Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])/[CH:4]=[C:5](\[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])/[CH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:8]=1[F:15].N#N>C1COCC1>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C@H:5]([NH:16][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:8]=1[F:15]
Reactant: COC(=O)/C=C(/Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Agent: N#N
Solvent: C1CCOC1
Product: COC(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.28 g (3.71 mmol) of (Z)-Methyl-3-[N-(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)but-2-enoate of Example 3, 2.2 mg TangPhosRh(COD)BF4 and 10 mL THF were charged to a pressure bomb under N2 atmosphere. The N2 atmosphere was replaced by H2 (10 bars). The mixture was stirred at rt for 18 h. The reaction solution was passed through a silica gel pad and evaporated to dryness. The reaction gave quantitative yield and 99.0% ee. 1H NMR (300 MHz, CDCl3) 7.10-7.00 (m, 1H), 6.95-6.85 (m, 1H), 5.10 (m, 1H), 4.20-4.10 (m, 1H), 3.70 (s, 3H), 2.85 (m, 1H), 2.60-2.50 (m, 1H), 1.39 (s, 9H)
Reaction SMILES: CC(OOC(C)(C)C)(CCC(C)(OOC(C)(C)C)C)C.C(OOC(C)(C)C)(C)(C)C.CC(OOC(C)(C)C)(C#CC(C)(OOC(C)(C)C)C)C.[C:51]([O:60][O:61][C:62]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)([CH3:64])[CH3:63])([C:54]1C=CC=CC=1)([CH3:53])[CH3:52]>>[C:51]([O:60][O:61][C:62]([C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1)([CH3:64])[CH3:63])([CH3:52])([CH3:53])[CH3:54]
Reactant: CC(C)(OOC(C)(C)c1ccccc1)c1ccccc1
Agent: CC(C)(C)OOC(C)(C)C
Agent: CC(C)(C)OOC(C)(C)C#CC(C)(C)OOC(C)(C)C
Agent: CC(C)(C)OOC(C)(C)CCC(C)(C)OOC(C)(C)C
Product: CC(C)(C)OOC(C)(C)c1ccccc1

Procedure:
2,5-dimethyl-2,5di(tert.butylperoxy) hexane (DHBP); di(tert.butyl) peroxide (DTBP); 2,5-dimethyl-2,5-di(tert.butylperoxy) hexine (DYBP); dicumylperoxide (DCUP).
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][O:8][N:9]=2)[CH:5]=[C:4]([Br:11])[CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[Br:11][C:4]1[CH:3]=[C:2]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:10]2[C:6]([CH:5]=1)=[N:7][O:8][N:9]=2
Reactant: C1CCNC1
Reactant: Brc1cc(Br)c2nonc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: Brc1cc(N2CCCC2)c2nonc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
4,6-dibromobenzo[c][1,2,5]oxadiazole (0.3122 g, 1.12 mmol), pyrrolidine (0.10 mL, 1.12 mmol) and DIPEA (0.20 mL, 1.12 mmol) were dissolved in NMP (2 mL) under argon and stirred in a sealed tube at 100° C. overnight. Upon cooling to room temperature, the reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with H2O (5×), 1 N HCl (aq), saturated NaHCO3 (aq) and brine before drying with Na2SO4, filtering and concentrating to give the crude 6-bromo-4-(pyrrolidin-1-yl)benzo[c][1,2,5]oxadiazole (0.2247 g, 75% yield). The crude material (0.1964 g, 0.73 mmol) and 3-acetylbenzeneboronic acid (0.1558 g, 0.95 mmol) were added to a tube. The tube was evacuated and purged with argon (3×). 2 M Na2CO3 (1.1 mL, 2.21 mmol) and DME (1.6 mL) were added and the solution was degassed for 15 minutes. Pd(PPh3)4 (0.0422 g, 0.0365 mmol) was quickly added and the tube was heated at 100° C. overnight. Upon cooling to room temperature, the reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with H2O (5×), saturated NaHCO3 (aq) and brine before drying with Na2SO4, filtering and concentrating. The crude material was dissolved in methanol (12 mL) and cooled to 0° C. NaBH4 (0.0552 g, 1.46 mmol) was added and the mixture was stirred at 0° C. for 3 hours. The reaction mixture was quenched with saturated NaHCO3. This thick mixture was diluted with water and extracted with DCM (5×). The extracts were then dried (Na2SO4), filtered and concentrated. The crude material was purified via chromatography (30% EtOAc/Hexane) to afford 0.2029 g (90% yield, over 2 steps) of TRV-1310. 1H NMR (CDCl3) δ=7.65 (s, 1H), 7.55 (d, J=7.0 Hz, 1H), 7.47-7.42 (m, 2H), 7.07 (s, 1H), 6.11 (s, 1H), 5.00-4.99 (m, 1H), 3.81 (s, 4H), 2.12-2.09 (m, 4H), 1.92 (d, J=3.0 Hz, 1H), 1.56 (d, J=6.5 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][C@@H:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[N+](C1C=CC=CC=1O)([O-])=O>>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([O:1][C@@H:16]([CH3:15])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: CCCCCC[C@@H](C)O
Agent: O=[N+]([O-])c1ccccc1O
Product: CCCCCC[C@H](C)Oc1ccc(C(=O)OC)cc1[N+](=O)[O-]

Procedure:
Methyl 4-hydroxy-3-nitrobenzoate was coupled with (R)-2-octanol using the same procedure as that given for alkylation of phenol 9, Scheme I, to give (S)-methyl-4-(1-methyheptyloxy)-3-nitrobenzoate (Compound 23, Scheme IV, R1 =(S)--OCH(CH3)C6H13). The product was purified by flash chromatography with hexanes/ethyl acetate (95/5) as eluent affording a yellow liquid, Rf [hexanes/ethyl acetate 95/5]: 0.25; 1H-NMR (300 MHz, CDCl3): δ0.82 (t, 3H, J =7.1 Hz); 1.14-1.50 (m, 8H); 1.34(d, 3H, J=6.1 Hz); 1.60(m, 1H); 1.75(m, 1H); 3.87(s, 3H); 4.57(m, 1H); 7.06(d, 1H, J=8.9 Hz); 8.11(dd, 1H, J=2.2 Hz, J =8.9 Hz); 8.39(d, 1H, J=2.2 Hz); 13C-NMR (300 MHz, CDCl3): δ13.96, 19.31, 22.47, 25.06, 29.02, 31.60, 36.00, 52.35, 76.80, 114.63, 121.80, 127.17. 134.80, 140.27, 154.91, 165.08; Mass Spectrum , m/z(rel.intensity): 309 (M+ 1), 197 (32), 166(46),112(48), 71(63), 57(100), 55(46).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:8]([OH:10])=O.[NH2:17][C@H:18]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:19]1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][N:20]2[CH2:21][CH2:22][C@H:18]([NH:17][C:8](=[O:10])[CH:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH2:19]2)=[CH:26][CH:27]=1
Reactant: O=C(O)C(c1ccccn1)c1ccccn1
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Product: O=C(N[C@H]1CCN(CCc2ccc(F)cc2)C1)C(c1ccccn1)c1ccccn1

Procedure:
Bis(2-pyridyl)acetic acid and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)bis(2-pyridyl)acetamide.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CNC.CN(C)[P:17](N(C)C)N(C)C>>[N:1]12[P:17]3[N:4]([CH2:5][CH2:6][CH2:7][N:8]3[CH2:9][CH2:10][CH2:11]1)[CH2:3][CH2:2]2
Reactant: C1CNCCCNCCNC1
Reactant: CN(C)P(N(C)C)N(C)C
Agent: CNC
Product: C1CN2CCCN3CCN(C1)P23
Temperature: 125 °C
Yield: 75.2 %

Procedure:
A mixture of 3.62 g of 1,4,8-triazacycloundecane and 3.75 g of hexamethylphosphorous triamide is heated to 125° C. with stirring and held at this temperature for 2 hours, by which time evolution of dimethylamine is complete. Evolution is vigorous for the first 45 minutes. Distillation affords 3.20 g (75%) 1,4,8-triaza-12-phosphatricyclo[6.3.1.04,12 ]dodecane as a water-white liquid which boils at 73°-75° C. at 0.30 mm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:18])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.[OH-].[Na+]>C(O)C.O>[Br:1][C:2]1[C:3]2[N:8]=[C:9]([C:10]3[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[S:18][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=S)Nc2ccccc2Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2nc3c(Br)cccc3s2)cc1
Temperature: 85 °C
Reaction time: 0.08 h

Procedure:
To a solution of EXAMPLE 1B (7.1 g) in ethanol (26 mL) was added 30% sodium hydroxide (17.63 mL) and the mixture was stirred for 5 minutes. Water (35 mL) was added and 4 mL aliquots of the mixture were added at 1-minute intervals to a heated (85° C.) solution of potassium ferricyanide(III) (29 g) in water (260 mL). The mixture was maintained at 85° C. for 30 minutes and cooled. The precipitate was collected, washed with water and dried to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:10]([NH:11][CH3:12])=[C:9]([I:18])[CH:8]=2)=[C:5]([CH3:19])[O:4][N:3]=1.CCO.[Sn](Cl)Cl>[OH-].[Na+]>[CH3:1][C:2]1[C:6]([C:7]2[CH:14]=[C:13]([NH2:15])[C:10]([NH:11][CH3:12])=[C:9]([I:18])[CH:8]=2)=[C:5]([CH3:19])[O:4][N:3]=1
Reactant: CNc1c(I)cc(-c2c(C)noc2C)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNc1c(N)cc(-c2c(C)noc2C)cc1I
Temperature: 110 °C

Procedure:
To a microwave vial containing 4-(3,5-dimethylisoxazol-4-yl)-2-iodo-N-methyl-6-nitroaniline (610 mg, 1.64 mmol, 1 equiv) was added EtOH (12 mL, 0.25M) and tin (II) chloride (622 mg, 3.28 mmol, 2 equiv). The reaction mixture was heated for 30 min at 110° C. The reaction was then stirred in 2N NaOH solution for 20 minutes and partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Purification was carried out by flash column chromatography to furnish 4-(3,5-dimethylisoxazol-4-yl)-6-iodo-N1-methylbenzene-1,2-diamine.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[C:8]([CH3:22])[CH:7]=1)=[O:5].[CH2:24]([Mg]Br)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].O.[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:22][C:8]1[CH:7]=[C:6]([C:4](=[O:5])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:11]=[CH:10][C:9]=1[C:12]1[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=1
Reactant: CON(C)C(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(C)c1
Reactant: CCCCCC[Mg]Br
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(C)c1
Yield: 82.6 %

Procedure:
Dissolve 2-methyl-4′-trifluoromethyl-biphenyl-4-carboxylic acid methoxy-methyl-amide (0.58 g, 1.8 mmol) in tetrahydro-furan (10 mL). Add hexyl magnesium bromide (2.0M ethyl ether, 2.69 mL, 5.39 mmol) at 0° C. under inert atmosphere and stir 1.5 hours. Quench reaction with saturated solution of ammonium chloride, dilute with ethyl acetate. Wash organic phase with water then saturated sodium chloride solution. Dry organic fraction with Na2SO4, filter and concentrate under reduced pressure. Purify on silica gel chromatography (0-30% Ethyl acetate/hexanes gradient) to provide 0.518 g of title compound (83%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:25]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:25])=[C:6]2[CH:5]=[N:4]1)=[CH:14][CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=3)[CH3:2]
Reactant: CCn1nccc1Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: CCn1ncc2c(Cl)c3ccc([N+](=O)[O-])cc3nc21
Temperature: 0 °C
Yield: 82 %

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl) -4-nitroanthranilic acid (3.4 g, 12.32 mmol) and POCl3 (20 ml) was refluxed for 8 hours. The reaction mixture was poured into ice-water, neutralized with concentrated NH4OH and the resulting solid was collected by filtration, washed with water and dried to afford 2.8 g (82%) of 1-ethyl-4-chloro-7-nitro-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]=[CH:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([Si@@]1(Cl)N(C)[C@H](C)C(C2C=CC=CC=2)O1)[CH:16]=[CH2:17]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][NH:9][C@H:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:17][CH:16]=[CH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C=NNC(=O)OC(C)(C)C
Reactant: C=CC[Si@]1(Cl)OC(c2ccccc2)[C@@H](C)N1C
Solvent: ClCCl
Product: C=CC[C@H](NNC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 0 °C
Reaction time: 6 h

Procedure:
N′-(2,2-Dimethyl-propylidene)-hydrazinecarboxylic acid tert-butyl ester (12 g, 59.9 mmoles) was charged to a dried, 3-neck, 1 L round bottom flask with thermometer, magnetic stirrer, and nitrogen atmosphere. Anhydrous methylene chloride (200 mL) was charged to the flask using a catheter. The mixture was chilled to 0° C. with an ice bath. (R,R)-2-Allyl-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine (24.07 g, 89.87 mmoles) was subsequently added to the flask under inert conditions. Within minutes, the originally light yellow solution turned transparent dark yellow. The reaction was stirred for 6 hr at 0° C., then allowed to warm to room temperature, and stirred overnight, while being monitored by TLC. The reaction was quenched by adding ca. 25 mL methanol, resulting in a lightening of color. The solution was concentrated and the residue was diluted with 100 mL of ethyl acetate and 100 mL of water. The phases were separated and the aqueous layer was extracted with ethyl acetate twice. The organic phases were combined, washed with brine, dried over Na2SO4 and concentrated. The resulting oil was purified by column chromatography using 10% ethyl acetate in hexanes. Purified (S)—N′-(1-tert-butyl-but-3-enyl)-hydrazinecarboxylic acid tert-butyl ester was obtained as an oil (2.87 g, 24.4% yield). An impure fraction was also collected (3.17 g). Rf=0.44 (5:1 hexanes:ethyl acetate, 12 visualization); 1H NMR (400 MHz, CDCl3) δ 6.07 (br, 1H, NH), 5.85 (m, 1H), 5.0 (dd, 2H), 2.6 (m, 1H), 2.33 (m, 1H), 2.3 (m, 1H), 1.4 (s, 9H), 0.9 (s, 9H).
Reaction SMILES: C([O:4][C:5]12[CH2:17][CH:13]([O:14][C:15]1=[O:16])[C:12]1[CH:7]([O:8][CH2:9][CH2:10][CH:11]=1)[CH2:6]2)(=O)C.[BH4-].[Na+]>[Cl-].[Na+].O>[OH:16][CH2:15][C@:5]1([OH:4])[CH2:6][C@@H:7]2[C:12](=[CH:11][CH2:10][CH2:9][O:8]2)[C@H:13]([OH:14])[CH2:17]1
Reactant: CC(=O)OC12CC3OCCC=C3C(C1)OC2=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: OC[C@@]1(O)C[C@@H](O)C2=CCCO[C@@H]2C1
Yield: 74.9 %

Procedure:
To a solution of tricyclic compound 8 (9.5 mg, 40 μmol) at 0° C. was added NaBH4. The resultant mixture was then stirred at room temperature for 18 h, a small volume of brine/saturated NH4Cl was added, and the solvents were removed in vacuum. The residue was washed several times with warm ethanol. The ethanol extracts were combined and evaporated to dryness with benzene. The solid residue was then washed few times with warm chloroform. The combined chloroform extracts were concentrated to a small volume and applied on a silica Sep-Pak cartridge. Elution with hexane/ethyl acetate (1:9, 20 mL) yielded a pure semisolid triol 9 (6 mg, 75%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:13][CH3:14])[CH:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([O:13][CH3:14])[CH:7]=[C:8]([NH2:10])[CH:9]=1
Reactant: COc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)cc(N)c1
Reaction time: 1 h
Yield: 63 %

Procedure:
3,5-Dinitroanisole (20 gm.) is suspended in methanol (250 ml.) and 5% palladium on charcoal (2.0 gm.) added. Reduction is carried out in a Parr apparatus for one hour. The solution is filtered with suction and the catalyst washed woth a few cc of methanol Removal of the methanol gives a clear brown glass which crystallized on standing. Extraction with boiling benzene (250 ml.) and treatment with Darco gives white needles (8.7 gm., m.p. 79-80°, 63% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[NH:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][C:11]=2[CH3:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[H-].[Na+].[CH3:22]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[N:14]([CH3:22])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][C:11]=2[CH3:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CI
Reactant: COC(=O)c1cc(C)c(-c2ccc(OC)c(Br)c2)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c(-c2ccc(OC)c(Br)c2)n1C
Yield: 85 %

Procedure:
A solution of methyl 5-(3-bromo-4-methoxyphenyl)-4-methyl-1H-pyrrole-2-carboxylate (prepared according to the procedure reported in J. Org. Chem., 2009, 74(2), 903-905, Org. Lett., 2007, Vol. 9, 25, 5191-5194, 1.40 g, 4.32 mmol) in DMF (3 ml) was added to a solution of sodium hydride (0.21 g 60% in paraffin oil, 4.75 mmol) in DMF (2 ml) at 0° C. under stirring. Methyl iodide (0.67 g, 0.29 ml, 4.75 mmol) was then added to the reaction mixture. The reaction mixture was stirred at room temperature for 45 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with water (5 ml) and then extracted with ethyl acetate (2×50 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product. The crude product was further purified by flash column chromatography using 20% ethyl acetate in hexanes as an eluent to obtain the title compound 10a (1.25 g, 85%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.Cl.[NH2:19][C@H:20]([C:22]([NH2:24])=[O:23])[CH3:21]>[Pd].[Pt].C(N(CC)CC)C>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH:19][C@@H:20]([CH3:21])[C:22]([NH2:24])=[O:23])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2F)cc1
Reactant: C[C@H](N)C(N)=O
Agent: [Pd]
Agent: [Pt]
Agent: Cl
Solvent: CCN(CC)CC
Product: C[C@H](NCc1ccc(OCc2ccccc2F)cc1)C(N)=O
Yield: 70 %

Procedure:
A mixture of 5 g of 4-(2-fluorobenzyloxy)benzaldehyde, prepared according to the Ex. 1 and the corresponding amount L-alaninamide hydrochloride and triethylamine is hydrogenated according to the same procedure of Example 2, but using wet (50% H2O) Pd/C 10% instead of wet (50% H2O) Pt/C 5% to obtain (S)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide (Ib) in a 70% yield.
Reaction SMILES: CC1C2C(=CC=CC=2)CCN1.C(O)C(O)C.[Cl:17]C1C(C)=C(C)N=C(NC2C=CC(F)=CC=2)N=1.[CH3:34][C:35]1[C:36]([N:50]2[CH2:59][CH2:58][C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH:51]2[CH3:60])=[N:37][C:38]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)=[N:39][C:40]=1[CH3:41]>C(N(CC)CC)C>[ClH:17].[CH3:34][C:35]1[C:36]([N:50]2[CH2:59][CH2:58][C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH:51]2[CH3:60])=[N:37][C:38]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)=[N:39][C:40]=1[CH3:41]
Reactant: Cc1nc(Nc2ccc(F)cc2)nc(Cl)c1C
Agent: CC1NCCc2ccccc21
Agent: Cc1nc(Nc2ccc(F)cc2)nc(N2CCc3ccccc3C2C)c1C
Solvent: CCN(CC)CC
Solvent: CC(O)CO
Product: Cl

Procedure:
75 ml of triethylamine and 65 g (442 mmole) of 1-methyl-1,2,3,4-tetrahydroisoquinoline were added to 100 ml of 1,2-propylene glycol. 100.9 g (0.40 mmole) of 4-chloro-2-(4-fluorophenylamino)-5,6-dimethylpyrimidine was added thereto and then reacted at 120° C. for 64 hours under refluxing to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 14 to obtain 91 g of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:63])[NH:21][C:22]3[C:27]([Cl:28])=[CH:26][C:25]([C:29]4[CH:34]=[CH:33][C:32]([C:35]5[N:36]=[C:37]([C@@H:40]6[CH2:44][C@H:43]([C:45]#[N:46])[CH2:42][N:41]6[C:47](=[O:57])[C@@H:48]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:49]([CH3:51])[CH3:50])[NH:38][CH:39]=5)=[CH:31][CH:30]=4)=[C:24]([O:58][C:59]([F:62])([F:61])[F:60])[CH:23]=3)=[CH:16][N:15]=2)[C@H:10]([CH3:64])[CH2:9]1)=O)(C)(C)C.[O:65]1CCOCC1>Cl>[CH3:56][O:55][C:53](=[O:54])[NH:52][C@H:48]([C:47]([N:41]1[CH2:42][C@@H:43]([C:45](=[O:65])[NH2:46])[CH2:44][C@H:40]1[C:37]1[NH:38][CH:39]=[C:35]([C:32]2[CH:33]=[CH:34][C:29]([C:25]3[CH:26]=[C:27]([Cl:28])[C:22]([NH:21][C:20]([C:17]4[CH:16]=[N:15][C:14]([N:11]5[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]5[CH3:64])=[CH:19][CH:18]=4)=[O:63])=[CH:23][C:24]=3[O:58][C:59]([F:60])([F:61])[F:62])=[CH:30][CH:31]=2)[N:36]=1)=[O:57])[CH:49]([CH3:50])[CH3:51]
Reactant: C1COCCO1
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C#N)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCN(C(=O)OC(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C(N)=O)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCNC[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C

Procedure:
A solution of (R)-4-[5-(5-chloro-4′-{2-[(2S,4S)-4-cyano-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester 2 TFA (6.3 mg, 0.0055 mmol; Example 17) in 4.0 M HCl in 1,4-dioxane (0.14 mL) was stirred at RT for 1 h and concentrated under vacuum to provide the title intermediate as a yellow powder. (m/z): [M+H]+ calcd for C39H43ClF3N9O6 826.30. found 826.5.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH2:12][C:13](OCC)=[O:14])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:18])[CH2:5][CH2:6]2.CC(C)([O-])C.[K+].O.Cl>C1(C)C=CC=CC=1>[NH:1]1[C:13](=[O:14])[CH2:12][O:11][C:10]2[CH:9]=[CH:8][C:7]3[CH2:6][CH2:5][C:4](=[O:18])[C:3]=3[C:2]1=2
Reactant: CCOC(=O)COc1ccc2c(c1N)C(=O)CC2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1COc2ccc3c(c2N1)C(=O)CC3
Yield: 67.7 %

Procedure:
To a solution of ethyl [(4-amino-3-oxoindan-5-yl) oxy]acetate (8.7 g, 34.9 mmol.) in toluene (200 mL) was added potassium t-butoxide (400 mg, 3.6 mmol.). The mixture was refluxed for 12 hours under argon atmosphere. The reaction mixture was cooled, which was poured into water, followed by neutralization with dilute hydrochloric acid. The organic matter was extracted with ethyl acetate, which was washed with a saturated aqueous saline solution and water, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of silica gel column chromatography (hexane:ethyl acetate=1:1) to afford the title compound (yield 4.8 g, 66%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH:14]=[CH:13][C:12]=2[NH:22]C(=O)OC(C)(C)C)=[O:9])=[CH:4][CH:3]=1.[CH2:30]([NH:32][C:33]([N:35]1[C:39]2([CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36]1)=[O:34])[CH3:31].CCN(CC)CC>CS(C)=O>[NH2:22][C:12]1[CH:13]=[CH:14][C:15]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[CH:16][C:11]=1[NH:10][C:8]([C:5]1[CH:4]=[CH:3][C:2]([N:42]2[CH2:41][CH2:40][C:39]3([N:35]([C:33]([NH:32][CH2:30][CH3:31])=[O:34])[CH2:36][CH2:37][CH2:38]3)[CH2:44][CH2:43]2)=[N:7][CH:6]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(Cl)nc1
Reactant: CCNC(=O)N1CCCC12CCNCC2
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCNC(=O)N1CCCC12CCN(c1ccc(C(=O)Nc3cc(-c4cccs4)ccc3N)cn1)CC2
Reaction time: 1 h

Procedure:
A solution of intermediate F (82 mg, 0.19 mmol), N-ethyl-1,8-diazaspiro[4.5]-decane-1-carboxamide (73 mg, 0.35 mmol), and NEt3 (43 μL, 0.31 mmol) in 5 mL of DMSO was stirred at 90° C. for 12 h. The reaction mixture was partitioned between EtOAc and saturated NaHCO3, the organic layer was dried (MgSO4), filtered and concentrated. The residue was stirred in 2 mL of TFA and 2 mL of CH2Cl2 for 1 h at room temperature and concentrated. Reverse-phase chromatography (10 to 100% MeCN/water with 0.05% TFA) followed by neutralization with EtOAc/saturated NaHCO3 extraction and drying with MgSO4 gave the title compound: MS (ESI+): cal'd [M+H]+ 505.2, obs'd 505.2.
Reaction SMILES: [CH3:1][C:2]1[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5]>[OH-].[NH4+]>[NH2:15][C:14]1[C:2]([CH3:1])=[C:3]([CH:11]=[CH:12][CH:13]=1)[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5]
Reactant: Cc1c(C(=O)CCC(=O)O)cccc1[N+](=O)[O-]
Agent: [NH4+]
Agent: [OH-]
Product: Cc1c(N)cccc1C(=O)CCC(=O)O

Procedure:
3-(2-methyl-3-nitrobenzoyl)propionic acid in ammonium hydroxide solution was reduced with ferrous sulphate to give 3-(3-amino-2-methylbenzoyl)propionic acid.