Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[C:3]1=O.[O:15]1[C:19]2([CH2:24]CC(=O)[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1.N>CO>[N+:8]([C:6]1[CH:7]=[N:2][C:3]2[CH2:21][CH2:20][C:19]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:24][C:4]=2[CH:5]=1)([O-:10])=[O:9]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Agent: N
Solvent: CO
Product: O=[N+]([O-])c1cnc2c(c1)CC1(CC2)OCCO1
Temperature: 60 °C
Reaction time: 17 h
Yield: 81.8 %

Procedure:
The title compound was prepared according to the procedure of Takada (J. Med. Chem. 1996, 39, 2844-2851). A 350 mL pressure vessel, equipped with a magnetic stir bar, was charged with 1-methyl-3,5-dinitropyridin-2(1H)-one (5.0 g, 25.1 mmol) and 1,4-dioxaspiro[4.5]decan-8-one (4.7 g, 30.1 mmol). Ammonia in MeOH (1M, 200 mL) was added, the vessel was sealed with a screw cap, and the mixture was heated to 60° C. and stirred for 17 hours. The reaction mixture was concentrated and the residue was partitioned with ethyl acetate (200 mL) and water (200 mL). The layers were separated and the aqueous portion was extracted with ethyl acetate (2×100 mL). The organic portions were combined, dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (7/3, hexanes/ethyl acetate) to afford the title compound (4.85 g, 82%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][C@@H:15](O)[CH2:14][C@H:13]2[C:18]([O:20][CH3:21])=[O:19])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(N(C(C)C)CC)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.Cl.[F:47][C:48]1([F:54])[CH2:53][CH2:52][CH2:51][NH:50][CH2:49]1>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][C@H:15]([N:50]3[CH2:51][CH2:52][CH2:53][C:48]([F:54])([F:47])[CH2:49]3)[CH2:14][C@H:13]2[C:18]([O:20][CH3:21])=[O:19])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: FC1(F)CCCNC1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1S(=O)(=O)c1cccc(C#N)c1
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1C[C@@H](N2CCCC(F)(F)C2)CN1S(=O)(=O)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of the compound of Step 1 (19.6 g, 63.2 mmol), diisopropylethylamine (16.5 g, 127 mmol), and CH2Cl2 (200 mL) was added trifluoromethanesulfonic anhydride (17.8 g, 63.2 mmol) via syringe pump at −60° C. over 30 minutes. The resulting solution was then warmed to −20° C. over 1.5 h, whereupon diisopropylethylamine (5.5 g, 42.5 mmol) was added followed by 3,3-difluoropiperidine hydrochloride (6.67 g, 42.5 mmol). The mixture was then slowly warmed to rt over 5 h. After 12 h at rt, the reaction was partitioned between H2O (150 mL) and CH2Cl2 (100 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×100 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified on silica gel (1:99→99:1 ethyl acetate-hexanes) to afford the title compound as a colorless foam: 1H NMR (500 MHz, CDCl3) δ 8.16 (s, 1H), 8.10 (d, 1H), 7.88 (d, 1H), 7.68 (t, 1H), 4.48-4.59 (m, 1H), 3.73 (s, 3H), 3.68-3.65 (m, 1H), 3.22-3.17 (m, 2H), 2.64 (br q, 1H), 2.51 (br q, 1H), 2.42-2.41 (m, 2H), 2.23-2.20 (m, 1H), 2.13-2.04 (m, 1H), 1.90-1.82 (m, 2H), 1.74-1.72 (m, 2H); LRMS (ESI) m/z 414 (414 calcd for C18H21F2N3O4S, M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[OH:20].C([O-])([O-])=O.[Na+].[Na+].CC(O)=O>N1C=CC=CC=1.O>[OH:20][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:14]=1[NH:13][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccncc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ccncc1O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
A solution of p-nitrobenzoyl chloride (4.8 g, 25.7 mmol) in pyridine (50 mL) was added to a solution of 4-amino-3-hydroxypyridine (2.5 g, 22.7 mmol) in pyridine (88 mL) at 10° C. and stirred at room temperature overnight. To the reaction mixture was added Na2CO3 (1.1 g, 10.4 mmol) in water (10 mL) and stirred for 1 hrs. 10% AcOH was added to neutralize the solution. The precipitate was collected by filtration, washed with 10% AcOH and dried to give N-(3-hydroxypyridin-4-yl)-4-nitrobenzamide as a yellow powder (2.27 g, yield: 52%). MS (ESI) calcd. for C12H9N3O4 (m/z): 259, found: 260 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18]([NH:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:19])=[C:5]2[OH:26].CCN(C(C)C)C(C)C.[C:36](O)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CS(C)=O.CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:9][CH2:10][N:11]([C:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:43])[CH2:12][CH2:13]1)[C:7](=[O:17])[C:6]([C:18]([NH:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:19])=[C:5]2[OH:26]
Reactant: O=C(O)c1ccccc1
Reactant: COC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCNCC2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: COC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCN(C(=O)c3ccccc3)CC2)C1=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of the hydrochloride salt of methyl N-((6-chloro-4-hydroxy-2-oxo-spiro[naphthalene-1,4′-piperidin]-3-yl)carbonyl)glycinate (0.050 g, 0.12 mmol) and Hunig's base (0.024 mL, 0.14 mmol) in DMF/DMSO (2:1, 1.5 mL) was stirred at 25° C. for 5 minutes. A mixture of benzoic acid (0.067 g, 0.54 mmol) and N-(3-dimethylaminopropyl)-n′-ethylcarbodiimide hydrochloride (0.13 g, 0.65 mmol) in DMF (1 mL) was added. The mixture was stirred at 60° C. for 8 hours. The solution was diluted with EtOAc (20 mL), and washed with brine (2×25 mL). The organic layer was dried over MgSO4, concentrated, and purified by flash column chromatography (silica, 0-1% MeOH in DCM) to give methyl N-((6-chloro-4-hydroxy-2-oxo-1′-(phenylcarbonyl)-spiro[naphthalene-1,4′-piperidin]-3-yl)carbonyl)glycinate. MS m/e=483.5 (M+H)+.
Reaction SMILES: [CH3:1][O:2][NH:3][CH:4]([CH:6]1[CH2:11][CH2:10][C:9]([CH3:12])=[CH:8][C:7]1([CH3:14])[CH3:13])[CH3:5].C(N(CC)CC)C.[F:22][CH:23]([F:33])[C:24]1[C:28]([C:29](Cl)=[O:30])=[CH:27][N:26]([CH3:32])[N:25]=1>ClCCl>[CH3:1][O:2][N:3]([CH:4]([CH:6]1[CH2:11][CH2:10][C:9]([CH3:12])=[CH:8][C:7]1([CH3:13])[CH3:14])[CH3:5])[C:29]([C:28]1[C:24]([CH:23]([F:33])[F:22])=[N:25][N:26]([CH3:32])[CH:27]=1)=[O:30]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CONC(C)C1CCC(C)=CC1(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)C1CCC(C)=CC1(C)C
Temperature: 24 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
To a stirred solution of O-methyl-N-[1-(2,2,4-trimethyl-cyclohex-3-enyl)-ethyl]-hydroxylamine (diastereomer A), prepared as described in example P7, (88 mg; 0.45 mmol) and triethylamine (75 μl; 0.54 mmol) in dichloromethane (2 ml) was added dropwise 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (87 mg; 0.45 mmol). The reaction mixture was stirred at 24° C. for 16 h under nitrogen atmosphere. The mixture was concentrated to an oil which was subject to flash-master column chromatography (elution gradient: cyclohexane/ethyl acetate 99:1 to 1:99) to afford 106 mg (66% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid methoxy-[1-(2,2,4-trimethyl-cyclohex-3-enyl)-ethyl]-amide as an amorph solid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[C:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17][C:11]=2[N:10]=[C:9]1[C:18]1[C:19]([CH3:41])=[CH:20][C:21]([CH3:40])=[C:22]([CH:39]=1)[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].I[CH:43]([CH3:45])[CH3:44].CCN(C(C)C)C(C)C>CN(C)C=O.C(OCC)(=O)C>[CH:43]([N:15]1[CH2:14][CH2:13][C:12]2[N:8]=[C:9]([C:18]3[C:19]([CH3:41])=[CH:20][C:21]([CH3:40])=[C:22]([CH:39]=3)[C:23]([N:25]3[CH2:26][CH2:27][CH:28]([C:31]4[CH:32]=[CH:33][C:34]([C:35]#[N:36])=[CH:37][CH:38]=4)[CH2:29][CH2:30]3)=[O:24])[NH:10][C:11]=2[CH2:17][CH2:16]1)([CH3:45])[CH3:44]
Reactant: Cc1cc(C)c(-c2nc3c([nH]2)CCNCC3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: CC(C)I
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(-c2nc3c([nH]2)CCN(C(C)C)CC3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 21.6 %

Procedure:
To a solution of 4-(1-(5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile trifluoroacetate (429.5, 80.0 mg, 0.140 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL) were added 2-iodopropane (270 mg, 1.59 mmol, 9.00 equiv) and DIEA (205 mg, 1.59 mmol, 9.00 equiv). The resulting solution was stirred overnight at 80° C. in an oil bath. After cooling to ambient temperature, the mixture was diluted with 50 mL of ethyl acetate, washed with 3×20 mL of brine, dried (Na2SO4), and concentrated. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:10) as eluent. The product (50 mg) was further purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.03% NH3H2O and CH3CN (38.0% CH3CN up to 51.0% in 8 min, up to 100.0% in 2 min, down to 38.0% in 1 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 15.0 mg (21%) of the title compound as a white solid. m/z (ES+) 496 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 7.69 (d, J=8.0 Hz, 2H), 7.49 (m, 2H), 7.33-7.23 (m, 2H), 4.86 (m, 1H), 3.65 (m, 1H), 3.30 (m, 1H), 3.15 (m, 1H), 2.99 (m, 6H), 2.80 (m, 4H), 2.45 (s, 3H), 2.40 and 2.29 (2 singlets, amide rotamers, 3H), 2.10 (m, 1H), 1.70 (m, 3H), 1.15 (d, J=6.8 Hz, 6H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH2:11])[C:3]=1[N+:12]([O-:14])=[O:13].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.C(N(CC)CC)C.II>C(OCC)(=O)C.CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=2)=[C:3]([N+:12]([O-:14])=[O:13])[C:4]=1[NH2:11])([O-:10])=[O:9]
Reactant: Nc1c([N+](=O)[O-])ccc(F)c1[N+](=O)[O-]
Reactant: NCc1ccc(F)cc1
Agent: II
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1c([N+](=O)[O-])ccc(NCc2ccc(F)cc2)c1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A round bottom flask is charged with 8 (2.01 g, 10 mmol, 1 equiv), 4-fluorobenzylamine (3.79 g, 30 mmol, 3 equiv) and triethylamine (1.21 g, 12 mmol, 1.2 equiv). DMF (40 mL) is then added to the above mixture followed by iodine (catalytic, 1 mg). The reaction mixture is then heated to 120° C. and stirred at 120° C. for 16 hrs after which the flask is allowed to cool to room temperature. The reaction mixture is diluted with ethyl acetate and washed with water (5×80 mL) and dried with brine and then over MgSO4. The suspension is filtered and concentrated to give a residue, which is purified by silica gel flash chromatography (hexanes/ethyl acetate) to give the desired product (9).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C:3]#[C:4][C:5]1[S:9][CH:8]=[C:7]([N:10]([CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[C:11]([C@@H:13]2[C@@H:18]([CH3:19])[CH2:17][C:16]([CH3:20])=[CH:15][CH2:14]2)=[O:12])[CH:6]=1.[BH4-].[Na+].Cl>CO>[CH3:28][C:2]([CH3:1])([CH3:29])[C:3]#[C:4][C:5]1[S:9][CH:8]=[C:7]([N:10]([C@H:21]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]2)[C:11]([C@@H:13]2[C@@H:18]([CH3:19])[CH2:17][C:16]([CH3:20])=[CH:15][CH2:14]2)=[O:12])[CH:6]=1
Reactant: CC1=CC[C@H](C(=O)N(c2csc(C#CC(C)(C)C)c2)C2CCC(=O)CC2)[C@@H](C)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1=CC[C@H](C(=O)N(c2csc(C#CC(C)(C)C)c2)[C@H]2CC[C@H](O)CC2)[C@@H](C)C1
Reaction time: 0.5 h

Procedure:
(1S,6S)-4,6-Dimethyl-cyclohex-3-ene-carboxylic acid [5-(3,3-dimethyl-but-1-ynyl)-thiophen-3-yl]-(4-oxo-cyclohexyl)-amide (2.0 g, 4.9 mmol) in MeOH (100 mL) was treated with sodium borohydride (230 mg, 6.0 mmol) at 0° C. After stirring for 30 min, 4M HCl (6 mL) was added and the reaction mixture was twice extracted with ethyl acetate. The combined organic layers washed with saturated NaHCO3 (aq), brine, dried over MgSO4, filtered, and concentrated. Silica gel chromatography (20-60% ethyl acetate/hexanes) gave the desired (1S,6S)-4,6-dimethyl-cyclohex-3-ene-carboxylic acid [5-(3,3-dimethyl-but-1-ynyl)-thiophen-3-yl]-(trans-4-hydroxy-cyclohexyl)-amide (1.74 g, 4.2 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[CH3:28][C:29]1([CH3:41])[O:33][C@@H:32]([C:34]2[N:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=2)[CH2:31][O:30]1.N1C=CC=CC=1.Cl>CN(C)C=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:40][C:37]2[CH:36]=[N:35][C:34]([C@H:32]3[CH2:31][O:30][C:29]([CH3:41])([CH3:28])[O:33]3)=[CH:39][N:38]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: CC1(C)OC[C@H](c2cnc(N)cn2)O1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](c2cnc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)cn2)O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.4 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 6.29 g, 19.01 mmol) and N,N-dimethylformamide (2 drops) in methylene chloride (70 mL) was stirred at 2° C. and then treated with oxalyl chloride (4.15 mL, 45.7 mmol). The mixture was stirred at 2° C. for 5 min and at 25° C. for 15 min. The reaction mixture was then concentrated in vacuo. The residue was dissolved in benzene (25 mL), and the evaporation was repeated. The resulting acid chloride was dissolved in methylene chloride (40 mL), cooled to at 0° C., and then treated with a solution composed of 5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-ylamine (3.65 g, 18.95 mmol), pyridine (4.6 mL, 56.9 mmol) and methylene chloride (40 mL). The mixture was stirred for 16 h without replenishing the cooling bath. The reaction mixture was then treated with a 1N aqueous hydrochloric acid solution (100 mL). The layers were separated, and the aqueous layer was extracted with methylene chloride (75 mL). The organic layers were washed with a saturated aqueous sodium bicarbonate solution (100 mL) and a saturated aqueous sodium chloride solution. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40 L, Silica, 1/1 ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-yl]-propionamide (8.9 g, 92%) as a white foam: (ES)+-HRMS m/e calcd for C24H30CiN3O5S (M+H)+ 508.1668, found 508.1671.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:16][OH:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[C:20]([CH3:22])=[CH2:21].CCN(CC)CC>CC(C)=O.B(F)(F)F.CCOCC>[CH3:15][O:14][C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[CH2:16][O:17][C:20]([CH3:22])([CH3:21])[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7]
Reactant: C=C(C)OC
Reactant: COC(=O)CC[C@@H](CO)NC(=O)OC(C)(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)CC[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
(S)-methyl 4-(tert-butoxycarbonylamino)-5-hydroxypentanoate (12 g, 48.6 mmol) and isopropenyl methyl ether (44.4 g, 427.3 mmol) was dissolved in acetone (200 mL) and BF3.Et2O (0.41 mL, 2.92 mmol) was added at rt and stirred for 1 hour. The reaction was stopped by addition of Et3N (5.8 mL). The reaction solution was washed with 100 mL of saturated NaHCO3 and evaporated, and (S)-tert-butyl 4-(3-methoxy-3-oxopropyl)-2,2-dimethyloxazolidine-3-carboxylate (10 g, yield 72%) was obtained as an oil that was used in the next step without further purification.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[CH3:26][C:27]1[CH:28]=[N:29][C:30]2[N:31]([N:33]=[C:34]([SH:36])[N:35]=2)[CH:32]=1>>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:36][C:34]3[N:35]=[C:30]4[N:29]=[CH:28][C:27]([CH3:26])=[CH:32][N:31]4[N:33]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Reactant: Cc1cnc2nc(S)nn2c1
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nc4ncc(C)cn4n3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 6-methyl[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol was used in place of 6-hydroxy-8-mercaptopurine monohydrate.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:20](=O)(O)[O-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:20])=[O:11])=[O:7])=[CH:13][CH:14]=1
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of 3-(4-fluorobenzoyl)-propionic acid (1.98 g, 10.0 mmol) in methanol (25 mL) was added 0.5 mL of conc. sulfuric acid. The resulting solution was stirred at room temperature under argon for 2 hours. The reaction mixture was neutralized with saturated sodium bicarbonate, the methanol was removed via rotary evaporator and the residue was dissolved in 50 mL of ethyl acetate. The resulting solution was washed with saturated sodium bicarbonate (3×50 mL) and brine (50 mL), dried over sodium sulfate and the solvent was removed in vacuo to give Methyl 3-(4-fluorobenzoyl)-propionate (2 g, 94%). IR (film) 3448, 3111, 3076, 3003, 3958, 1734, 1678, 1601, 1423, 1300, 1240, 1155, 1099 cm-1 ; 1H-NMR (CDCl3) δ 7.97 (2H, dd, J=9.0, 5.5 Hz), 7.10 (2H, t, J=8.9 Hz), 3.67 (3H, s) , 3.25 (2H, t, J=6.6 Hz), 2.73 (2H, t, J=6.6 Hz); 13C-NMR (CDCl3) δ 196.50, 173.34, 167.54, 164.17, 132.98, 130.77, 115.91, 115.62, 51.91, 33.31, 28.00.
Reaction SMILES: [Br:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:18](=[O:28])[CH2:19][NH:20][C:21](OC(C)(C)C)=[O:22])[CH:7]2[CH2:13]C(OC)=O.BrC1C(F)=CC=C2C=1CCNC2CC(OC)=O.C(NCC(O)=O)(OC(C)(C)C)=O.C(N(CC)CC)C.Cl>CCOC(C)=O.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>[Br:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:18](=[O:28])[CH2:19][NH:20][C:21](=[O:22])[CH:13]=[C:7]12
Reactant: COC(=O)CC1c2ccc(F)c(Br)c2CCN1C(=O)CNC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: COC(=O)CC1NCCc2c1ccc(F)c2Br
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1C=C2c3ccc(F)c(Br)c3CCN2C(=O)CN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
methyl 2-(5-bromo-2-(2-((tert-butoxycarbonyl)amino)acetyl)-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate. To a stirred solution of methyl 2-(5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (41.58 g, 138 mmol), Boc-glycine (26.5 g, 151 mmol) and triethylamine (38.4 mL, 275 mmol) in AcOEt (690 mL), T3P (98 mL, 165 mmol, 50% m/m in AcOEt) was added and the solution was stirred at RT for 1 h. 0.2N aqueous HCl (200 mL) was added and the reaction mixture was stirred for 5 min. The organic layer was separated and washed with 0.2N aqueous HCl (1×200 mL), saturated aqueous NaHCO3 (2×200 mL) and brine (1×200 mL). The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was dried under high vacuo overnight to yield the title compound as white foam (62.6 g) which was used without further purification. UPLC-MS: MS 459.3/461.3 (M+H+); UPLC rt 1.13 min.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:15][O:14][CH:13]([O:16][CH3:17])[CH2:12][O:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Cc1ccc(O)c(C=O)c1
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(COc1ccc(C)cc1C=O)OC
Yield: 94.1 %

Procedure:
To a solution of 100 mg (0.73 mmol) of 2-hydroxy-5-methyl-benzaldehyde in DMF (1 ml) were added 109 μl (0.92 mmol) of 2-bromo-1,1-dimethoxy-ethane and 112 mg (0.81 mmol) of potassium carbonate. The reaction mixture was heated to reflux for 90 min. Then water was added at RT and the mixture was extracted with ether. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated to yield 2-(2,2-dimethoxy-ethoxy)-5-methyl-benzaldehyde as a yellow oil (154 mg, 93%). 1HNMR (CDCl3, 300 MHz): δ 2.32 (s, 3H), 3.48 (s, 6H), 4.09 (d, J=5.3 Hz, 2H), 4.75 (t, J=5.3 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 7.34 (dd, J=8.4 and 2.3 Hz, 1H), 7.64 (d, J=2.3 Hz, 1H), 10.48 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:24][C:10]1[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:13]=[C:8]([C:4]2[CH:3]=[C:2]([C:29]3[CH:28]=[N:27][C:26]([NH2:25])=[N:31][CH:30]=3)[CH:7]=[CH:6][CH:5]=2)[N:9]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)c2)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3cnc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-trifluoromethyl-phenyl)-6-methyl-pyrimidine (example E.47) (0.175 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as an off-white solid (0.021 g, 10%). MS (ISP) 408.3 [(M+H)+]; mp 290° C.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]([CH2:45][CH3:46])[CH3:44])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]([CH2:45][CH3:46])[CH3:44])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CCN(C)C(=O)CCl
Product: CCN(C)CCOc1ccc(CN(CC)c2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)cc1F
Yield: 68.4 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-ethyl-N-methylacetamide (7.9 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (10 mg) was obtained.