Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([CH:14]=1)[C:12]#[N:13])(C)C.[Cl:15][C:16]1[CH:17]=[C:18](I)[CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:15][C:16]1[CH:21]=[C:20]([C:5]#[C:6][C:7]2[CH:8]=[N:9][CH:10]=[C:11]([CH:14]=2)[C:12]#[N:13])[CH:19]=[CH:18][CH:17]=1
Reactant: Clc1cccc(I)c1
Reactant: C[Si](C)(C)C#Cc1cncc(C#N)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1cncc(C#Cc2cccc(Cl)c2)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 72.1 %

Procedure:
Combine 5-Trimethylsilanylethynyl-nicotinonitrile (3.00 g, 15.0 mmol), (prepared as described in PREPARATION 3), bis(triphenylphosphine)palladium (II) dichloride (526 mg, 0.750 mmol), copper (I) iodide (286 mg, 1.50 mmol), and 3-chloroiodobenzene (2.24 μL, 18.0 mmol) in triethylamine (29.3 mL, 210 mmol). Cool the mixture to −78° C. and add a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (15.3 mL, 15.3 mmol). After 5 min warn to room temperature and stir 72 h. Filter the reaction through diatomaceous earth, washing with ethyl acetate. Concentrate the filtrate and purify by silica gel chromatography, eluting with a gradient from 95:5 to 70:30 (90:10 hexanes:ethyl acetate):dichloromethane. Further purify by silica gel chromatography, eluting with dichloromethane, then 90:10 dichloromethane:ethyl acetate. Dissolve the chromatographed material (2.91 g) in cyclohexane (120 mL) at 80° C. and cool to room temperature. Collect the recrystallized material via vacuum filtration to give the title compound as a white crystalline solid (2.58 g, 72%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][N:6]=[CH:5]2.[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([CH2:23]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].CCCCCC.CCOCC>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH2:23][CH:21]3[CH2:22][N:19]([C:17]([O:16][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:18])[CH2:20]3)[N:7]=2)[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(C(=O)OC(C)(C)C)C2)cc1
Reactant: Cc1cc2[nH]ncc2cc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1cc2nn(CC3CN(C(=O)OC(C)(C)C)C3)cc2cc1Br

Procedure:
To a solution of 6.18 g of 5-bromo-6-methyl-1H-indazole and 15 g of tert-butyl-3-[(tosyl-oxy)methyl]azetidin-1-carboxylate in 200 ml DMF were added 9.54 g of caesium carbonate and 10.8 g of tetrabutylammonium iodide at 25° C., and this was then heated under reflux for 1.5 hrs. After cooling, the reaction mixture was treated with 1:1 hexane/ether and water, the phases separated and the aqueous phase extracted twice with 250 ml portions of 1:1 hexane/ether. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulphate, and concentrated in vacuo after filtration.
Reaction SMILES: ClC1C(Cl)=NC2C(=CC=C([N+]([O-])=O)C=2)N=1.Cl[C:17]1[C:26](Cl)=[N:25][C:24]2[C:19](=[CH:20][C:21]([CH3:31])=[C:22]([N+:28]([O-:30])=[O:29])[CH:23]=2)[N:18]=1.[K][S:33][C:34](=[C:37]([C:40]#[N:41])[C:38]#[N:39])[S:35][K]>>[N+:28]([C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[CH3:31])[N:18]=[C:17]1[S:33][C:34](=[C:37]([C:40]#[N:41])[C:38]#[N:39])[S:35][C:26]1=[N:25]2)([O-:30])=[O:29]
Reactant: N#CC(C#N)=C(S[K])S[K]
Reactant: Cc1cc2nc(Cl)c(Cl)nc2cc1[N+](=O)[O-]
Agent: O=[N+]([O-])c1ccc2nc(Cl)c(Cl)nc2c1
Product: Cc1cc2nc3c(nc2cc1[N+](=O)[O-])SC(=C(C#N)C#N)S3
Yield: 71 %

Procedure:
The process of Example 13 is followed except that the 2,3-dichloro-6-nitroquinoxaline is replaced by 1.5 g of 2,3-dichloro-6-nitro-7-methylquinoxaline and 1.5 g of the di(potassiomercapto)methylenemalononitrile is used. The recovered material is a dark yellow powder weighing 1.35 g with a calculated overall yield of 71 percent and has a melting point of 283° to 284° C.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][C@@H:24]1[C@H:28]2[N:29]([C:32](=[O:56])[C@@H:33]([NH:38][C:39](=[O:55])[C:40]3[CH:45]=[CH:44][C:43]([N:46]4[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][CH3:54])[CH2:48][CH2:47]4)=[CH:42][CH:41]=3)[CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:30][CH2:31][C@H:27]2[O:26][CH2:25]1>ClCCl>[CH3:37][CH:35]([CH3:36])[CH2:34][C@H:33]([NH:38][C:39](=[O:55])[C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][CH3:54])[CH2:48][CH2:47]2)=[CH:42][CH:41]=1)[C:32](=[O:56])[N:29]1[CH2:30][CH2:31][C@H:27]2[O:26][CH2:25][C:24](=[O:23])[C@@H:28]12
Reactant: CCCN1CCN(c2ccc(C(=O)N[C@@H](CC(C)C)C(=O)N3CC[C@H]4OC[C@H](O)[C@H]43)cc2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCCN1CCN(c2ccc(C(=O)N[C@@H](CC(C)C)C(=O)N3CC[C@H]4OCC(=O)[C@H]43)cc2)CC1
Reaction time: 18.5 h
Yield: 323.4 %

Procedure:
Oxidation to Example 3 Dess-Martin periodinane (1.83 g, 4.30 mmol) was added to a stirred solution of N—((S)-1-((3R,3aR,6aR)-3-hydroxydihydro-2H-furo[3,2-b]pyrrol-4(5H,6H, 6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide (250 mg, 0.546 mmol) in dichloromethane (45 mL) under an atmosphere of argon. The mixture was stirred for 18.5 hours then diluted with dichloromethane (200 mL). The organic phase was washed with aqueous sodium hydroxide solution (1M, 70 mL) then the aqueous extracted with dichloromethane (75 mL). The organic layer was washed with aqueous sodium hydroxide solution (1M, 70 mL) then brine (70 mL), then dried (Na2SO4), filtered and reduced in vacuo to give Example 3 as a pale yellow solid (0.831 g, 82%). TLC (Rf=0.30, MeOH:CH2Cl2 1:9), analytical HPLC main peak, Rt=9.80 min., HPLC-MS 471.3 [M+H]+, 489.3 [M+H2O+H]+, 963.6 [2M+Na]+; [α]D21−92.8° (c=3.29, CHCl3); δH (500 MHz, CDCl3)-hydrate not assigned here 0.91 (3H, d, J=6.58 Hz, CH(CH3)2), 0.93 (3H, t, J=7.32 Hz, CH2CH3), 1.00 (3H, d, J=6.47 Hz, CH(CH3)2), 1.52-1.78 (5H, m, CH2CH(CH3)2 and CH2CH3), 2.06-2.15 (1H, m, NCH2CH2CH), 2.29 (1H, dd, J=13.69 and 6.09 Hz, NCH2CH2CH), 2.40-2.45 (2H, m, NCH2CH2CH3), 2.66 (4H, brt, J=4.80 Hz, CH2NCH2CH2CH3), 3.35 (4H, brt, J=5.01 Hz, CH2CH2NCH2CH2CH3), 3.55-3.62 (1H, m, NCH2CH2CH), 3.98 (1H, d, J=17.03 Hz, OCH2C═O), 4.14 (1H, d, J=16.96 Hz, OCH2C═O), 4.17 (1H, brt, J=8.89 Hz, NCH2CH2CH), 4.66 (1H, d, J=5.16 Hz, NCH2CH2CHCH), 4.89 (1H, t, J=4.35 Hz, NCH2CH2CHCH), 5.01-5.06 (1H, m, CHCH2CH(CH3)2), 6.79 (1H, d, J=8.45 Hz, NH), 6.87 (2H, brd, J=8.97 Hz, aromatic CH), 7.70 (2H, brd, J=8.94 Hz, aromatic CH); δC (125 MHz, CDCl3) 11.91 (CH2CH3), 19.95 (CH2CH3), 22.12/23.28 and 24.77 (CH(CH3)2), 32.48 (NCH2CH2CH), 42.67 (CH2CH(CH3)2), 45.60 (NCH2CH2CHCH), 47.72 (NCH2CH2NCH2CH2CH3), 49.52 (CHCH2CH(CH3)2), 52.89 (NCH2CH2NCH2CH2CH3), 60.58 (NCH2CH2CH3), 62.15 (NCH2CH2CHCH), 71.02 (OCH2C═O), 80.78 (NCH2CH2CHCH), 114.06/114.09/128.51 and 128.59 (aromatic CH), 123.26 (aromatic quaternary), 153.49 (aromatic quaternary), 166.78 (NHC═O), 172.41 (CH2NC═O), 208.43 (ketone C═O).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:13][C:12]=2[C:24]([NH2:26])=[O:25])=[CH:7][CH:6]=1.C([NH:34][CH2:35][CH2:36][OH:37])C1C=CC=CC=1.COC1C=CC(C2NC(C(N)=O)=C(C3C=CC(OC)=CC=3)N=2)=CC=1>CO.[Pd]>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[C:14]1[O:15][C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:34][CH2:35][CH2:36][OH:37])=[CH:6][CH:7]=2)=[C:12]([C:24]([NH2:26])=[O:25])[N:13]=1
Reactant: OCCNCc1ccccc1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCCCl)cc1
Agent: [Pd]
Agent: COc1ccc(-c2nc(-c3ccc(OC)cc3)c(C(N)=O)[nH]2)cc1
Solvent: CO
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCCNCCO)cc1

Procedure:
The title compound was prepared by reaction of 5-(4-(2-chloroethoxy)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide with 2-(benzylamino)ethanol, according to the procedure described in example S-1, step c, followed by deprotection with the H-cube hydrogenation system (full H2 mode, 10% Pd\C catalyst, 1 ml/min, 60° C., 0.05M in MeOH). 1H NMR (DMSO) δ 2.79 (2H, t), 3.17 (2H, t), 3.55 (2H, t), 4.20 (2H. t), 7.05-7.15 (2H, m), 7.35-7.45 (2H, m), 7.60-7.80 (3H, m), 8.20-8.30 (2H, m). LCMS (2) 2.17 min; m/z (ES+) 404.
Reaction SMILES: C([Mg]Cl)(C)C.[NH:6]1[C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[CH:8]=[CH:7]1.[CH2:15]([O:17][C:18](=[O:32])[C:19](=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:16]>C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH2:23]([O:22][C:20](=[O:21])[CH:19]([CH:25]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:8]1[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:14]=2[NH:6][CH:7]=1)[C:18]([O:17][CH2:15][CH3:16])=[O:32])[CH3:24]
Reactant: CCOC(=O)C(=Cc1ccccc1)C(=O)OCC
Reactant: c1cc2[nH]ccc2cn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C(c1ccccc1)c1c[nH]c2ccncc12
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 70 %

Procedure:
To a RT solution of isopropylmagnesium chloride (1.5 M in THF, 2.4 mL, 3.6 mmol) in THF (10 mL) was added a solution of 1H-pyrrolo[3,2-c]pyridine (350 mg, 3 mmol) in THF (3 mL), followed by a solution of ZnCl2 in THF (1 M, 3.4 mL). After stirring the resulting mixture at 50° C. for 5 minutes, 2-benzylidene-malonic acid diethyl ester (1.0 mL, 4.5 mmol) was added dropwise. The mixture was stirred at 50° C. for 3 h, cooled to RT, quenched by addition of a saturated solution of NH4Cl, and extracted 3 times with EtOAc. The combined extracts were dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (EtOAc), affording 2-[Phenyl-(1H-pyrrolo[3,2-c]pyridin-3-yl)-methyl]-malonic acid diethyl ester (0.77 g, 70% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:6]1[NH:10][N:9]=[N:8][N:7]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[CH2:23]([N:8]1[N:9]=[N:10][C:6]([CH:5]([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)[C:4]([O:3][CH2:1][CH3:2])=[O:16])=[N:7]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C(c1nnn[nH]1)C1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(c1nnn(Cc2ccccc2)n1)C1CCCC1
Temperature: 50 °C
Reaction time: 14 h

Procedure:
To a stirred mixture of α-cyclopentyltetrazole-5-acetic acid, ethyl ester (step 1 of Example 14) and K2CO3 (12.3 g, 89.0 mmol) in acetone (200 mL) was added benzyl bromide (4.84 mL, 40.7 mmol) at ambient temperature. The resulting mixture was stirred at 50° C. for 14 h and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with hexane/ethyl acetate (10:1) to give 2.95 g (27% in 2 steps) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([O:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])[CH:13]=[C:12]([F:23])[CH:11]=2)=O)=[CH:4][C:3]=1[O:24][CH:25]([CH3:27])[CH3:26].Cl.[NH2:29][OH:30]>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([O:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])[CH:13]=[C:12]([F:23])[CH:11]=2)=[N:29][OH:30])=[CH:4][C:3]=1[O:24][CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)Oc1cc(C(=O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)Oc1cc(C(=NO)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 100 °C
Yield: 77 %

Procedure:
To a solution of (4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone, prepared as described in Procedure 3, 4, 59 and 68, (207 mg, 0.53 mmol) in pyridine (1.5 mL) was added hydroxylamine hydrochloride (192 mg, 2.8 mmol) and the reaction mixture was heated at 100° C. for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (50 mL). The organic portion was washed with 1 N HCl (2×20 mL), water (20 mL) and sat. NaCl (20 mL), then dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by ISCO (40 g silica gel column, 0-30% EtOAc/hexane over 30 min) to yield (4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone oxime (216 mg, 77% yield) as a colorless oil. LCMS: RT=2.13 min [M+H] 408.2 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:16])=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[N:8]([CH2:13][CH3:14])[C:7]2=[O:15].P(Cl)(Cl)([Cl:19])=O.CCN(C(C)C)C(C)C.[OH-].[Na+]>O>[Br:1][C:2]1[C:3]([F:16])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:19])[N:8]([CH2:13][CH3:14])[C:7]2=[O:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1c(=O)[nH]c2c(Br)c(F)ccc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCn1c(Cl)nc2c(Br)c(F)ccc2c1=O
Temperature: 25 °C
Yield: 98.3 %

Procedure:
A solution of 8-bromo-3-ethyl-7-fluoroquinazoline-2,4(1H,3H)-dione (512b, 2.20 g, 7.66 mmol), phosphorous oxychloride (Acros Organics, Geel, Belgium; 3.57 mL, 38.3 mmol), and DIPEA (5.34 mL, 30.6 mmol) was heated over a 130° C. oil bath for 4.5 h. The reaction mixture was then cooled to RT and poured onto ice, and the resulting mixture was diluted with water (250 mL) to provide a brown suspension. 10 N aqueous NaOH was added to the vigorously stirred suspension (maintaining the reaction mixture at 0° C.) until a pH of 10 was achieved. The precipitated solid was collected by vacuum filtration, washed with water (3×20 mL), and dried in vacuo to provide 8-bromo-2-chloro-3-ethyl-7-fluoroquinazolin-4(3H)-one (2.301 g, 7.53 mmol, 98% yield) as a tan solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.22 (1H, dd, J=8.9, 5.8 Hz), 7.23-7.29 (1H, m), 4.37 (2H, q, J=7.1 Hz), 1.41 (3H, t, J=7.0 Hz). 19F NMR (376 MHz, CDCl3) δ ppm −93.38 (1F, s). m/z (ESI, +ve) 304.7/306.8/308.7 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)=[C:5]([CH3:14])[NH:4][C:3]=1[C:15](O)=[O:16].C(OCC)(OCC)OCC>C(O)(C(F)(F)F)=O>[CH3:1][C:2]1[C:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)=[C:5]([CH3:14])[NH:4][C:3]=1[CH:15]=[O:16]
Reactant: Cc1[nH]c(C(=O)O)c(C)c1C1CCN(C)CC1
Solvent: CCOC(OCC)OCC
Solvent: O=C(O)C(F)(F)F
Product: Cc1[nH]c(C=O)c(C)c1C1CCN(C)CC1
Temperature: 25 °C
Yield: 91.7 %

Procedure:
A solution of 3,5-dimethyl-4-(1-methyl-piperidin-4-yl)-1H-pyrrole-2-carboxylic acid (12.67 mmol) in TFA (75 mL) was stirred at 0° C. for 30 mins. To the mixture was added triethyl orthoformate (20 mL), it was then allowed to warm up slowly to rt for 2 hours. The solvent was removed and to the residue was added NaHCO3, extracted with ethyl acetate, dried and concentrated to give 2.56 g of 3,5-dimethyl-4-(1-methyl-piperidin-4-yl)-1H-pyrrole-2-carbaldehyde as a light yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]2[N:20]([CH2:21][CH2:22][C:23](O)=[O:24])[C:19](=[O:26])[CH2:18][S:17]2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1>[C:12]([C:9]1[CH:8]=[C:7]([CH:16]2[N:20]([CH2:21][CH2:22][CH2:23][OH:24])[C:19](=[O:26])[CH2:18][S:17]2)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(C2SCC(=O)N2CCC(=O)O)cc(C(C)(C)C)c1O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C2SCC(=O)N2CCCO)cc(C(C)(C)C)c1O
Temperature: -7.5 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a solution of the resulting 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(2-carboxyethyl)-1,3-thiazolidin-4-one (100 mg) in tetrahydrofuran (3 ml) were added dropwise triethylamine (27 mg) and ethyl chloroformate (28 mg) at -10° C. under a nitrogen atmosphere, followed by stirring at -10 to -5° C. for 1 hour. To the mixture was added sodium borohydride (100 mg), the mixture was stirred at room temperature for 3 hours, then poured into ice-water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform-methanol, 98:2) to afford 70 mg (73%) of the product which was identical with that of Reference Example 15.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.[F:29][C:30]1[CH:38]=[C:37]2[C:33]([CH2:34][N:35]([CH:40]([CH3:42])[CH3:41])[C:36]2=[O:39])=[CH:32][C:31]=1B(O)O>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][C:30]=3[F:29])[C:36](=[O:39])[N:35]([CH:40]([CH3:42])[CH3:41])[CH2:34]4)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: CC(C)N1Cc2cc(B(O)O)c(F)cc2C1=O
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4cc5c(cc4F)C(=O)N(C(C)C)C5)c3cn2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and (6-fluoro-2-isopropyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)boronic acid. LCMS (M+H)+=483.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)Cl
Reactant: Oc1ccc(F)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1ccc(F)cc1F
Reaction time: 2 h
Yield: 97 %

Procedure:
104 g (796 mmol) of 2,4-difluorophenol was dissolved in 800 ml of dichloromethane, 132 ml of triethylamine and 92.0 ml of ethyl chloroformate were added under ice-cooling and the mixture was stirred at -10° to 0° C. for 2 hours. The reaction solution was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 156 g (97%) of 2,4-difluoro-O-ethoxycarbonylphenol.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][C:24](=[O:26])[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].CC(C)=O>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][CH:24]([OH:26])[CH3:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)COC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: CC(O)COC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1
Reaction time: 7 h
Yield: 60.5 %

Procedure:
To a solution of {2S,4R)-1-benzyloxycarbonyl-2-(2-oxopropyl)oxymethyl-4-methanesulfonyloxypyrrolidine (12 g) in ethanol (120 ml) was added by portions sodium borohydride (2.4 g) at 0° C. After 7 hours, to the reaction mixture was added dropwise acetone (20 ml) carefully at 0° C. and the solvent was evaporated in vacuo. To the resultant residue were added ethyl acetate (200 ml) and water (100 ml), the organic layer was separated, washed with brine (100 ml) and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (500 ml) eluting with 5% methanol in dichloromethane (V/V) gave (2S,4R)-1-benzyloxycarbonyl-2-(2-hydroxypropyl)oxymethyl-4-methanesulfonyloxypyrrolidine (7.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH2:14])=[N:10][CH:9]=2)=[CH:4][C:3]=1[F:15].Cl[CH:17]([C:20]1([C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[N:29]=[CH:28][CH:27]=[CH:26]3)[CH2:22][CH2:21]1)[CH:18]=O.O.C(N(CC)CC)C>C(O)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:17]([C:20]4([C:23]5[CH:24]=[C:25]6[C:30](=[CH:31][CH:32]=5)[N:29]=[CH:28][CH:27]=[CH:26]6)[CH2:22][CH2:21]4)=[CH:18][N:14]=3)[N:13]=2)=[CH:4][C:3]=1[F:15]
Reactant: Nc1ncc(-c2ccc(Br)c(F)c2)nn1
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Solvent: O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Fc1cc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3n2)ccc1Br

Procedure:
A mixture of 6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (80.0 mg, 0.297 mmol, Example 7, Steps 1-5) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (0.088 g, 0.36 mmol) in isopropyl alcohol (3 mL) and a drop of water was heated at 110° C. for 48 h. The mixture was adjusted to pH 9 with triethylamine. The volatiles were removed under reduced pressure. The residue was purified by chromatography on silica gel with EtOAc in CH2Cl2 (0-60%) to afford the desired product. LCMS: (M+H)=459.9/461.9.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]1[CH2:15][CH3:16].[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(O)(=O)C.C1(C)C=CC=CC=1.C(O)C>[CH2:15]([C:5]1[N:4]([CH2:3][CH2:2][N:28]2[CH2:27][CH2:26][N:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:31])([F:32])[F:17])[CH:20]=3)[CH2:30][CH2:29]2)[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)[CH3:16]
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: CCc1nc2ccccc2c(=O)n1CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCc1nc2ccccc2c(=O)n1CCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 98.9 %

Procedure:
3-(2-chloroethyl)-2-ethylquinazoline-4 (3H)-one (1.5 g; 6.34 mmol), 1-(3-(trifluoromethyl)phenyl)piperazine (1.459 g; 6.34 mmol), sodium carbonate (0.672 g; 6.34 mmol), sodium iodide (0.95 g; 6.34 mmol), ethanol (100 mL) and toluene (200 mL) were added to a 100 mL reactor. The reaction medium was heated to reflux and kept under agitation for a period of 24 hours, during which 250 mL of solvent were slowly removed with assistance from a Dean Stark. The reaction was monitored through CG/MS until completion. After the end of the reaction, ethyl acetate (250 mL) was added, together with an aqueous solution of acetic acid (100 mL; 10%). The mixture was maintained under agitation for a period of 30 minutes. The organic phase was separated, washed with two portions of 50 mL of NaHCO3 at 5%, dried with MgSO4 and evaporated at reduced pressure, yielding a pale yellow colored oil (2.7 g of raw 2-ethyl-3-(2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl) quinazoline-4 (3H)-one). This oil was dissolved in isopropanol, adding 2.0 mL of concentrated HCl to the resulting solution. The solution was kept under agitation at room temperature, until completing precipitation of the solids. The solids were vacuum filtered, washed with two portions of 5 mL of isopropanol and dried, yielding 2-ethyl-3-(2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)quinazoline-4 (3H)-one hydrochloride as a pale white solid (2.36 g, 5.48 mmol, yield: 87%).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=3[F:25])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2].FC1C=C(N[C:61](=[O:67])[C:62]([O:64][CH2:65][CH3:66])=[O:63])C=CC=1OC1C=CN=C2C=C(C3C=CC(OCCN4CCOCC4)=C(OC)C=3)SC=12>>[F:25][C:19]1[CH:20]=[C:21]([NH:24][C:61](=[O:67])[C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH:22]=[CH:23][C:18]=1[O:17][C:14]1[CH:13]=[CH:12][N:11]=[C:10]2[CH:9]=[C:8]([C:6]3[N:5]=[CH:4][N:3]([CH2:1][CH3:2])[CH:7]=3)[S:16][C:15]=12
Reactant: CCOC(=O)C(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(OCCN5CCOCC5)c(OC)c4)sc23)c(F)c1
Reactant: CCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Product: CCOC(=O)C(=O)Nc1ccc(Oc2ccnc3cc(-c4cn(CC)cn4)sc23)c(F)c1
Yield: 14 %

Procedure:
Starting from the amine 15 (scheme 4) and following the same procedure as described for the synthesis of compound 140 (scheme 40), title compound 142 was obtained as white solid in 14% yield. MS (m/z): 455.1 (M+H).