Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].[C:19]([O:23][C:24](=[O:27])[CH2:25]Br)([CH3:22])([CH3:21])[CH3:20]>CN1CCCC1=O>[C:3]1(=[O:12])[N:2]([O:1][CH2:25][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:27])[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]12
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)CON1C(=O)c2ccccc2C1=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 92.8 %

Procedure:
N-hydroxyphthalimide (3.87 g, 23 mmol) and potassium carbonate (2.14 g, 15.5 mmol) were suspended in 1-methyl-2-pyrrolidinone (23 mL) and heated to 40° C. t-Butyl-bromoacetate (4.58 g, 23 mmol) was added, and the reaction temperature was increased to 50° C., and held at this temperature for 4 hours, and then poured into 50 mL of ice water to precipitate the product. The solid was collected on a glass filter funnel and washed with water until the filtrate was colorless. The precipitate was dried on the filter funnel with the house vacuum, and by azeotroping with chloroform. This afforded 5.92 g (91% yield) of product with a melting point of 143-144° C. The compound was characterized as NMR and MS as follows: 1) C-NMR (CDCl3): 28.39, 73.82, 83.38, 124.04, 129.22, 134.99, 163.40, 166.29 ppm; 2) H-NMR (CDCl3): 1.46 (s, 9H); 4.68 (s, 2H); 7.74 (m, 2H); 7.83 (m, 2H) ppm; and 3) MS (ESI): 300.2 [M+Na]+, 577.3 [2M+Na]+.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:45])[O:16][C@@H:17]2[C@@H:29]3[C:30](=[O:33])[O:31][CH2:32][C@H:28]3[C@H:27]([C:34]3[CH:39]=[C:38]([O:40][CH3:41])[C:37]([OH:42])=[C:36]([O:43][CH3:44])[CH:35]=3)[C:26]3[C:18]2=[CH:19][C:20]2[O:24][CH2:23][O:22][C:21]=2[CH:25]=3)=[CH:10][CH:9]=1.Cl[C:47]([O:49][C:50]1[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][CH:51]=1)=[O:48].C([O-])(O)=O.[Na+]>ClCCl>[C:47](=[O:48])([O:49][C:50]1[CH:51]=[CH:52][C:53]([N+:56]([O-:58])=[O:57])=[CH:54][CH:55]=1)[O:42][C:37]1[C:36]([O:43][CH3:44])=[CH:35][C:34]([C@H:27]2[C@@H:28]3[CH2:32][O:31][C:30](=[O:33])[C@H:29]3[C@@H:17]([O:16][C:15]([NH:14][C:11]3[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=3)=[O:45])[C:18]3[C:26]2=[CH:25][C:21]2[O:22][CH2:23][O:24][C:20]=2[CH:19]=3)=[CH:39][C:38]=1[O:40][CH3:41]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc([C@@H]2c3cc4c(cc3[C@H](OC(=O)Nc3ccc(F)cc3)[C@@H]3C(=O)OC[C@@H]23)OCO4)cc(OC)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc([C@@H]2c3cc4c(cc3[C@H](OC(=O)Nc3ccc(F)cc3)[C@@H]3C(=O)OC[C@@H]23)OCO4)cc(OC)c1OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
1.07 mmol of pyridine and then, dropwise, a solution of 0.59 mmol of the compound of Example 4 in 5 ml of dichloromethane, are added, under argon, to a solution of 0.83 mmol of para-nitrophenyl chloroformate in 20 ml of anhydrous dichloromethane. After stirring for 1 hour, the reaction mixture is hydrolysed by the addition of a saturated aqueous NaHCO3 solution, and then the extracted organic phases are washed, neutralised, dried, filtered and concentrated under reduced pressure. Chromatography on silica gel (cyclohexane/ethyl acetate: 3/1) enables the expected product to be isolated.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.C1OCCOCCOCCOCCOC1.[H-].[Na+].Br[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43]([C:46]([O:48][CH3:49])=[O:47])=[CH:42][CH:41]=2)=[C:36]([O:50][CH3:51])[CH:35]=1>CN(C=O)C.O>[CH3:51][O:50][C:36]1[CH:35]=[C:34]([CH2:33][N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]2=[O:1])[CH:39]=[CH:38][C:37]=1[C:40]1[CH:45]=[CH:44][C:43]([C:46]([O:48][CH3:49])=[O:47])=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: COC(=O)c1ccc(-c2ccc(CBr)cc2OC)cc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3=O)cc2OC)cc1
Temperature: 60 °C

Procedure:
A solution of Example 500B (328 mg, 1.64 mmol) in DMF (4 mL) at room temperature was treated with 15-crown-5 (361 mg, 1.64 mmol) and 60% sodium hydride in mineral oil (66 mg, 1.64 mmol). The mixture was treated with a solution of Example 500C (500 mg, 1.49 mmol) in DMF (2 mL), heated to 60° C. for 16 hours, cooled to room temperature, treated with water (20 mL), and extracted three times with ethyl acetate (50 mL). The combined extracts were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 1:1 ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[C:19]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]([O:27][CH2:28][CH3:29])=[O:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([I:18])=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(C=Cc1ccc(Cl)cc1)c1ccc(I)cc1
Product: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1ccc(I)cc1)c1ccc(Cl)cc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 3-(4-chlorophenyl)-1-(4-iodophenyl)prop-2-en-1-one and diethyl malonate, diethyl 2-(1-(4-chlorophenyl)-3-(4-iodophenyl)-3-oxopropyl)malonate was obtained as beige coloured solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:20]([NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([C:28]#[CH:29])[CH:27]=3)=[N:19][CH:18]=[N:17][C:9]2=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16].N#N.C(Cl)[Cl:33]>C(#N)C>[C:28]([C:26]1[CH:25]=[CH:24][C:23]([Cl:33])=[C:22]([NH:21][C:20]2[C:8]3[C:9](=[CH:10][C:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=3)[N:17]=[CH:18][N:19]=2)[CH:27]=1)#[CH:29]
Reactant: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Reactant: ClCCl
Agent: N#N
Solvent: CC#N
Product: C#Cc1ccc(Cl)c(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Reaction time: 0.5 h

Procedure:
300 mg erlotinib was dissolved in 200 mL CH2Cl2 at −78° C. cooled by dry-ice/acetone bath. A mixture of F2 and N2 gas containing 20% F2/80% N2 was passed through the reaction vessel continuously at a flow rate of 2 L/min. Reaction was stopped after 30 min and the solvent was removed under vacuum. Dried reaction products were dissolved in 3 mL acetonitrile and was separated on an Agilent Zorbax C8 250×4.6 mm column, gradient elution from 30% MeOH/70% 0.1% formic acid in dd-H2O to 90% MeOH/10% 0.1% formic acid in dd-H2O, 1 ml/min total flow rate. Each fraction was analyzed by mass spectrometry. Fractions containing reaction products without excess amount of the starting material erlotinib, were mixed to form the modified erlotinib mixture compound library for drug property screening to identify components with improved properties over erlotinib. A component with m/z value corresponding to mono-chlorinated erlotinib was isolated and purified by successive preparative HPLC separations. The purified compound was analyzed by LC-MS/MS and NMR to provide the structure of the title compound. The observed m/z value 428.1371 (Thermo Finnigan LTQ Orbitrap, positive ion mode), is consistent with calculated m/z of protonated mono-chlorinated erlotinib (m/z(calc)=428.1372), molecular formula: C22H23ClN3O4+. High resolution MSn (n=2-4) experiments on LTQ orbitrap indicate the fluorine substitution is on the 3-ethynylphenyl ring of erlotinib (fragment at m/z 152.0262, calc: 152.0261 for C8H7ClN+). 1H-NMR spectra data indicate the chlorine substitution is at the 6-position of the 3-ethynylphenyl ring of erlotinib. 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.36 (s, 3H), 3.38 (s, 3H), 3.88 (m, 4H), 4.3-4.4 (m, 5H), 7.38 (s, 1H), 7.46 (dd, J=8.6, 2.7, 1H), 7.87 (d, J=8.6, 1H), 7.96 (d, J=2.7, 1H), 8.53 (s, 1H), 8.87 (s, 1H).
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6](=O)[CH2:7][C:8]1[S:9][C:10]2[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:11]=2[N:12]=1)C>C(O)C.C1COCC1>[Br:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([CH2:7][CH2:6][OH:5])[S:9][C:10]=2[CH:16]=1
Reactant: CCOC(=O)Cc1nc2ccc(Br)cc2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: OCCc1nc2ccc(Br)cc2s1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred mixture of sodium borohydride (1.11 g, 29.3 mmol) in ethanol (10 mL) at room temperature was added a solution of the (6-bromo-benzothiazol-2-yl)-acetic acid ethyl ester (2.2 g, 7.3 mmol) in THF (25 mL) at 23–28° C. The mixture was stirred at room temperature for 15 hr, cooled to 3° C. and quenched with 20 mL water at 3–5° C. The product was extracted with 40 mL methylene chloride, washed with 20 mL 15% NaCl and concentrated to crude oil. The crude product was purified by column chromatography (silica gel, 10:90 MeOH:CHCl3) to give the pure 2-(6-Bromo-benzothiazol-2-yl)-ethanol: 1H NMR (CDCl3 400 MHz) δ 3.30 (t, 2H, J=6 Hz), 4.11 (t, 2H, J=6 Hz), 7.54 (dd, 1H, J=5, 2 Hz), 7.78 (d, 1H, J=5 Hz), 7.95 (d, 1H, J=2 Hz). 13C NMR (CDCl3, 400 MHz) δ 36.7, 60.8, 118.3, 123.3, 129.2, 136.1, 151.3, 169.5; (DCI/NH3) m/z 258, 260 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][C@H:18]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][C:12]=3[CH:11]=[C:10]([C:37]([NH:39][NH2:40])=[O:38])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[C:41](N1C=CN=C1)(N1C=CN=C1)=[O:42].N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:29][C@H:30]4[CH2:31][CH2:32][C@H:33]([CH3:36])[CH2:34][CH2:35]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][C@H:18]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][C:12]=3[CH:11]=[C:10]([C:37]3[O:38][C:41](=[O:42])[NH:40][N:39]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(C(=O)NN)nc(-c4cncc(Cl)c4)c32)CC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(-c4n[nH]c(=O)o4)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carbohydrazide (4.5 g, 8.03 mmol) and 1,1′-carbonyldiimidazole (1.43 g, 8.84 mmol) dissolved in acetonitrile (53.6 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.8 mL, 32.1 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was washed with water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% methanol/dichloromethane, and then 0-100% ethyl acetate/hexanes, linear gradient) to afford 5-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,3,4-oxadiazol-2(3H)-one. MS ESI calc'd. for O31H32ClN7O3 [M+H]+ 586. found 586. 1H NMR (500 MHz, DMSO-d6) δ 12.62 (s, 1H), 8.79 (d, J=8.3, 2H), 8.27 (s, 1H), 7.87 (s, 1H), 7.42 (t, J=10.0, 2H), 7.25 (t, J=7.2, 2H), 7.22-7.17 (m, 1H), 4.76 (s, 1H), 4.05-3.81 (m, 4H), 3.80-3.69 (m, 1H), 3.67-3.47 (m, 2H), 3.27 (s, 1H), 1.37 (t, J=13.0, 2H), 1.03 (broad, 1H), 0.83 (broad, 1H), 0.68 (d, J=6.2, 4H), 0.64-0.52 (m, 2H), 0.51-0.27 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][S:7][C@@H:8]2[CH2:13][O:12][C@@H:11](/[C:14](/[CH3:26])=[CH:15]/[C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[O:10][CH2:9]2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:37])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][S:7]([C@@H:8]2[CH2:9][O:10][C@@H:11](/[C:14](/[CH3:26])=[CH:15]/[C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:18][CH:17]=3)[O:12][CH2:13]2)=[O:37])=[CH:27][CH:28]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C/C(=C\c1ccc(C(F)(F)F)cc1)[C@H]1OC[C@H](SCc2ccc(Cl)cc2)CO1
Solvent: ClCCl
Product: C/C(=C\c1ccc(C(F)(F)F)cc1)[C@H]1OC[C@H](S(=O)Cc2ccc(Cl)cc2)CO1
Reaction time: 0.25 h

Procedure:
In 10 ml of methylene chloride were dissolved 382 mg (0.89 mmol) of trans-5-[(4-chlorobenzyl)thio]-2-[(E)-1-methyl-2-[4-(trifluoromethyl)phenyl]vinyl]-1,3-dioxane, and 188 mg (0.92 mmol) of m-chloroperbenzoic acid (purity: 85%) were added to the solution, followed by stirring of the resulting mixture for 15 minutes. The reaction mixture was washed with an aqueous sodium hydrogencarbonate solution and the solid obtained by evaporation of the solvent was washed with a mixed solvent of ethyl acetate-hexane to obtain 328 mg (yield: 83%) having a melting point of 192 to 194° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.B(Br)(Br)[Br:18].O>C(Cl)Cl>[Br:18][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: BrB(Br)Br
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: O
Solvent: ClCCl
Product: Clc1ccc(C(Br)c2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 15.14 g (59.3 mmol) of bis(4-chlorophenyl)methanol in 100 mL of methylene chloride was added slowly a solution of 71.2 mL of BBr3 (71.2 mmol, 1M in CH2Cl2). The solution was stirred for at 0° C. for 1 h. Then 60 mL of water was added to quench the reaction and the reaction mixture was poured into 200 mL of methylene chloride. The water layer was extracted with methylene chloride (60 mL×2) and the combined organic layer was dried over Na2SO4 and concentrated to give the title compound; 1NMR (CDCl3) δ 6.24 (s, 1H), 7.36 (d, 4H, J=8.7 Hz), 7.41 (d, 2H, J=8.7 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:12][O:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:24][CH3:25]>C(#N)C>[C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]1[CH2:12][O:11][N:10]([CH2:24][CH3:25])[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCBr
Reactant: CC(C)(C)OC(=O)NC1CONC1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCN1OC[C@@H](NC(=O)OC(C)(C)C)C1=O
Temperature: 140 °C

Procedure:
(3-Oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester (0.2 g, prepared from (D)-cycloserine as described in Chem. Pharm. Bull. 2002, 50(4) 554-557) was dissolved in acetonitrile (20 ml) then potassium carbonate (0.69 g), potassium iodide (0.175 g) and bromoethane (0.13 g) were added. The reaction was heated under microwave irradiation for 1 hour at 140° C. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, brine and then dried over sodium sulphate. The solvent was removed in vacuo and the crude product was purified by column chromatography (eluent cyclohexane/ethyl acetate) to afford ((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester as a yellow solid. LCMS (method A) 1.29 min, MH+(-BOC) 131; 1H-NMR (CDCl3, 400 MHz): 5.10 (m, 1H), 4.75 (m, 1H), 4.55 (m, 1H), 3.95 (m, 1H), 3.60 (m, 2H), 1.50 (s, 9H), 1.20 (m, 3H).
Reaction SMILES: [I-].[K+].CS(O[CH2:8][CH2:9][O:10][C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=3)=[C:23]([F:35])[CH:22]=2)[NH:13][N:12]=1)(=O)=O.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[F:35][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[N:17]=[CH:16][N:15]=[C:14]3[NH:13][N:12]=[C:11]([O:10][CH2:9][CH2:8][N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[C:19]=23)[CH:26]=[CH:25][C:24]=1[O:27][C:28]1[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCOS(C)(=O)=O)c34)cc2F)cn1
Reactant: C1COCCN1
Agent: [I-]
Agent: [K+]
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCOCC5)c34)cc2F)cn1
Yield: 46 %

Procedure:
The procedure described in Example 23 was repeated (except that potassium iodide was not used) using 2-{[4-({3-fluoro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy}ethyl methanesulfonate and morpholine to give the title compound in 46% yield; NMR Spectrum: 2.45 (s, 3H), 2.51 (hidden by DMSO, 4H), 2.84 (t, 2H), 3.57 (s, 4H), 4.46 (t, 2H), 7.27 (m, 3H), 7.56 (dd, 1H), 8.00 (dd, 1H), 8.24 (d, 1H), 8.36 (s, 1H), 8.62 (br s, 1H); Mass Spectrum: 466 (MH+).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[C:17]12([CH2:27][C:28](Cl)=[O:29])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2>>[C:17]12([CH2:27][C:28]([NH:1][N:2]3[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]3=[O:16])=[O:29])[CH2:24][CH:23]3[CH2:22][CH:21]([CH2:20][CH:19]([CH2:25]3)[CH2:18]1)[CH2:26]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1nc(C(F)(F)F)c2ccccc2c1=O
Yield: 77 %

Procedure:
The product of Example 11B (50.6 mg) and (adamantan-1-yl)acetyl chloride (54 mg, 0.25 mmol) were treated as in Example 6 to give the title compound (69 mg, 0.17 mmol) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.47 (s, 1H), 8.44 (dd, 1H), 8.18-7.98 (m, 3H), 2.08 (s, 2H), 1.99-1.92 (m, 3H), 1.75-1.55 (m, 12H); MS (DCI) M/Z 423.3 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]2[C:10]3[CH:17]=[CH:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:4][N:3]=1.[CH3:18][C:19]1[CH:28]=[CH:27][C:26]2[C:25]([NH:29][C:30]3[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=3[CH3:40])=[N:24][CH:23]=[CH:22][C:21]=2[C:20]=1[NH2:41].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:41][C:20]2[C:21]3[CH:22]=[CH:23][N:24]=[C:25]([NH:29][C:30]4[CH:35]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:33]=[CH:32][C:31]=4[CH3:40])[C:26]=3[CH:27]=[CH:28][C:19]=2[CH3:18])[C:5]([C:9]2[C:10]3[CH:17]=[CH:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:4][N:3]=1
Reactant: Cc1ccc(C(F)(F)F)cc1Nc1nccc2c(N)c(C)ccc12
Reactant: Clc1ncc(-c2ncnc3[nH]ccc23)c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(F)(F)F)cc1Nc1nccc2c(Nc3nc(Cl)ncc3-c3ncnc4[nH]ccc34)c(C)ccc12
Temperature: 70 °C

Procedure:
A mixture of 4-(2,4-dichloropyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidine (89 mg, 335 μmol) and 6-methyl-N1-(2-methyl-5-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine (111 mg, 335 μmol) in DMSO (2 mL) was treated with DIPEA (0.3 mL). The mixture was heated to 70° C. in an oil bath for 2 days. Additional quantities of 4-(2,4-dichloropyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidine (3×20 mg) were added during the course of the reaction. The reaction mixture was cooled to rt and poured onto 50 g of ice with 20 mL of NaHCO3. The resulting suspension was extracted with EtOAc (3×50 mL). The EtOAc solution was washed with brine then dried over Na2SO4 and concentrated. The residue was purified via prep LCMS on silica [4% 1M NH3-MeOH in DCM-EtOAc (5-1)]. The residue was further purified by trituation in MeOH to give the title compound as a light yellow solid. MS (ESI, pos. ion) m/z: 561.2 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9](=[O:10])[CH2:8][CH2:7][C@@H:6]1[C:11]([NH:13][CH:14]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:15]([OH:19])[C:16]([OH:18])=O)=[O:12].[CH:31]1([NH2:34])[CH2:33][CH2:32]1.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>>[CH:31]1([NH:34][C:16](=[O:18])[CH:15]([OH:19])[CH:14]([NH:13][C:11]([C@H:6]2[CH2:7][CH2:8][C:9](=[O:10])[N:5]2[CH2:4][C:3]2[CH:27]=[CH:28][CH:29]=[CH:30][C:2]=2[F:1])=[O:12])[CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:33][CH2:32]1
Reactant: NC1CC1
Reactant: O=C(O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1F

Procedure:
The reaction was carried out in analogy to reaction step 20.3 by reacting 3-((R)-1-(2-fluorobenzyl)-5-oxopyrrolidine-2-carboxamido)-2-hydroxy-4-phenylbutanoic acid with cyclopropanamine using HATU (1.2 equivalents) as coupling reagent and DIPEA (3 equivalents) as base. ESI-MS [M+H]+=454.2.
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:3]([N:4]([CH2:12][CH2:13][C:14]([C:27]4[NH:31][N:30]=NN=4)([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:5]3)[CH2:2]1)[CH2:9]2.[C:32](OC(=O)C)(=[O:34])[CH3:33].N1C=CC=CC=1>O>[CH:8]12[CH2:7][CH:6]3[CH2:11][CH:1]([CH2:2][CH:3]([N:4]([CH2:12][CH2:13][C:14]([C:27]4[O:34][C:32]([CH3:33])=[N:30][N:31]=4)([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:5]3)[CH2:10]1)[CH2:9]2
Reactant: c1ccc(C(CCN2CC3CC4CC(C3)CC2C4)(c2ccccc2)c2nnn[nH]2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: Cc1nnc(C(CCN2CC3CC4CC(C3)CC2C4)(c2ccccc2)c2ccccc2)o1

Procedure:
A solution of 48 parts of 5-{3-[4-azatricyclo(4.3.1.13,8)undecan-4-yl]-1,1-diphenylpropyl}-1H-tetrazole and 140 parts of acetic anhydride in 400 parts of pyridine is heated at the boiling point under reflux for 3 hours, then cooled and thereupon diluted with 100 parts of water. The resultant mixture is stirred for 10 minutes, whereupon solvent is removed by vacuum distillation and the residue partitioned between a saturated aqueous solution of sodium bicarbonate and diethyl ether. The ethereal phase is separated and consecutively washed with a saturated aqueous solution of sodium bicarbonate and water, then extracted with 2% hydrochloric acid. The acid extract is made alkaline, and the resultant mixture is extracted with ether. The ether extract is washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate, stripped of solvent by vacuum distillation, affords 2-{3-[4-azatricyclo(4.3.1.13,8)undecan-4-yl]-1,1-diphenylpropyl}-5-methyl-1,3,4-oxadiazole melting at approximately 120°-121° as the residue. It has the formula ##STR11##
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:5][C@@H:4]1[C:6]([NH:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:13][N:12]=1)[CH3:10])=[O:7].[C:23]1(O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.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>O1CCCC1.O>[O:1]([CH2:2][C@H:3]1[CH2:5][C@@H:4]1[C:6]([NH:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([F:22])([F:20])[F:21])=[CH:13][N:12]=1)[CH3:10])=[O:7])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[C@@H](NC(=O)[C@H]1C[C@@H]1CO)c1ccc(OCC(F)(F)F)cn1
Reactant: Oc1ccccc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)[C@H]1C[C@@H]1COc1ccccc1)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.6 %

Procedure:
To a mixture of (1S*,2S*)-2-(hydroxymethyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cy clopropanecarboxamide (30 mg, 0.094 mmol) and phenol (16.0 mg, 0.17 mmol) in tetrahydrofuran (1 mL), triphenylphosphine (45 mg, 0.17 mmol) and di-tert-butyl azodicarboxylate (28.2 mg, 0.12 mmol) were added successively. After stirring at room temperature for 1 day, the mixture was poured into water, and the aqueous layer was extracted with dichloromethane three times. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative LC-MS to give 12.1 mg (33% yield) of the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-:14].[Na+]>CC(=O)CC>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][I:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCCCc1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: ICCCCCCc1ccccc1

Procedure:
6-Phenylhexyl iodide [VIa; Ar is C6H5, R is H] was prepared from 16 g. of 6-phenylhexyl bromide (Preparation C12) and 10.95 g. of sodium iodide in 325 ml. of 2-butanone, to give 19.1 g. of product as an oil.