hours to drive the reaction to completion. Then, the reaction mixture was filtered to give N-methyl-N-butylpyrrolidinium bromide (hereinafter referred to as MBPyBr) as slightly yellowish white crystals. These crystals were then washed with MEK twice to give 187 g (yield 90%) of white MBPyBr.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[C:24]3=[N:25][CH:26]=[N:27][C:28](Cl)=[C:23]3[CH:22]=[N:21]2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[F:30][C:31]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:32]=1[OH:39].O>CN(C)C=O.C(OCC)C>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[C:24]3=[N:25][CH:26]=[N:27][C:28]([O:39][C:32]4[CH:33]=[C:34]([F:38])[C:35]([F:37])=[CH:36][C:31]=4[F:30])=[C:23]3[CH:22]=[N:21]2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: Oc1cc(F)c(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4cc(F)c(F)cc4F)ncnc32)CC1
Temperature: 100 °C
Yield: 49 %

Procedure:
Potassium carbonate (53 mg, 0.39 mmol) was added to a solution of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 100 mg, 0.3 mmol) and 2,4,5-trifluoro-phenol (available from Alfa Aesar, Ward Hill, Mass., USA; 57 mg, 0.39 mmol) in dimethylformamide (5 mL). The reaction mixture was heated at 100° C. in an oil bath overnight, then it was cooled to room temperature, and water and diethyl ether were added. The aqueous phase was extracted twice with diethyl ether and three times with hexane. The combined organic phases were evaporated and the resulting residue was purified by C18 reversed phase HPLC using a gradient of 20-100% acetonitrile/water to give 4-[4-(2,4,5-trifluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (66 mg, 50%) as a white powder. 1H NMR (300 MHz, CDCl3) δ 1.49 (s, 9H), 1.95-2.06 (m, 2H), 2.18-2.34 (m, 2H), 2.90-3.06 (m, 2H), 4.26-4.38 (m, 2H), 4.90-5.02 (m, 1H), 7.09-7.21 (m, 2H), 8.16 (s, 1H), 8.49 (s, 1H). HRMS Calcd. for C21H23F3N5O3 (MH+): 450.1748. Found: 450.1745.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][O:10][C:9]2=[O:19])[CH:5]=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:28]([NH2:30])[CH3:29])[CH:24]=[CH:25][C:26]=1[Cl:27]>CS(C)=O.CCOC(C)=O>[Cl:20][C:21]1[CH:22]=[C:23]([C@H:28]([NH:30][C:2]2[N:7]=[C:6]([N:8]3[C@H:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:11][O:10][C:9]3=[O:19])[CH:5]=[CH:4][N:3]=2)[CH3:29])[CH:24]=[CH:25][C:26]=1[Cl:27].[Cl:20][C:21]1[CH:22]=[C:23]([C@@H:28]([NH:30][C:2]2[N:7]=[C:6]([N:8]3[C@H:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:11][O:10][C:9]3=[O:19])[CH:5]=[CH:4][N:3]=2)[CH3:29])[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: O=C1OC[C@@H](c2ccccc2)N1c1ccnc(Cl)n1
Reactant: CC(N)c1ccc(Cl)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C[C@@H](Nc1nccc(N2C(=O)OC[C@H]2c2ccccc2)n1)c1ccc(Cl)c(Cl)c1
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@H]2c2ccccc2)n1)c1ccc(Cl)c(Cl)c1

Procedure:
A solution of (R)-3-(2-chloropyrimidin-4-yl)-4-phenyloxazolidin-2-one (83 mg, 0.30 mmol) and 1-(3,4-dichlorophenyl)ethanamine (260 mg, 1.37 mmol, 4.5 equiv) in DMSO (1.5 mL) was heated at 110° C. for 1½ h. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3×8 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 0 to 40%) provided (R)-3-(2-((R)-1-(3,4-dichlorophenyl)ethylamino)pyrimidin-4-yl)-4-phenyloxazolidin-2-one and (R)-3-(2-((S)-1-(3,4-dichlorophenyl)ethylamino)pyrimidin-4-yl)-4-phenyloxazolidin-2-one.