Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:11]=2[NH:10][C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[N:39]=[C:38](C(Cl)(Cl)Cl)[O:37][N:36]=2)=[CH:25][CH:24]=1.CN(C)C=[O:47].[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:11]=2[N:10]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:39][C:38](=[O:47])[O:37][N:36]=3)=[CH:25][CH:24]=2)[C:9]1=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: CCc1cc2c(=O)n(Cc3ccccc3)c(=O)[nH]c2s1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(Cc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 50 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a mixture of 3-benzyl-6-ethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (1.66 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (0.15 g), and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To the obtained residue was added 1N aqueous sodium hydroxide solution (50 mL), and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was adjusted to pH 4 with 1N hydrochloric acid, and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and the obtained solid was recrystallized from tetrahydrofuran-diethyl ether to give the title compound as colorless crystals (1.12 g, 60%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([OH:24])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26][S:27][CH2:28][CH2:29][CH2:30][N:31]([CH2:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:32](=[O:36])[C@@H:33]([CH3:35])[NH2:34]>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([NH:34][C@@H:33]([C:32]([N:31]([CH2:30][CH2:29][CH2:28][S:27][CH3:26])[CH2:37][CH2:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:36])[CH3:35])=[O:24])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSCCCN(CCCc1ccccc1)C(=O)[C@@H](C)N
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)O
Agent: Cl
Product: CSCCCN(CCCc1ccccc1)C(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OC(C)(C)C

Procedure:
By the method of part B of Example 8, N-(tert-butyloxycarbonyl)-O-(tert-butyl)-L-tyrosine (1.50 g.) was condensed with N-[3-(methylthio)propyl]-N-(3-phenylpropyl)-D-alaninamide hydrochloride (1.470 g.), affording N-(tert-butyloxycarbonyl)-O-(tert-butyl)-L-tyrosyl-N-[3-(methylthio)propyl]-N-(3-phenylpropyl)-D-alaninamide as a viscous oil (2.716 g.). ##STR21##
Reaction SMILES: [OH:1]O.N1(CCCNC2N=[N+:15]([O-:27])[C:16]3[CH:26]=[C:25]4[C:20]([CH2:21][CH2:22][CH2:23]O4)=[CH:19][C:17]=3[N:18]=2)CCOCC1.[C:28](O)([C:30](F)(F)F)=[O:29]>C(Cl)Cl.N>[N+:15]([C:16]1[CH:26]=[C:25]2[C:20]([CH2:21][CH2:22][CH2:23]2)=[CH:19][C:17]=1[NH:18][C:28](=[O:29])[CH3:30])([O-:27])=[O:1]
Reactant: [O-][n+]1nc(NCCCN2CCOCC2)nc2cc3c(cc21)OCCC3
Reactant: OO
Reactant: O=C(O)C(F)(F)F
Agent: N
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
H2O2 (70%, 0.74 mL, ca. 14.7 mmol) was added dropwise to a stirred solution of TFM (2.1 mL, 14.7 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 243 (509 mg, 1.5 mmol) and TFA (0.57 mL, 7.4 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 20° C. for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 243 (80 mg, 16%) and (ii) 1,4-dioxide 244 (75 mg, 16%) as a red solid: mp (MeOH/EtOAc) 173-176° C.; 1H NMR δ 8.33 (br t, J=4.9 Hz, 1H, NH), 8.01 (s, 1H, H-5), 7.62 (s, 1H, H-10), 4.31 (br dd, J=5.3, 5.2 Hz, 2H, H-8), 3.83 (br t, J=4.6 Hz, 4H, 2×CH2O), 3.62-3.68 (m, 2H, CH2N), 3.03-3.08 (m, 2H, H-6), 2.58 (br dd, J=6.2, 6.0 Hz, 2H, CH2N), 2.50 (m, 4H, 2×CH2N), 2.07-2.13 (m, 2H, H-7), 1.84-1.91 (m, 2H, CH2); 13C NMR δ 154.5, 148.7, 136.1, 133.2, 129.9, 117.3, 105.2, 67.1, 66.9 (2), 57.8, 53.8 (2), 41.6, 26.1, 24.4, 21.3. Anal. calcd for C17H23N5O3.¼H2O: C, 55.8; H, 6.5; N, 19.1. Found: C, 55.8; H, 6.5, 18.8%.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[NH2:27].[Br:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41](O)=[O:42]>>[Br:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([NH:27][C:26]1[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:24]([O:23][CH3:22])[CH:25]=1)=[O:42]
Reactant: O=C(O)CCCCCBr
Reactant: COc1cc(N)cc(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Product: COc1cc(NC(=O)CCCCCBr)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 39.4 %

Procedure:
WSC (2.11 g, 11 mmols) and HOBt (1.68 q, 11 mmols) were added to a (15 ml) solution of 3,4,5-trimethoxyaniline (2.75 g, 15 mmols) and 6-bromohexanoic acid (1.95 g, 10 mmols), and stirred at room temperature for 12 hours. The reaction mixture was extracted with ether, The organic layer was washed with water, 1 N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified through silica, gal column chromatography (developer:hexane/acetone=5/1), and the resulting crystals were recrystallized from ether-hexane to obtain 1.42 g (yield: 40%) of 6-bromo-N-(3,4,5-trimethoxyphenyl) hexanamide colorless needle-like crystals.
Reaction SMILES: [C:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P(OCC)(OCC)OCC1C=CC=CC=1>O>[C:13]1([NH:12][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: Oc1cccc2ccccc12
Agent: CCOP(OCC)OCc1ccccc1
Solvent: O
Product: c1ccc(Nc2cccc3ccccc23)cc1
Temperature: 200 °C
Yield: 87 %

Procedure:
288 parts of α-naphthol, 205 parts of aniline and 15 parts of benzyl diethyl phosphite are mixed and heated to 200° C. The elimination of water commences at this temperature and has ended when the internal temperature is 235° C. 33 parts of water are removed in the course of 5 hours. After distilling off excess α-naphthol and aniline, 381 parts of phenyl-α-naphthylamine, boiling at 202° - 204° C/5 mm Hg. are obtained; the product has a melting point of 55° - 58° C and corresponds to a yield of 87% of theory.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:9][CH2:8][CH2:7][C@H:6]2[N:3]1[C:4](=[O:12])[C@@H:5]2[N+:10]#[C-:11].C([Li])CCC.[CH3:19][C:20]([CH3:22])=[O:21].C(O)(=O)C>O1CCCC1.CCCCCC>[CH3:1][C:2]1([CH3:13])[O:9][CH2:8][CH2:7][C@H:6]2[N:3]1[C:4](=[O:12])[C@@:5]2([C:20]([OH:21])([CH3:22])[CH3:19])[N+:10]#[C-:11]
Reactant: [C-]#[N+][C@H]1C(=O)N2[C@@H]1CCOC2(C)C
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: [C-]#[N+][C@]1(C(C)(C)O)C(=O)N2[C@@H]1CCOC2(C)C
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
To a solution of (6R,7R)-2,2-dimethyl-7-isocyano-1-aza-3-oxabicyclo[4.2.0]octan-8-one (500 mg) in tetrahydrofuran (15 ml) was added a solution of n-butyllithium in hexane (2.33 ml of 1.55M solution) at -70° C. and the mixture was stirred at -70° C. for 15 minutes. A solution of acetone (0.265 ml) in tetrahydrofuran (2.4 ml) was added to the reaction mixture at -70° C. and the mixture was stirred at -70° C. for 25 minutes. Acetic acid (0.477 ml) was added to the mixture at -70° C. After stirring at -70° C. for 20 minutes, the mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate (80 ml) and the solution was washed with aqueous sodium bicarbonate. The aqueous layer was separated and extracted with ethyl acetate (20 ml). The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The crystalline residue was washed with isopropyl ether and filtered to give (6R,7R)-2,2-dimethyl-7-(1-hydroxy-1-methylethyl)-7-isocyano-1-aza-3-oxabicyclo[4.2.0]octan-8-one (460 mg). The mother liquor was chromatographed on silica gel (5 g) eluting with a mixture of hexane and ethyl acetate (20:1-1:1) to give additional (6R,7R)-2,2-dimethyl-7-(1-hydroxy-1-methylethyl)-7-isocyano-1-aza-3-oxabicyclo[4.2.0]octan-8-one (65 mg) [(6R,7R)-isomer] and its (6R,7S)-isomer (103 mg).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH2:13]([C@@H:15]1[O:17][CH2:16]1)Cl>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C(O)(C)C>[CH2:13]([C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:5][C:1](=[O:11])[C:2]=12)=[O:6])[C@H:15]1[O:17][CH2:16]1
Reactant: ClC[C@H]1CO1
Reactant: O=C1NC(=O)c2ccccc21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [K]
Solvent: CC(C)O
Product: O=C1NC(=O)c2c(C[C@@H]3CO3)cccc21
Reaction time: 46 h
Yield: 83.1 %

Procedure:
Into a reaction vessel were put potassium phthalimide (50.0 g, 0.27 mol), benzyltrimethylammonium chloride 5.00 g, 0.027 mol) and isopropanol (500 ml), and the mixture was cooled to 10° C. Thereto was added (R)-epichlorohydrin (74.9 g, 0.81 mol) and the mixture was stirred for 46 hours while being cooled. The solvent was removed and to the residue was added ethyl acetate (250 ml). The mixture was washed with water (250 ml), and then ethyl acetate was removed to give crude (R)-glycidylphthalimide (optical purity: 97% e.e.). The crude product was crystallized from ethyl acetate-hexane to give the object (R)-glycidylphthalimide (45.6 g, yield: 83%, optical purity: 98% e.e.) as white crystals. mp 100–102° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]3[CH:17]=[C:18]([CH:21]=[C:22]([F:24])[CH:23]=3)[C:19]#[N:20])[CH:8]=2)[NH:3]1.[CH2:25]([O:27][CH:28](OCC)[O:29][CH2:30][CH3:31])[CH3:26]>>[CH2:25]([O:27][CH:28]([O:29][CH2:30][CH3:31])[N:3]1[C:4]2[C:9](=[CH:8][C:7]([C:16]3[CH:17]=[C:18]([CH:21]=[C:22]([F:24])[CH:23]=3)[C:19]#[N:20])=[CH:6][CH:5]=2)[C:10]2([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[C:2]1=[O:1])[CH3:26]
Reactant: CCOC(OCC)OCC
Reactant: N#Cc1cc(F)cc(-c2ccc3c(c2)C2(CCCCC2)C(=O)N3)c1
Product: CCOC(OCC)N1C(=O)C2(CCCCC2)c2cc(-c3cc(F)cc(C#N)c3)ccc21
Yield: 56.4 %

Procedure:
A solution of 3-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluorobenzonitrile (1.0 eq, 0.27 g, 0.84 mmol) in triethylorthoformate (2 mL, 12 mmol) was heated to 150° C. for 1 h. The reaction mixture was allowed to cool, the excess triethylorthoformate was removed in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with 10% EtOAc/hexane) to give the title compound (0.2 g, 56%) as a white powder, mp 146° C. 1H NMR (DMSO-d6; 400 MHz) δ 1.13 (t, 6H, J=7 Hz), 1.60-1.96 (m, 10H), 3.48 (m, 2H), 3.66 (m, 2H), 6.17 (s, 1H), 7.35 (d, 1H, J=8.3 Hz), 7.68 (dd, 1H, J=2.0, 8.3 Hz), 7.77 (ddd, 1H, J=1.3, 2.4 Hz), 7.89 (d, 1H, J=2.0 Hz), 7.92 (dt, 1H, J=2.4, 10.5 Hz), 8.08 (dd, 1H, J=1.3, 2.9 Hz). MS ((+)−EI) m/z 422 [M+]. Anal. Calcd for C25H27FN2O3: C, 71.07; H, 6.44; N, 6.63. Found: C, 70.75; H, 6.48; N, 6.52.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[H-].[Na+].[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH2:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][N:16]=1>CN(C=O)C>[ClH:14].[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH2:28][CH2:29][CH2:30][N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][N:16]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: O=C1Cc2cc(Br)ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(C3C(=O)Nc4ccc(Br)cc43)ncnc2cc1OCCCN1CCOCC1
Product: Cl
Yield: 39.3 %

Procedure:
Using an analogous procedure to that described in Example 50, 5-bromooxindole (318 mg, 1.5 mmol), (prepared according to J. Am. Chem. Soc. 1975, 67, 1656), was treated with sodium hydride (60 mg, 1.5 mmol) in DMF (4 ml) and 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (169 mg, 0.5 mmol), (prepared as described for the starting material in Example 5), to give 4-(5-bromooxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline hydrochloride (108 mg, 35%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[CH2:9]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[C:21](=O)[CH2:22][CH2:23][CH2:24][CH:25]=2)[CH2:16][CH2:15]1)[CH2:10][CH2:11][CH2:12][CH3:13].Cl.C([O:30]CC)C>>[CH2:9]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH2:21][CH2:22][C:23]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([OH:30])[CH2:24][CH:25]=2)[CH2:16][CH2:15]1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCC[C@H]1CC[C@H](C2=CCCCC2=O)CC1
Reactant: Brc1ccccc1
Reactant: CCOCC
Agent: Cl
Agent: [Mg]
Product: CCCCC[C@H]1CC[C@H](C2=CCC(O)(c3ccccc3)CC2)CC1

Procedure:
A solution of 5.0 g of bromobenzene in 20 ml of anhydrous diethyl ether was added dropwise under stirring at 10°-15° C. to 0.66 g of magnesium metal powder, followed by reaction at room temperature for 1 hour so that a Grignard reagent was formed. After 5 g of trans-4-pentylcyclohexylcyclohexenone were added under stirring at -10° to 0° C. to the thus-formed Grignard reagent, they were reacted at room temperature for additional 1 hour. After the completion of the reaction, diluted hydrochloric acid was added dropwise to the reaction mixture, followed by the extraction of the reaction mixture with diethyl ether. After the extract was washed with saturated NaCl, anhydrous sodium sulfate was added to dry the extract. The diethyl ether was distilled off under reduced pressure, whereby 1-(trans-4-pentylcyclohexyl)-4-phenyl-4-hydroxycyclohexene was obtained as a crude reaction product.
Reaction SMILES: [CH3:1][O:2]/[C:3](=[CH:8]\[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:34])[C:22](OC3C=CC([N+]([O-])=O)=CC=3)=[O:23])[CH:16]=2)=[CH:11][CH:10]=1)/[C:4]([O:6][CH3:7])=[O:5].[CH2:35]([NH2:39])[CH2:36][CH2:37][CH3:38]>>[CH2:35]([NH:39][C:22](=[O:23])[N:21]([C:17]1[CH:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9](/[CH:8]=[C:3](\[O:2][CH3:1])/[C:4]([O:6][CH3:7])=[O:5])=[CH:14][CH:13]=2)[CH:20]=[CH:19][CH:18]=1)[CH3:34])[CH2:36][CH2:37][CH3:38]
Reactant: COC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)c2)cc1)OC
Reactant: CCCCN
Product: CCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)OC)cc2)c1
Yield: 64 %

Procedure:
In a manner similar to that of Example 10d, starting with 1.7 g (3.2 mmol) of methyl (Z)-2-methoxy-3-{3′-[methyl-(4-nitrophenoxycarbonyl)amino]biphenyl-4-yl}acrylate and 0.4 mL (3.9 mL) of n-butylamine, 0.8 g (64%) of methyl (Z)-3-[3′-(3-butyl-1-methylureido)biphenyl-4-yl]-2-methoxyacrylate is obtained in the form of a white solid with a melting point of 89° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[OH:25])[N:8]=2)[CH2:3]1.[CH:26]1([C:29](O)=[O:30])[CH2:28][CH2:27]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:25])[C:18]=1[C:9]1[N:8]=[C:7]([N:4]2[CH2:5][CH2:6][C@@H:2]([NH:1][C:29]([CH:26]3[CH2:28][CH2:27]3)=[O:30])[CH2:3]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=C(O)C1CC1
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3c(O)cccc3F)nc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)C4CC4)C3)nc(-c3c(O)cccc3F)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a solution of 2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol (100 mg, 0.295 mmol) in 10 mL DMF, at −2° C., was added cyclopropanecarboxylic acid (23 μL, 0.30 mmol), followed by the addition of triethylamine (82 μL, 0.59 mmol) and a solution of HATU (124 mg, 0.32 mmol) in 4 mL DMF. The mixture was warmed to room temperature and stirred for 1 h. Cold water was added to the reaction mixture which resulted in the formation of a precipitate which was collected by filtration and dissolved in CH2Cl2. The solution was then dried over MgSO4, filtered, and concentrated to afford N-((R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)cyclopropanecarboxamide (80 mg, 66%) LC/MS: m/z 407.5 (M+H)+ at 2.08 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:11]=[C:10]([OH:20])[CH:9]=2)[CH:3]=1.Cl.C(C1C=CC=CN=1)(=N)N.Cl.C(C1C=C([Cl:41])C=CN=1)(=N)N>>[Cl:41][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:12]2[N:11]=[C:10]([OH:20])[CH:9]=[C:8]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=3)[N:13]=2)[CH:19]=1
Reactant: Oc1cc(-c2cc(Cl)ccn2)nc(-c2ccccn2)n1
Reactant: N=C(N)c1cc(Cl)ccn1
Agent: Cl
Agent: N=C(N)c1ccccn1
Product: Oc1cc(-c2cc(Cl)ccn2)nc(-c2cc(Cl)ccn2)n1

Procedure:
The procedure is as described in the case of 6-(4-chloropyrid-2-yl)-2-pyrid-2-yl-pyrimidin-4-ol (ligand PM1) in Example 3 except that, instead of 2-amidinopyridine hydrochloride, the 2-amidino4-chloropyridine hydrochloride from Example 8 is used. After recrystallisation from DMSO, 2,6-bis(4-chloropyrid-2-yl)-pyrimidin-4-ol (ligand PM5) is obtained in the form of a colourless solid. 1H-NMR (360 MHz, DMSO-d6): 12.53 (br s, 1H); 8.74 (d, J=5.0 Hz, 1H); 8.74 (s, 1H); 8.71 (d, J=5.0 Hz, 1H); 8.64 (d, J=2.3 Hz, 1H); 7.83 (dd, J=5.0, 2.3 Hz, 1H); 7.71 (dd, J=5.0, 2.3 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11][CH:12]=1)=[O:5].Cl[C:30]([C:32]1[CH:33]=[C:34]([CH:43]=[CH:44][CH:45]=1)[CH2:35][S:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])=[O:31].N1C=CC=CC=1>O1CCCC1>[C:13]1([C:10]2[N:11]=[CH:12][C:7]([NH:6][C:4]([C:3]3[CH:19]=[C:20]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:21]=[CH:22][C:2]=3[NH:1][C:30]([C:32]3[CH:33]=[C:34]([CH:43]=[CH:44][CH:45]=3)[CH2:35][S:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])=[O:31])=[O:5])=[CH:8][N:9]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1cnc(-c2ccccc2)nc1
Reactant: COC(=O)CCSCc1cccc(C(=O)Cl)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2cnc(-c3ccccc3)nc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-amino-N-(2-phenylpyrimidin-5-yl)-5-(piperidin-1-yl)benzamide (138 mg, 0.37 mmol, 1.00 equiv) in tetrahydrofuran (6 mL) was added methyl 3-(3-(chlorocarbonyl)benzylthio)propanoate (112 mg, 0.41 mmol, 1.10 equiv) and pyridine (60 mg, 0.76 mmol, 2.00 equiv) and the resulting solution was stirred for 5 h at room temperature. The reaction progress was monitored by LCMS. The crude product was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5](I)=[CH:4][N:3]=1.[CH2:14]([N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])[CH2:15][CH2:16][C:17]#[CH:18].O>CN(C)C=O.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5]([C:18]#[C:17][CH2:16][CH2:15][CH2:14][N:19]2[C:20](=[O:29])[C:21]3[C:22](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:24])=[CH:4][N:3]=1
Reactant: Clc1ncc(I)c(N2CCCC2)n1
Reactant: C#CCCCN1C(=O)c2ccccc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCC#Cc1cnc(Cl)nc1N1CCCC1
Reaction time: 4 h
Yield: 63.9 %

Procedure:
To a suspension of bis(triphenylphosphine)palladium(II) dichloride (1.02 g) and copper(I) iodide (558 mg) in N,N-dimethylformamide (90 mL), triethylamine (10.2 mL), 2-chloro-5-iodo-4-(pyrrolidin-1-yl)pyrimidine (H1, 4.49 g), and N-(4-pentynyl)phthalimide (4.65 g) were added at room temperature under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 4 hours. To the reaction mixture, water was added. The solid matter was taken by filtration, washed with water, then dried under reduced pressure, and purified by silica gel column chromatography. The obtained solid matter was washed with ethyl acetate, and then dried under reduced pressure to obtain 2-(5-(2-chloro-4-(pyrrolidin-1-yl)pyrimidin-5-yl)-4-pentyn-1-yl)isoindoline-1,3-dione (H2, 3.66 g).
Reaction SMILES: [NH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[S:2]1(=[O:14])=[O:13].[H-].[Na+].Cl[CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.O>CN(C)C=O.C(OCC)(=O)C>[F:33][C:30]1[CH:29]=[CH:28][C:27]([N:24]2[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][CH2:18][N:1]3[C:11]4=[C:12]5[C:7](=[CH:8][CH:9]=[CH:10]4)[CH2:6][CH2:5][CH2:4][N:3]5[S:2]3(=[O:13])=[O:14])[CH2:26][CH2:25]2)=[CH:32][CH:31]=1
Reactant: Fc1ccc(N2CCN(CCCCl)CC2)cc1
Reactant: O=S1(=O)Nc2cccc3c2N1CCC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=S1(=O)N(CCCN2CCN(c3ccc(F)cc3)CC2)c2cccc3c2N1CCC3
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 65.8 %

Procedure:
A solution of 5,6-dihydro(1H,4H)-1,2,5-thiadiazolo[4,3,2-ij]quinoline 2,2-dioxide (5.34 g) in dry N,N-dimethylformamide (50 cc) is added dropwise to a suspension of sodium hydride (0.72 g, 80% suspension in oil) in N,N-dimethylformamide (20 cc). After 15 minutes' stirring, 1-(3-chloropropyl)-4-(4-fluoro-phenyl)piperazine (7.68 g) is added. The reaction mixture is heated to 100° C. for 1 hour and 30 minutes and is then cooled and poured into a mixture of water (300 cc) and ethyl acetate (500 cm). The organic phase is washed with water (3×200 cc), is dried over magnesium sulphate and is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.2-0.063-mm particle size, 6-cm diameter, 50-cm height) and eluted at a pressure of 0.7 bars of nitrogen with a mixture of cyclohexane and ethyl acetate (80-20 by volume), 125-cc fractions being collected. Fractions 10 to 28 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is recrystallized from ethanol (80 cc). 1-[3-(4-(4-Fluorophenyl)piperazinyl)propyl]-5,6-dihydro(1H,4H)-1,2,5-thiadiazolo[4,3,2-ij]quinoline 2,2-dioxide (7.2 g) is obtained, melting at 98° C.