Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19](O)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:2].Cl.[CH3:23][O:24][C:25]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[C:31]2[C:26]=1[CH2:27][CH2:28][NH:29][CH2:30]2>>[O:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19]([N:29]3[CH2:28][CH2:27][C:26]4[C:31](=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:25]=4[O:24][CH3:23])[CH2:30]3)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: COc1cccc(-c2nc(C(=O)O)c3ccccc3n2)c1
Reactant: COc1ccc2c(c1OC)CCNC2
Agent: Cl
Product: COc1cccc(-c2nc(C(=O)N3CCc4c(ccc(OC)c4OC)C3)c3ccccc3n2)c1
Yield: 11 %

Procedure:
Reaction of 2-(3-methoxylphenyl)quinazoline-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 49 (11% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.92 and 3.15 (2t, 2H), 3.57 and 4.17 (2t, 2H), 3.82-3.98 (m, 9H), 4.47 and 5.07 (2s, 2H), 6.53 and 6.91 (2d, 1H), 6.72 and 7.02 (2d, 1H), 7.11-7.14 (m, 1H), 7.44-7.50 (t, 1H), 7.63-7.69 (m, 1H), 7.98-8.09 (m, 2H), 8.29-8.38 (m, 3H); MS (ESI) m/z 456 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[C:4]([CH3:9])[C:5]([F:8])=[CH:6][CH:7]=1.[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH2:9][Br:11])[C:3]=1[Cl:10]
Reactant: Cc1c(F)ccc(Br)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(Br)c(Cl)c1CBr
Yield: 98.9 %

Procedure:
3-Bromo-2-chloro-6-fluoro-toluene (8.0 g), N-bromosuccinimide (NBS) (6.42 g) and a catalytic amount of benzoyl peroxide in carbon tetrachloride (40 ml) were heated to reflux. A 500 watt tungsten halogen lamp was used to initiate the reaction. The reaction mixture was heated to reflux and irradiated for 30 minutes. The reaction mixture was allowed to cool and then filtered. The filtrate was concentrated to give a colourless oil which solidified on standing to give 1-bromo-3-bromomethyl-2-chloro-4-fluorobenzene as an off-white solid (10.7 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[C:9](Br)[CH:8]=[CH:7][C:6]=1[O:12][CH3:13].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:52]([C:54]([OH:86])([CH2:84][CH3:85])/[CH:55]=[CH:56]/[C:57]1[CH:62]=[CH:61][C:60]([C:63]([CH2:81][CH3:82])([C:66]2[CH:71]=[CH:70][C:69](B3OC(C)(C)C(C)(C)O3)=[CH:68][CH:67]=2)[CH2:64][CH3:65])=[CH:59][C:58]=1[CH3:83])[CH3:53].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[C:9]([C:69]2[CH:68]=[CH:67][C:66]([C:63]([CH2:81][CH3:82])([C:60]3[CH:61]=[CH:62][C:57](/[CH:56]=[CH:55]/[C:54]([CH2:84][CH3:85])([OH:86])[CH2:52][CH3:53])=[C:58]([CH3:83])[CH:59]=3)[CH2:64][CH3:65])=[CH:71][CH:70]=2)[CH:8]=[CH:7][C:6]=1[O:12][CH3:13]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1C)CC
Reactant: COC(=O)Cc1cc(Br)ccc1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3ccc(OC)c(CC(=O)OC)c3)cc2)cc1C)CC
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 64 %

Procedure:
(5-Bromo-2-methoxy-phenyl)-acetic acid methyl ester (Example 180-(1); 40.5 mg, 0.156 mmol), palladium acetate (2.2 mg, 0.010 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (8.6 mg, 0.021 mmol), potassium phosphate (66 mg, 0.312 mmol) and water (0.2 mL) were added to a solution of (E)-3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example 39-(5); 49.7 mg, 0.104 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for 1.5 hours. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give the target compound as a colorless oil (35.2 mg, 64%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=[CH:12][CH3:13])[CH:6]=1.C([O-])(O)=O.[Na+].[H][H]>[Pd].CCOC(C)=O.CCO>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][CH3:13])[CH:6]=1
Reactant: [H][H]
Reactant: CC=Cc1cccc(OCOC)c1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCc1cccc(OCOC)c1
Yield: 100.3 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (11.0 g, 90.1 mmol) in DMF (110 mL) at 0° C. was added methoxymethyl chloride (7.5 mL, 99.1 mmol) followed by NaH (99.1 mmol, 3.96 g, 60% dispersion in oil) in three portions (violent deprotonationl). The mixture was stirred at 0° C. for 15 min and then at room temperature for 15 h. The reaction was quenched with water and more water was added until all the precipitate dissolved. The solution was extracted in ether (2×150 mL) with water (50 mL), then with saturated Na2CO3 (100 mL), and finally with water (100 mL). The crude product was used in the next reaction. To a suspension of (ethyl)triphenylphosphonium bromide (36.8 g, 99.1 mmol, dried at 90° C. under high vacuum overnight) in THF (250 mL) at 0° C. was added n-BuLi (39.6 mL, 99.1 mmol, 2.5 M in hexanes) over five min. The resulting pretty dark burgundy mixture was stirred at 0° C. for 10 min and then at room temperature for 30 min. It was re-cooled to 0° C. and a solution of the above crude 3-methoxymethoxybenzaldehyde in THF (15 mL) was added slowly. The resulting medium brown mixture was stirred at 0° C. for 2 h and then at room temperature for 2 h. The mixture was quenched by exposing it to air for several min. Because filtering the mixture for this particular Wittig reaction would result in a sticky precipitate clogging the sintered-glass filter, the THF was removed in vacuo and the crude material was dissolved in DMF (100 mL). Extraction in hexanes (4×100 mL) with 50% saturated brine (100 mL) eliminated triphenylphosphonium oxide into the aqueous layer. Flash chromatography with silica gel (gradient to 6% ether/hexanes) produced 1-(methoxymethoxy)-3-(1-propenyl)benzene [(E)/(Z)˜1:1] as a colorless liquid (13.2 g, 82% yield for two steps). A suspension of 3 produced 1-(methoxymethoxy)-3-(1-propenyl)benzene (13.2 g, 74.1 mmol), NaHCO3 (1.24 g, 14.8 mmol), and 10% palladium on carbon (3.3 g) in EtOAc (75 mL) and EtOH (19 mL) was stirred at room temperature for 20 h with a hydrogen balloon attached. The round-bottom flask was purged with nitrogen, the mixture was filtered through Celite, and the Celite was washed well with EtOAc to furnish 1-(methoxymethoxy)-3-propylbenzene as a colorless liquid (13.4 g, 100% yield): 1H NMR (300 MHz, CDCl3) δ 0.94 (t, 3H, J=7.4 Hz), 1.64 (m, 2H), 2.56 (t, 2H, J=7.7 Hz), 3.48 (s, 3H), 5.17 (s, 2H), 6.80-6.90 (three overlapping peaks, 3H), 7.19 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9]12[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:14]C(=O)O[C:10]2=O.C(=O)=O.[OH-].[Na+]>O>[O:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:10]1[C:9]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:14]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Nc1ccccc1O
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccccc1-c1nc2ccccc2o1

Procedure:
An intimate mixture of 2-aminophenol (109.13 g) and isatoic anhydride (203.9 g) was heated at 140° C. for 2 to 4 h until the formation of carbon dioxide ceased. Then the mixture was placed under vacuum (at a constant pressure of 50 mmHg) and the heating was continued at 180° C. for 3 to 4 h until the formation of water ceased. The melt was poured into a porcellanic mortar and, after cooling, the cold material was pestled, then boiled in a solution of caustic soda (12 g) in water (3.5 L) for 2 to 3 h. After cooling, the precipitate was isolated by filtration, and washed with cold water until the pale blue fluorescence disappeared in the washings. The precipitate was dried at 80° C. to afford 2-(benzo[d]oxazol-2-yl)phenylamine (180 to 185 g). The product was used without further purification in the next stage of preparation.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:17])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:25]1[C:30]([CH3:31])=[CH:29][C:28]([N+:32]([O-:34])=[O:33])=[CH:27][C:26]=1[CH3:35]>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[O:17][C:25]1[C:26]([CH3:35])=[CH:27][C:28]([N+:32]([O-:34])=[O:33])=[CH:29][C:30]=1[CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Reactant: COc1ccc(O)cc1OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
To a solution of 3-benzyloxy-4-methoxyphenol (3 g) in DMSO (2 mL) was added potassium t-butoxide (1.6 g). After 30 min, 4-chloro-3,5-dimethyl-nitrobenzene (2 g) was added and the resulting solution was heated at 80° C. for 2 h. The reaction mixture was partitioned between ethyl acetate and 1 N aqueous NaOH, and the organic layer was washed with water, brine, dried over sodium sulfate and concentrated in vacuo to afford 4-(3-benzyloxy-4-methoxyphenoxy)-3,5-dimethylnitrobenzene (1.9 g) as an orange solid.
Reaction SMILES: C([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)C1C=CC=CC=1.[Li]CCCC.[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>C1COCC1>[C:19]([N:9]1[CH2:8][CH2:12][O:11][C:10]1=[O:13])(=[O:22])[CH2:20][CH3:21]
Reactant: CCC(=O)Cl
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(=O)N1CCOC1=O

Procedure:
Compound 28 was prepared by reaction of (R)-(+)-4-benzyl-2-oxazolidinone with BuLi and propionyl chloride in THF according to standard literature procedures (See, Evans, D. A. Aldrichimica Acta 1982, 15, 23).
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC(OP(OC2C=CC=CC=2)([N:19]=[N+:20]=[N-:21])=O)=CC=1.[C:29]([O:33][C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42]1[CH:47]=[CH:46][C:45]([CH2:48][N:49]2[C:53]3[CH:54]=[C:55]([C:59](O)=[O:60])[CH:56]=[C:57]([CH3:58])[C:52]=3[N:51]=[C:50]2[CH2:62][CH2:63][CH3:64])=[CH:44][CH:43]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>CN(C=O)C.[Na+].[Cl-]>[C:29]([O:33][C:34]([C:36]1[C:37]([C:42]2[CH:43]=[CH:44][C:45]([CH2:48][N:49]3[C:53]4[CH:54]=[C:55]([C:59]([N:19]=[N+:20]=[N-:21])=[O:60])[CH:56]=[C:57]([CH3:58])[C:52]=4[N:51]=[C:50]3[CH2:62][CH2:63][CH3:64])=[CH:46][CH:47]=2)=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:35])([CH3:30])([CH3:32])[CH3:31]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CCCc1nc2c(C)cc(C(=O)O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1nc2c(C)cc(C(=O)N=[N+]=[N-])cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
DIPEA (0.43 mL, 25 mmol) and diphenylphosphonic azide (489 μL, 2.3 mmol) were added to a solution of 3-(2′-t-butoxycarbonylbiphenyl-4-ylmethyl)-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylic acid (1.0 g, 2.1 mmol; prepared as described in Preparation 3) in DMF (15 mL). The mixture was stirred at room temperature for 16 hours, diluted with saturated aqueous NaCl (100 mL), then extracted with EtOAc (200 mL). The organic layer was evaporated to dryness to yield crude Intermediate (10a). MS m/z: [M+H+] calcd for C30H31N5O3, 510.2. found 510.6.
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].[NH2:14][C@H:15]([C:23]([NH:25][C@H:26]([C:37]([OH:39])=[O:38])[CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([BH3-])#N.[Na+]>>[C:3]([CH:2]([NH:14][C@H:15]([C:23]([NH:25][C@H:26]([C:37]([OH:39])=[O:38])[CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=[O:24])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:5])=[O:4]
Reactant: N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O=C(O)C(=O)CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C(O)C(CCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
In the manner described in example 24, one can condense 2-oxo-4-phenylbutyric acid and L-phenylalanyl-L-tryptophan in the presence of sodium cyanoborohydride to yield N-(1-carboxy-3-phenylpropyl)-L-phenylalanyl-L-tryptophan.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]2[C:12]([C:13](=[O:27])[C:14]3[CH:19]=[C:18]([O:20][CH2:21][O:22][CH3:23])[CH:17]=[CH:16][C:15]=3[N+:24]([O-:26])=[O:25])=[C:11]([C:28]([O:30]CC)=[O:29])[N:10]=[N:9]2)=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([C:13](=[O:27])[C:14]3[CH:19]=[C:18]([O:20][CH2:21][O:22][CH3:23])[CH:17]=[CH:16][C:15]=3[N+:24]([O-:26])=[O:25])=[C:11]([C:28]([OH:30])=[O:29])[N:10]=[N:9]2)=[CH:33][CH:34]=1
Reactant: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1C(=O)c1cc(OCOC)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCOc1ccc([N+](=O)[O-])c(C(=O)c2c(C(=O)O)nnn2Cc2ccc(OC)cc2)c1

Procedure:
In the same manner as above, a solution of ethyl 1-(4-methoxybenzyl)-5-(5-methoxymethoxy-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylate (b-2) (1.23 g, 2.62 mmole) in tetrahydrofuran (25 ml) was hydrolyzed with a 1N aqueous sodium hydroxide solution (5.2 ml) at room temperature for 5 hours to give 1-(4-methoxybenzyl)-5-(5-methoxymethoxy-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylic acid (c-2': MP) (1.08 g, 93%)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[CH:14]1[C:19]([OH:20])=[CH:18][CH:17]=[C:16]([CH3:21])[CH:15]=1.[OH-].[K+].O>C(O)C.C(Cl)Cl>[C:16]1([CH3:21])[CH:15]=[CH:14][C:19]([O:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=[CH:18][CH:17]=1
Reactant: OCCCCCCCCCCCBr
Reactant: Cc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: Cc1ccc(OCCCCCCCCCCCO)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
The 11-bromoundecan-1-ol 15 (3.68 g) and 4.88 g of p-cresol were dissolved in 20 ml of ethanol, and 2.57 g of potassium hydroxide was added to that, followed by 24-hour refluxing. After cooled to room temperature, the reaction solution is moved into a separating funnel, and 100 ml of ion-exchange water and 50 ml of methylene chloride were added so as to cause separation. After the organic phase was collected and was dehydrated with sodium sulfate, the desiccant agent was removed by filtration, and the solvent of the filtrate was distilled away under reduced pressure. The resultant solid was re-dissolved in 50 ml of toluene, and was washed twice with 10 wt % of aqueous potassium hydroxide solution, and was then washed with 50 ml of saturated saline. After that, the organic phase was collected, and was dehydrated with sodium sulfate. The desiccant agent was removed by filtration, and the solvent of the filtrate was distilled away under reduced pressure, to obtain 4.08 g of 11-(p-tolyloxy)undecan-1-ol 16, which is a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[NH:14][C:13]2=[O:26])=[C:4]([F:27])[CH:3]=1.[C:28](=O)(O)[O-].[Na+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:25])([F:24])[C:20]([F:23])([F:21])[F:22])[N:14]=[C:13]2[O:26][CH3:28])=[C:4]([F:27])[CH:3]=1
Reactant: CC(C)Oc1cc(-n2c(=O)cc(C(F)(F)C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(OC(C)C)c(Cl)cc1F

Procedure:
using 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-6-pentafluoroethyl-2,4(1H,3H)-pyrimidinedione with sodium bicarbonate and dimethyl sulphate in acetone there is obtained 1-(4-chloro-2-fluoro-5-isopropoxyphenyl)-2-methoxy -4-pentafluoroethyl-6(1H)-pyrimidinone, m.p. 79°-81° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]3[C:17]=2[CH2:18][C:19](O)=[O:20])=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][NH:29][CH2:30][CH3:31].Cl.C(OCC)C>ClCCl>[ClH:1].[CH2:30]([N:29]([CH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=1)[C:19](=[O:20])[CH2:18][C:17]1[N:11]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]2=[N:9][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH3:31]
Reactant: Cc1ccn2c(CC(=O)O)c(-c3ccc(Cl)cc3)nc2c1
Reactant: CCNCc1ccccn1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCN(Cc1ccccn1)C(=O)Cc1c(-c2ccc(Cl)cc2)nc2cc(C)ccn12
Yield: 51.2 %

Procedure:
According to the method of Example 13, 2-(4-chlorophenyl)-7-methylimidazo[1,2-a]pyridine-3-acetic acid and N-(2-pyridinylmethyl)ethylamine were used as raw materials for synthesis, salified with hydrochloric acid-ethyl ether solution in dry dichloromethane, then crystallized with methanol-tetrahydrofuran to obtain a corresopnding hydrochloride pure product. Yellow solid powder, yield 51.2%. m.p. 178-180° C., ESI-MS m/z: 420[M+H]+, 1H NMR(D2O, 400 MHz)δ: 0.95(t, 0.5H, J=7.00 Hz), 1.14(t, 2.5H, J=7.00 Hz), 2.38(s, 2.5H), 2.40(s, 0.5H), 3.30(q, 0.4H, J=7.00 Hz), 3.56(q, 1.6H, J=7.00 Hz), 4.14(s, 0.4H), 4.36(s, 1.6H), 4.76(s, 1.6H), 4.86(s, 0.4H), 7.14-7.24(m, 1H), 7.30-7.46(m, 4H), 7.50(s, 1H), 7.69-7.75(m, 2H), 8.11-8.13(m, 1H), 8.33-8.53(m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([OH:15])=O)[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:8]=2)=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([NH:30]C(=O)OC(C)(C)C)[CH2:26][CH2:25]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:24]3[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]3)=[O:15])[N:10]=[C:9]([C:16]3[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=3)[CH:8]=2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(O)Cn1nc(-c2ccncc2)cc1Cc1ccc(F)cc1
Product: NC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1

Procedure:
The title compound was prepared as in Example 7, except [5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetic acid (3.40 g, 10.93 mmol) and tert-butyl piperidin-4-ylcarbamate (2.36 g, 12.02 mmol) were used. The title compound was isolated as an off-white solid, 3.8 g, 90%. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.53 (d, 2 H), 7.66 (d, 2 H), 7.30 (t, 2 H), 7.14 (t, 2 H), 6.51 (s, 1 H), 5.16 (q, 2 H), 4.09 (d, 1 H), 3.94 (s, 2 H), 3.78 (d, 1 H), 3.07 (t, 1 H), 2.68-2.83 (m, 2 H), 1.63-1.79 (m, 2 H), 1.13-1.28 (m, 1 H), 0.99-1.12 (m, 1 H); m/z (APCI+) for C22H24N5OF 394.2 (M+H)+.
Reaction SMILES: [Cu]([C:4]#[N:5])C#N.Br[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([F:14])[C:12]=1[CH3:13]>CN(C)C=O>[F:14][C:11]1[CH:10]=[N:9][CH:8]=[C:7]([C:12]=1[CH3:13])[C:4]#[N:5]
Reactant: N#C[Cu]C#N
Reactant: Cc1c(F)cncc1Br
Solvent: CN(C)C=O
Product: Cc1c(F)cncc1C#N
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
Copper cyanide (1.87 g, 0.021 mol) was added at room temperature to a sealed tube containing a solution of 3-bromo-5-fluoro-4-methylpyridine (E; 2.0 g, 0.0105 mol) in dimethylformamide (20 mL). The reaction mixture was heated to 150° C. for 16 h. It was then cooled to RT, quenched with 20% aqueous ammonia (30 mL) solution and stirred for 5 min. The reaction mixture was extracted with diethyl ether (2×100 mL). The organic layers were washed with water (2×50 mL), dried over anhydrous sodium sulphate and concentrated to afford 5-fluoro-4-methylnicotinonitrile. 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.56 (s, 1H), 2.56 (s, 3H).
Reaction SMILES: [NH2:1][C:2](=[O:42])[CH2:3][C:4]1[CH:41]=[CH:40][CH:39]=[CH:38][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[N:9]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[N:25]1([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:10]3[N:9]=[C:8]([CH2:7][CH2:6][C:5]4[CH:38]=[CH:39][CH:40]=[CH:41][C:4]=4[CH2:3][C:2]([NH2:1])=[O:42])[C:13]([C:14]([F:16])([F:15])[F:17])=[CH:12][N:11]=3)=[CH:20][CH:21]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCNCC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.8 %

Procedure:
tert-Butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I8) (0.131 g, 0.224 mmol) was dissolved in DCM (7 mL) under an atmosphere of nitrogen. Trifluoroacetic acid (0.857 mL, 11.2 mmol) was added to the solution and the reaction was stirred at room temperature for 24 hours. Volatiles were removed in vacuo, EtOAc (70 mL) and 2 M aq. NaOH (70 mL) were added to the oil and the layers were separated. The aqueous layer was extracted with EtOAc (50 mL), the combined organics were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. The resulting solid was taken up in DCM (˜5 mL) and methanol (˜1 mL) and concentrated in vacuo. The process was repeated with only DCM twice to give the title compound (1) (0.104 g, 96% yield) as a pale yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 9.96 (s, 1H), 8.60 (s, 1H), 7.61-7.53 (m, 2H), 7.43 (br s, 1H), 7.25-7.13 (m, 4H), 6.98-6.86 (m, 3H), 3.50 (s, 2H), 3.12-3.05 (m, 2H), 3.04-2.94 (m, 6H), 2.86-2.78 (m, 4H). LCMS Method C: rt 4.774 min; m/z 485.2 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][NH:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]3[CH:40]=[CH:39][C:35]4[O:36][CH2:37][O:38][C:34]=4[CH:33]=3)[CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].FC(F)(F)C(O)=O>O.C(#N)C>[C:1]1([CH2:7][NH:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]3[CH:40]=[CH:39][C:35]4[O:36][CH2:37][O:38][C:34]=4[CH:33]=3)[CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC(=O)NCc2ccccc2)c1)c1ccc2c(c1)OCO2
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: O=C(O)CC(NC(=O)CNC(=O)c1cccc(NC(=O)NCc2ccccc2)c1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 410.3 %

Procedure:
The compound of Example 121 (400 mg, 0.094 mmol) was dissolved in water/acetonitrile (1:1), followed by the addition of lithium hydroxide (100 mg, 0.4 mmol). The reaction mixture was stirred at 25° C., and monitored by HPLC. After complete hydrolysis (1-2 hours) trifluoroacetic acid was added until pH=2. The product was purified by reverse phase chromatography (water/acetonitrile) and lyophilized to result in a white solid (200 mg). MS and 1H-NMR were consistent with the proposed structure.