Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:3]([C:11]2([CH2:32][OH:33])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=3[C:23]([O:25][CH3:26])=[O:24])[C:12]2=[O:31])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[O:31]=[C:12]1[C:11]2([C:3]3=[CH:4][C:5]4[O:9][CH2:8][O:7][C:6]=4[CH:10]=[C:2]3[O:33][CH2:32]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]1[CH2:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1ccccc1CN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2ccccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: COC(=O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Yield: 74 %

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using methyl 2-{[3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoate to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained as a white powder in 74% yield: mp 166-167° C.; 1H NMR (300 MHz, CDCl3) δ 8.05 (m, 1H), 7.44 (m, 1H), 7.34 (t, 1H), 7.22-7.10 (m, 3H), 7.03 (m, 1H), 6.70 (d, 1H), 6.52 (s, 1H), 6.21 (s, 1H), 5.90-5.84 (m, 2H), 5.52-5.33 (m, 2H), 4.99 (d, 1H), 4.72 (d, 1H), 3.95 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.8, 167.5, 156.0, 148.9, 142.4, 142.3, 137.4, 132.8, 132.1, 131.4, 129.0, 128.6, 127.4, 126.5, 123.9, 123.6, 119.4, 109.5, 103.1, 101.5, 93.7, 80.7, 58.4, 52.3, 42.4; MS (ES+) m/z 430.3 (M+1), 452.3 (M+23).
Reaction SMILES: [I-:1].O.[F:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][C@H:13]([CH2:15][OH:16])[O:12][C:11]2=[O:17])[CH:7]=[CH:8][CH:9]=1>[Ag+].FC(F)(F)C([O-])=O>[I:1][C:9]1[CH:8]=[CH:7][C:6]([N:10]2[CH2:14][C@H:13]([CH2:15][OH:16])[O:12][C:11]2=[O:17])=[CH:5][C:4]=1[F:3]
Reactant: [I-]
Reactant: O=C1O[C@@H](CO)CN1c1cccc(F)c1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: O
Product: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.9 %

Procedure:
In 300 ml of acetonitryl was dissolved 30 g of (R)-3-(3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol prepared in the Preparation example 2, and 46 g of trifluoroacetic acid silver salt (CF3COOAg) and 43 g of iodide were added to the solution. After being stirred for one day at room temperature, the solution was added with water and was extracted with ethyl acetate. The organic layer, thus separated, was washed with brine and dehydrated. And then the residue was filtered, concentrated in vacuo and dried thereby to form the title compound 44 g. Yield 94%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:21])[C:9]2[CH:20]=[CH:19][C:12]3[N:13]([CH3:18])[C:14]([NH:16][CH3:17])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:22][S:23]([CH2:26][C:27]1[CH:28]=[C:29]([NH2:33])[CH:30]=[CH:31][CH:32]=1)(=[O:25])=[O:24]>>[CH3:22][S:23]([CH2:26][C:27]1[CH:28]=[C:29]([NH:33][C:2]2[N:7]=[C:6]([N:8]([CH3:21])[C:9]3[CH:20]=[CH:19][C:12]4[N:13]([CH3:18])[C:14]([NH:16][CH3:17])=[N:15][C:11]=4[CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:30]=[CH:31][CH:32]=1)(=[O:24])=[O:25]
Reactant: CS(=O)(=O)Cc1cccc(N)c1
Reactant: CNc1nc2cc(N(C)c3ccnc(Cl)n3)ccc2n1C
Product: CNc1nc2cc(N(C)c3ccnc(Nc4cccc(CS(C)(=O)=O)c4)n3)ccc2n1C

Procedure:
The title compound was prepared following the procedure of Example 1 with N5-(2-chloropyrimidin-4-yl)-N2,N5,1-trimethyl-1H-benzimidazole-2,5-diamine (48 mg, 0.16 mmol) and 3-methanesulfonylmethyl-phenylamine (30 mg, 0.16 mmol) as a white solid (75 mg, 83%). 1H NMR (300 MHz, d6-DMSO) δ 9.23 (s, 1H), 7.89 (s, 1H), 7.79 (d, J=6.0 Hz, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.19-7.27 (m, 3H), 7.13 (s, 1H), 6.87-6.93 (m, 2H), 5.66 (d, J=6.0 Hz, 1H), 4.33 (s, 2H), 3.54 (s, 3H), 3.43 (s, 3H), 2.93 (d, J=4.5 Hz, 3H), 2.89 (s, 3H). MS (ESI) m/z=452 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-])=O.Br[CH2:10][CH2:11][OH:12]>CN(C=O)C>[NH2:1][C:4]1[N:5]=[CH:6][N:7]([CH2:10][CH2:11][OH:12])[CH:8]=1
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: OCCBr
Solvent: CN(C)C=O
Product: Nc1cn(CCO)cn1

Procedure:
2-(4-amino-1H-imidazol-1-yl)ethanol was prepared by Procedure A using 4-nitro-1H-imidazole and 2-bromoethanol in DMF instead of ACN.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]Br)[CH:10]=1.[Na]>O1CCCC1>[CH3:6][O:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:10]=1
Reactant: C1CCNC1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [Na]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a stirred solution of pyrrolidine (7.3 mL, 87 mmol) in dry tetrahydrofuran (5 mL), a solution of 3-bromomethyl-benzoic acid methyl ester (2.0 g, 8.7 mmol) in 5 mL of dry tetrahydrofuran was added dropwise and the mixture stirred at room temperature for 4 hours. The reaction mixture was then poured into 100 mL of saturated aqueous solution of sodium hydrogenocarbonate, extracted with 100 mL of ethyl acetate, dried over sodium sulfate and evaporated to dryness affording the title compound as yellow oil (1.85 g).
Reaction SMILES: [N:1]1([CH:6]=[CH:7][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Ni]>[N:1]1([CH2:6][CH2:7][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C=CN1CCCC1)c1ccccc1-c1ccccc1
Agent: [Ni]
Solvent: CCO
Product: CC(CCN1CCCC1)c1ccccc1-c1ccccc1

Procedure:
A solution of 2.77 g of 1-pyrrolidino-3-p-biphenylyl-1-butene (obtainable from 3-p-biphenylyl-butanal and pyrrolidine) in 35 ml of ethanol is hydrogenated, over 0.5 g of Raney nickel, for 3 hours at 6 atms and 60°. The catalyst is filtered off and the solution is evaporated to give 1-pyrrolidino-3-p-biphenylyl-butane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([CH:25]1[CH2:27][CH2:26]1)[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1.[Cu][C:29]#[N:30]>CN(C=O)C.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([CH:25]1[CH2:27][CH2:26]1)[C:18]1[CH:23]=[CH:22][C:21]([C:29]#[N:30])=[CH:20][CH:19]=1
Reactant: N#C[Cu]
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccc(Br)cc2)(C2CC2)N1CC(F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Product: N#Cc1ccc(C2(C3CC3)c3cc(Cl)ccc3NC(=O)N2CC(F)(F)F)cc1
Temperature: 190 °C

Procedure:
To a solution of 0.39 g (0.85 mmol) 6-chloro-4-cyclopropyl-4-(4-bromophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one in 2.5 mL DMF was added 0.13 g (1.4 mmol) copper(I) cyanide and the mixture heated in a sealed tube at 190° C. for 2 hours. After cooling to room temperature, the reaction mixture was diluted with 125 mL ether, washed 2×100 mL water and 1×100 mL brine, dried over dried over MgSO4, filtered, and concentrated in vacuo. Purification by normal phase chromatography (40 g silica gel cartridge, linear gradient 5-75% EtOAc/hexanes) followed by preperative chiral chromatography (5×50 mm Chiralcel OD, 100% MeOH) provided the first peak (−) 6-chloro-4-cyclopropyl-4-(4-cyanophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one. Optical rotation −83° (c=0.00175 g/mL in CH2Cl2, Na lamp,) 1H NMR (CDCl3, 400 MHz) δ 8.18 (s, NH); 7.64 (br d, 2H, J=7.88 Hz); 7.39 (br d, 2H, J=6.22 Hz); 7.26 (obscured, 1H); 6.85 (br m, 1H); 6.74 (d, 1H, J=8.24 Hz); 4.34 (m, 1H); 4.23 (br m, 1H); 1.62 (m, 1H); 0.82 (m, 2H); 0.20 (m, 1H); 0.097 (m, 1H); MS (Electrospray): exact mass calculated for C20H15ClF3N3O+H 406.0925 found 406.0935 Collect 0.1 g second peak Optical rotation +100° (c=0.002 g/mL in CH2Cl2, Na lamp,).
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[C:15]1([S:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[CH:30]=O)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:32][O:33][C:34](=[O:47])[CH2:35][N:36]1[C:44]2[C:39](=[CH:40][C:41]([F:45])=[CH:42][CH:43]=2)[CH:38]=[C:37]1[CH3:46]>ClCCl.ClCCCl>[CH3:32][O:33][C:34](=[O:47])[CH2:35][N:36]1[C:44]2[C:39](=[CH:40][C:41]([F:45])=[CH:42][CH:43]=2)[C:38]([CH2:30][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][C:24]=2[S:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:22])=[O:23])=[C:37]1[CH3:46]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1cnccc1S(=O)(=O)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COC(=O)Cn1c(C)c(Cc2cnccc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 14.1 %

Procedure:
A mixture of triethylsilane (5.1 g), trifluoroacetic acid (3.1 g) and 1,2-dichloroethane (20 mL) at −10° C. was treated dropwise with a mixture of 4-phenylsulfonylpyridine-3-carbaldehyde (1.9 g), (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (0.66 g) and 1,2-dichloroethane (20 mL), and the resulting mixture was stirred at room temperature for 20 hours. The mixture was treated with additional triethylsilane (5.1 g) and trifluoroacetic acid (3.1 g), and stirred at room temperature for 3 hours and then at 50° C. for 20 hours. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 0:1 by volume), followed by trituration with diethyl ether to afford the title compound as a yellow powder (0.19 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:13][C@@H:12]3[C@@H:9]([CH2:10][N:11]3C(OC(C)(C)C)=O)[CH2:8]2)[CH:2]=1.O.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(O)C>[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:27][CH:28]=1.[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:27][CH:28]=1.[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:13][C@@H:12]3[C@@H:9]([CH2:10][NH:11]3)[CH2:8]2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN(c3cccnc3)C[C@H]21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: c1cncc(N2C[C@@H]3CN[C@@H]3C2)c1
Reaction time: 6 h
Yield: 74.8 %

Procedure:
The product of Example 38K (100 mg, 0.36 mmol) in ethanol (10 mL) was treated with 4-methylbenzenesulfonic acid monohydrate (144 mg, 0.76 mmol) at 80° C. and allowed to stir for 6 hours. The mixture was concentrated under reduced pressure and the residue was diluted with warm methyl tert-butyl ether (20 mL) and stirred at ambient temperature for 10 hours. The precipitate was isolated by filtration and dried under reduced pressure at 40-50° C. to provide the title compound (140 mg, 86% yield). 1H NMR (MeOH-d4, 300 MHz) δ 2.40 (s, 6H), 3.28 (dd, J=10.9, 6.4 Hz, 1H), 3.40 (dd, J=12.9, 5.5 Hz, 1H), 3.60 (m, 1H), 3.78 (dd, J=11.1, 5.0 Hz, 1H), 4.04 (d, J=10.8 Hz, 1H), 4.28 (d, J=12.9 Hz, 1H), 4.30 (m, 1H), 5.14 (dd, J=7.1, 5.4 Hz, 1H), 7.24 (d, J=7.8 Hz, 4H), 7.68 (d, J=8.1 Hz, 4H), 7.88 (dd, J=8.8, 5.4 Hz, 1H), 8.02 (ddd, J=9.1, 2.7, 1.3 Hz, 1H), 8.20 (d, J=5.4 Hz, 1H), 8.34 (d, J=3.0 Hz, 1H); m/z 176 (M+H)+; Anal. calculated for C10H13N3.2.4TsOH.H2O: C, 53.07; H, 5.68; N, 6.93. Found: C, 52.99; H, 5.23; N, 6.62.
Reaction SMILES: N1(C[N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)CCCC1.C([Li])CCC.[C:17]([C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:29]=1[O:30]COCCOC)[C:24](N)=[O:25])([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[CH3:40][C:37]([C:28]1[CH:27]=[C:23]([C:24]([C:11]2[CH:10]=[CH:9][NH:8][N:7]=2)=[O:25])[CH:22]=[C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:29]=1[OH:30])([CH3:38])[CH3:39]
Reactant: c1cnn(CN2CCCC2)c1
Reactant: COCCOCOc1c(C(C)(C)C)cc(C(N)=O)cc1C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)c2cc[nH]n2)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
To a solution of 1-(1-pyrrolidinomethyl)-pyrazole (Katrikzky, A. R.; Rewcastle, G. W.; Fan, W-Q., J. Org. Chem., 1988, 53, 5688) (3.32 g, 0.022 mole) in THF (75 mL) at -70° C. is added 1.6M n-butyllithium (14 mL) over a 20-minute period. After stirring at that temperature 1.5 hours a solution of N-methoxy-N-methyl-[3,5-di-tert-butyl-4[(2-methoxyethoxy) methoxy] -benzamide (Example 6) (7.62 g, 0.02 mole) in THF (75 mL) is added over a 30-minute period. The reaction mixture is allowed in warm to room temperature, treated with ice-cold 2N HCl (200 mL) and concentrated to remove the THF. The concentrated mixture is extracted with CH2Cl2. The extracts are washed with saturated NaHCO3 and brine, dried with Na2SO4 and evaporated. The residue is purified by flash chromatography (0-30% EtOAc/CH2Cl2) on silica gel to give 6.25 g of an oil. This product is deprotected by allowing to stand in 5% (w/v) HCl/MeOH (150 mL) for 2 days. The acid solution is evaporated and the residue is taken up in Et2O. The resulting solution is washed with saturated NaHCO3 and brine, and dried with Na2SO4. The ethereal solution is concentrated causing the precipitation of 3.62 g (75% of a white solid, [3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1H-pyrazol-3-yl methanone, mp 216°-219° C. 1H NMR (DMSO-d6) δ 1.42 (s, 18H, tert-butyl), 6.84 (m, 1H, OH), 8.19 (s, 2H, phenyl aromatics); pyrazole aromatics and NH appear as several poorly defined signals because of tautomerization at 7.6-7.9, 13.4, 13.9; IR (KBr) 1430, 1592, 1643 cm-1 ; MS (DEI) m/e 301 (M+ +1), 300 (M+), 95.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[S:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:23]3[CH:24]=[CH:25][S:21][CH:22]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:19]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: OB(O)c1ccsc1
Product: COc1ccc2c(-c3ccsc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and thiophene-3-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-(1-thiophen-3-yl-6-methoxy-isoquinolin-3-yl)-amine. LC-MS m/e 337(MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7]([CH2:15][CH2:16][CH3:17])([CH2:12][CH2:13][CH3:14])[C:6]=2[N:5]=[C:4]([CH3:18])[N:3]=1.[Cl:19][C:20]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:21]=1[NH2:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl.CCOCC>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:19][C:20]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:21]=1[NH:22][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7]([CH2:15][CH2:16][CH3:17])([CH2:12][CH2:13][CH3:14])[C:6]=2[N:5]=[C:4]([CH3:18])[N:3]=1
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: CCCC1(CCC)CCCc2c(Cl)nc(C)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCC1(CCC)CCCc2c(Nc3ccc(Cl)cc3Cl)nc(C)nc21
Temperature: 25 °C
Yield: 84.3 %

Procedure:
4-Chloro-2-methyl-8,8-dipropyl-5,6,7,8-tetrahydroquinazoline (114 mg, 0.42 mmol), 2,4-dichloroaniline (76 mg, 0.47 mmol), and 4-toluenesulfonic acid hydrate (203 mg, 1.06 mmol) were combined in toluene (4 mL) and heated in an oil bath at 100° for 28 hrs. The mixture was cooled to room temp, diluted with EtOAc (30 mL), washed with sat. NaHCO3 solution, brine and dried over MgSO4. Evaporation afforded 262 mg of crude product which was purified by flash chromatography and eluted with CH2Cl2:hexane (1:1). This afforded 151 mg (90%) as a viscous liquid which crystallized on standing. This material was dissolved in EtOAc (1.5 mL) and then treated all at once with 2N HCl in Et2O (0.40 mL, 2 eq). The resulting white solid was filtered off, washed with a little Et2O and dried to afford 139 mg of (2,4-dichlorophenyl)-(2-methyl-8,8-dipropyl-5,6,7,8-tetrahydroquinazolin-4-yl)amine as a hydrochloride salt. Mp 238.3°−243.9° C. MS (ES+) 392 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][CH:8]=[C:9]([CH2:11][C:12](OCC)=[O:13])[N:10]=1.[Li].[H-]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][CH:8]=[C:9]([CH2:11][CH2:12][OH:13])[N:10]=1
Reactant: CCOC(=O)Cc1coc(-c2cccs2)n1
Agent: [H-]
Agent: [Li]
Product: OCCc1coc(-c2cccs2)n1
Yield: 73 %

Procedure:
In substantially the same manner as in Reference Example 72. ethyl 2-(2-thienyl)-4-oxazolylacetate was subjected to reduction with lithium alminum hydride to obtain 2-[2-(2-thienyl)-4-oxazolyl]ethanol as an oil. The yield was 73%.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[C:3]1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(Cl)Cl.C(N(CC)CC)C>CO>[O:1]=[C:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][C:8]([OH:10])=[O:9])[C@@H:3]1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCC1=C(CC(=O)O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CCCCC[C@@H]1C(=O)CC[C@@H]1CC(=O)O
Reaction time: 0.08 h

Procedure:
Into a Schlenk type vessel, kept anhydrous and under Ar, there was injected the precatalytic solution (6.75 ml) containing 47 mg (0.05 mmole) of bis(trifluoro-acetato)[(+)-(R)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl]ruthenium (II), 3-oxo-2-pentyl-1-cyclopentene-1-acetic acid (0.5 g, 2.4 mmole), CH2Cl2 (5 ml), methanol (5 ml) and triethylamine (10.28 mg, 0.1 mmole, 14 μl, dist. over KOH). After stirring for 5 min, the orange soltion was filtered through a single use filter (Acrodisc 0.45 μm) in a dry autoclave (100 ml/107Pa) under Ar. The autoclave was then connected to a source of hydrogen and rinsed 5× with hydrogen at a pressure of 106Pa. The autoclave was then pressurized at 9×106Pa. Stirring at this pressure and 25° was carried out during 120 h. Afterwards, the pressure was gently released, the autoclave opened and the orange solution concentrated.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH2:23][CH2:24][C:25]5[N:26]([C:28]([C:31]([F:34])([F:33])[F:32])=[N:29][N:30]=5)[N:27]=4)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:35](O)(=[O:40])[CH2:36][CH2:37][CH2:38][CH3:39]>>[C:35]([N:4]1[CH2:3][CH2:2][N:1]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH2:23][CH2:24][C:25]5[N:26]([C:28]([C:31]([F:33])([F:34])[F:32])=[N:29][N:30]=5)[N:27]=4)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:40])[CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: FC(F)(F)c1nnc2n1N=C(N1CCC(c3ccc(OCCN4CCNCC4)cc3)CC1)CC2
Reactant: CCCCC(=O)O
Product: CCCCC(=O)N1CCN(CCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Yield: 36 %

Procedure:
Obtained in 36% yield by an analogous method to Example 4.1, starting from 6-[4-[4-[2-(piperazin-1-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine and pentanoic acid.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH2:17][CH:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)[C:6]=3[C:5]1=2)#[N:2].[OH:31][Li].O.OO>CO.C(OCC)(=O)C>[NH:21]1[CH2:20][CH2:19][CH:18]([CH2:17][O:16][C:7]2[N:8]=[CH:9][N:10]=[C:11]3[C:6]=2[C:5]2[C@@H:4]([CH2:3][C:1]([NH2:2])=[O:31])[CH2:15][CH2:14][C:13]=2[S:12]3)[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ncnc3sc4c(c23)[C@@H](CC#N)CC4)CC1
Reactant: [Li]O
Agent: OO
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: NC(=O)C[C@H]1CCc2sc3ncnc(OCC4CCNCC4)c3c21
Temperature: 0 °C

Procedure:
To a solution of tert-butyl 4-([[(3R)-3-(cyanomethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]methyl)piperidine-1-carboxylate (290 mg, 0.68 mmol, 1.00 equiv) in methanol (20 mL) were added LiOH.H2O (114 mg, 2.71 mmol, 4.01 equiv). This was followed by the addition of H2O2 (30%) (114 mg, 4.00 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 4 h at room temperature. The resulting solution was diluted with 50 mL of ethyl acetate. The resulting mixture was washed with 3×20 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum. This resulted in 220 mg (73%) of tert-butyl 4-([[(3R)-3-(carbamoylmethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]methyl)piperidine-1-carboxylate as a white solid.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19].Br[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19]
Reactant: Cc1ccc(B(O)O)cc1[N+](=O)[O-]
Reactant: Brc1ncccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ncccn2)cc1[N+](=O)[O-]
Yield: 55 %

Procedure:
To a toluene (40 ml)-ethanol (40 ml) mixed solvent were added 4-methyl-3-nitrophenylboronic acid (2.66 g, 14.7 mmol), 2-bromopyrimidine (3.15 g, 19.81 mmol), tetrakis(triphenylphosphine)palladium(0) (1.01 g, 0.874 mmol) and sodium carbonate (3.93 g, 37.08 mmol), and the mixture was heated under reflux for 24 hr. The reaction mixture was cooled, diluted with ethyl acetate, washed with diluted aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give a solid. This was purified by silica gel column chromatography (ethyl acetate-dichloromethane) to give the title compound (1.74 g, yield 55%) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][N:9]([CH:12]3[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13]3)[C:8]2=[O:18])=[C:4]([Cl:21])[CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[Cl:21][C:4]1[CH:3]=[C:2]([C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:5]=1[CH2:6][CH:7]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13]2)[C:8]1=[O:18]
Reactant: O=C1C(Cc2ccc(Br)cc2Cl)CCN1C1CC=CCC1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: O=C1C(Cc2ccc(-c3cccnc3)cc2Cl)CCN1C1CC=CCC1
Temperature: 25 °C
Yield: 16.2 %

Procedure:
Combine 3-(4-bromo-2-chloro-benzyl)-1-cyclohex-3-enyl-pyrrolidin-2-one (370 mg, 1.01 mmol), 3-pyridine boronic acid (372 mg, 3.03 mmol), tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.10 mmol), Na2CO3 (2.14 g, 20.2 mmols), water (1.5 mL), 1,2-dimethoxy-ethane (8 mL) and heat at 80° C. for 20 hours. Cool the reaction mixture to room temperature, add saturated aqueous NaHCO3 (5 mL) and extract with EtOAc (3×10 mL). Dry the organic layer over anhydrous Na2SO4, remove the solvent and purify the residue by chromatography over silica gel eluting with EtOAc in hexane (0 to 100%) to obtain 3-(2-chloro-4-pyridin-3-yl-benzyl)-1-cyclohex-3-enyl-pyrrolidin-2-one as a clear oil (60 mg, 16%): MS (ES+) m/z=367 (M+H)+.