Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH3:14][C:15]1([CH3:23])[NH:20][C:19](=[O:21])[CH2:18][C:17](=[O:22])[CH2:16]1.C(N(CC)CC)C.CC(C)(O)C#N>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([CH:18]2[C:17](=[O:22])[CH2:16][C:15]([CH3:23])([CH3:14])[NH:20][C:19]2=[O:21])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CC1(C)CC(=O)CC(=O)N1
Agent: CC(C)(O)C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CC(=O)C(C(=O)c2ccc(Cl)cc2[N+](=O)[O-])C(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.1 %

Procedure:
A solution of 4-chloro-2-nitrobenzoyl chloride (4.4 g) in dry dichloromethane (5 ml) was added at 5°-10° C. to a stirred solution of 6,6-dimethylpiperidine-2,4-dione (2.8 g) and triethylamine (2.8 ml) in dry dichloromethane (50 ml) and the mixture was stirred at ambient temperature for 18 hours. Triethylamine (8.4 ml) and acetone cyanohydrin (0.4 ml) were added successively to the solution and the mixture was stirred at ambient temperature for 4 hours. The resulting solution was washed successively with 2N hydrochloric acid (25 ml) and water (3×25 ml), dried over sodium sulphate and evaporated under reduced pressure to give a yellow solid which was recrystallised from acetonitrile to give 3-(4-chloro-2-nitrobenzoyl)-6,6-dimethylpiperidine-2,4-dione (4 g), mp 162°-162.5° C., as a yellow crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C@@H:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:4][CH:3]=1.[NH2:36][C:37]1[S:38][CH:39]=[C:40]([CH2:42][C:43](O)=[O:44])[N:41]=1>>[NH2:36][C:37]1[S:38][CH:39]=[C:40]([CH2:42][C:43]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]3[CH2:11][CH2:10][C@H:9]([C@H:12]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:8]3[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:34][CH:35]=2)=[O:44])[N:41]=1
Reactant: Nc1nc(CC(=O)O)cs1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(N)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(NC(=O)Cc3csc(N)n3)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1

Procedure:
The title compound was prepared from tert-butyl (2S,5R)-2-(4-aminobenzyl)-5-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]pyrrolidine-1-carboxylate (i-4a) and (2-amino-1,3-thiazol-4-yl)acetic acid according to the procedure of Example 1, step A. The crude product was purified by preparative TLC plate eluting with 5% MeOH in dichloromethane to afforded the product (4.1 mg, 21%). m/z (ES) 637 (MH)+, 659 (MNa)+.
Reaction SMILES: [NH4+].C(OC(=O)[NH:8][C@@:9]([CH3:32])([CH2:26][O:27][P:28]([OH:31])([OH:30])=[O:29])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[O:19][C:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[N:17][C:16]=2[CH:25]=1)(C)(C)C.Cl>C(OCC)C>[NH2:8][C@:9]([CH3:32])([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[O:19][C:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[N:17][C:16]=2[CH:25]=1)[CH2:26][O:27][P:28](=[O:29])([OH:31])[OH:30]
Reactant: CCCCCc1nc2cc(CC[C@](C)(COP(=O)(O)O)NC(=O)OC(C)(C)C)ccc2o1
Agent: Cl
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCCc1nc2cc(CC[C@@](C)(N)COP(=O)(O)O)ccc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of [(R)-1-Methyl-3-(2-pentyl-benzoxazol-5-yl)-1-phosphonooxymethyl-propyl]-carbamic acid tert-butyl ester ammonium salt (18 mg, 0.0369 mmol) in diethyl ether (2 ml) was treated with 2M HCl in diethyl ether and stirred for 2 hours at RT. The reaction was quenched by the addition of a solution of 28% aqueous ammonium hydroxide (2 ml), methanol (2 ml) and DCM (1 ml). After evaporation of the solvents in vacuum the residue was purified using preparative reversed phase chromatography (X-Terra, C-18, eluent: gradient of 10 mM NH4HCO3 in water/acetonitrile. The title compound was obtained as an amorphous solid. MS(MH−) 269.3.
Reaction SMILES: C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:19][CH:20]([C:23]1[N:28]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27](=[O:36])[C:26]2=[CH:37][CH:38]=[CH:39][N:25]2[N:24]=1)[CH2:21][CH3:22].[C:40]1(=O)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>ClCCCl>[CH2:29]([N:28]1[C:27](=[O:36])[C:26]2=[CH:37][CH:38]=[CH:39][N:25]2[N:24]=[C:23]1[CH:20]([NH:19][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[CH2:21][CH3:22])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1CCCCC1
Reactant: CCC(N)c1nn2cccc2c(=O)n1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCC(NC1CCCCC1)c1nn2cccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.5 %

Procedure:
Acetic acid (65 μl, 0.95 mmol) and sodium triacetoxyborohydride (200 mg, 0.95 mmol) were added to a solution of 2-(1-amino-propyl)-3-benzyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 26, 180 mg, 0.64 mmol) and cyclohexanone (62 mg, 0.64 mmol) in 1,2-dichloroethane (5 mL). The mixture was stirred for 4 h at room temperature concentrated under reduced pressure and the residue partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was separated, dried (MgSO4) and concentrated to give the title compound (211 mg, 91%) as a white solid: 1H NMR (DMSO-d6) δ 0.69–1.19 (m, 10H), 1.38–1.89 (m, 6H), 1.99 (m, 1H), 3.63 (m, 1H), 4.82 (m, 1H), 5.80 (m, 1H), 6.55 (s, 1H), 7.06 (s, 1), 7.15 (m, 2H), 7.22–7.35 (m, 4H).
Reaction SMILES: C(N(CC)CC)C.[CH:8]([N:10]1[CH:14](C(O)=O)[CH2:13][S:12][CH:11]1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=O.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.Cl[C:36](=[CH2:39])[C:37]#[N:38]>ClCCl.O>[C:37]([C:36]1[CH:39]=[CH:8][N:10]2[C:14]=1[CH2:13][S:12][CH:11]2[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)#[N:38]
Reactant: C=C(Cl)C#N
Reactant: O=CN1C(C(=O)O)CSC1c1cccnc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccn2c1CSC2c1cccnc1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
Triethylamine (4.67 g) is added to a suspension of 3-formyl-2-(3-pyridyl)-4-thiazolidinecarboxylic acid (10 g) in dichloromethane (15 cc) at a temperature close to 20° C. A clear light yellow solution is obtained. This solution is added dropwise in the course of 1 hour at 40° C. to a mixture of tosyl chloride (8.8 g) in dichloromethane (17 cc). The reaction mixture becomes homogeneous and orange-red in colour. 2-Chloroacrylonitrile (4.10 g) is then added quickly, followed, while the reaction medium is maintained at reflux, by triethylamine (9.37 g). The reaction mixture is maintained refluxing for a further 1 hour and 25 minutes. After cooling to room temperature, the reaction medium is hydrolysed with water (12 cc). The organic phase is decanted and the aqueous phase extracted with dichloromethane. The organic extracts are combined and dried overnight over sodium sulphate. After filtering, the solvent is evaporated under reduced pressure (20 mm Hg; 2.7 Pa) at 20° C. A crude product (11.11 g) is obtained, and is purified by chromatography on a column (diameter 4.5 cm) containing silica (100 g) (0.063-0.2 mm), eluting with a mixture of ethyl acetate and dichloromethane. 7-Cyano-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole (8.36g) is thereby obtained in the form of light beige-coloured crystals, m.p. 110° C. (yield 88.4% relative to the acid used).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl.[OH-].[Na+]>[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.C1(C)C=CC=CC=1>[O:24]1[CH:22]([CH2:20][O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:23]1
Reactant: ClCC1CO1
Reactant: OCCCCCCCCCCCCC1CCCCC1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C(CCCCCCC1CCCCC1)CCCCCOCC1CO1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A mixture of 26.5 g (99 millimole) of 12-cyclohexyldodecanol, 27.4 g (296 millimole) of epichlorohydrin, 52.6 g (658 millimole) of 50% aqueous solution of sodium hydroxide, 2.0 g of cetyltrimethylammonium chloride and 300 ml of toluene was stirred at 60° C. for 24 hours. The reaction mixture was washed with water, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. The residue was subjected to silica gel (550 g) column chromatography, and eluted with hexane-ethyl acetate (30:1), to give 1,2-epoxy-3-(12-cyclohexyldodecyloxy)propane as colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:27])=[C:4]2[C:24](=[CH:25][CH:26]=1)[C:8]1[NH:9][C:10]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N:11][C:7]=1[CH2:6][CH2:5]2.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1C=CC=CC=1>[Br:1][C:2]1[C:3]([F:27])=[C:4]2[C:24](=[CH:25][CH:26]=1)[C:8]1[NH:9][C:10]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[N:11][C:7]=1[CH:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2c([nH]1)-c1ccc(Br)c(F)c1CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc3c(F)c(Br)ccc3c2[nH]1
Temperature: 80 °C
Reaction time: 16 h
Yield: 63.5 %

Procedure:
To a solution of (S)-tert-butyl 2-(7-bromo-6-fluoro-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (324 mg, 0.74 mmol) in benzene (7 mL) was added DDQ (185 mg, 0.82 mmol) and the mixture was heated to 80° C. After stirring for 16 h, the reaction mixture was cooled to rt and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (45% to 100% EtOAc/hexanes) to afford (S)-tert-butyl 2-(7-bromo-6-fluoro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (204 mg, 63%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4](S(CC)(=O)=O)[N:3]=1.[C:24]([O:28][C:29]([N:31]1[CH2:35][CH2:34][C@H:33]([NH2:36])[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29]([N:31]1[CH2:35][CH2:34][C@H:33]([NH:36][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=3[O:17][CH3:18])=[CH:6][N:5]=2)[CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2cc(F)ccc2OC)c(N)n1
Product: COc1ccc(F)cc1C(=O)c1cnc(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)nc1N

Procedure:
The same procedure was used as described in Example 9 starting from (4-amino-2-ethanesulfonyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone, Example 48, and (S)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (Astatech), to give (S)-3-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester. MS (M+H)+, 432.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH2:9][N:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:7]1)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:19]([N:8]1[CH2:9][CH:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH:6]([CH:4]=[O:5])[CH2:7]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CON(C)C(=O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=CC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of (3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid methoxy-methyl-amide (3A) 6.58 g (0.017 mol) dissolved in THF (100 mL) was added 16 mL (0.017 mol) of lithiumaluminiumhydride (1.0M in THF) dropwise at 0° C. and stirred for one hour. The reaction was quenched by aq. ammonium chloride solution and extracted with ethylacetate twice. The combined organic layers were dried on anhydrous sodium sulfate and concentrated in vaccuo. The residue was purified by silica gel column chromatography eluted by a mixture of heptane and ethyl acetate (3:2) yielding 5.21 g (93%) of the title compound as a light yellow oil. ES-MS m/e: 334.2 (M+H+).
Reaction SMILES: C[O-].[Na+].[N+:4]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([O-:6])=[O:5].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[CH:17]=[O:18].C(O)(=O)C>CO.O>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]([C:7]2([N+:4]([O-:6])=[O:5])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[OH:18])[CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: O=[N+]([O-])C1CCCCC1
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])C1(C(O)c2cc(Cl)cc(Cl)c2)CCCCC1
Reaction time: 0.5 h

Procedure:
25% sodium methoxide solution (24.9 mmol, 5.7 mL) was diluted with methanol (40 mL), cooled in an ice bath, and nitrocyclohexane was added dropwise over 10 min. The mixture was stirred for 30 min, cooled in an ice bath, and solid 3,5-dichlorobenzaldehyde was added. The mixture was stirred over the weekend, recooled in an ice bath, and treated with 2 mL of glacial acetic acid. The mixture was poured into water (125 mL) and extracted with ether (2×75 mL). The combined ether extracts were washed with water (100 mL) and dried over MgSO4. Removal of the solvent left crude (3,5-dichloro-phenyl)-(1-nitro-cyclohexyl)-methanol (8.93 g) as a yellow oil. Flash chromatography on silica gel, eluting with a 0-100% ether in hexanes gradient provided product of increased purity (ca. 70%). 1H NMR (500 MHz, CDCl3) δ (ppm): 7.35 (s, 1H), 7.19 (s, 2H), 4.90 (s, 1H), 0.9-1.8 (m, 10H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4][N:3]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[OH-].[K+]>CO.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:6]2[CH2:5][CH2:4][N:3]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:2]([CH3:1])[CH2:7]2)=[CH:10][CH:11]=1
Reactant: C[C@H]1CN(Cc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C[C@H]1CN(Cc2ccc(N)cc2)CCN1C(=O)OC(C)(C)C
Reaction time: 0.67 h
Yield: 98.4 %

Procedure:
To 1,1-dimethylethyl (2S)-2-methyl-4-[(4-nitrophenyl)methyl]-1-piperazinecarboxylate (D1) (4.62 g, 13.78 mmol) and KOH (7.79 g, 138.8 mmol) in MeOH (100 mL) was added wet (50% w/w water) 10% Pd/C catalyst (4 g) and the mixture was hydrogenated at room temperature and atmospheric pressure for 40 mins. The catalyst was removed by filtration and the filtrate concentrated in vacuo. The residue was partitioned between DCM and water and aqueous layer was further extracted with DCM (×2). The combined organics were washed with brine, dried and concentrated to give the title compound as a colourless gum (4.14 g) which was used in the next step without further purification. δH (CDCl3, 400 MHz) 7.10 (2H, d), 6.64 (2H, d), 4.16 (1H, br.s), 3.78 (1H, d), 3.62 (2H, s), 3.42 (1H, d), 3.28 (1H, d), 3.08 (1H, td), 2.74 (1H, m), 2.58 (1H, m), 2.06 (1H, dd), 1.95 (1H, m), 1.46 (9H, s), 1.21 (3H, d).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:13][CH3:14])=[CH:7][NH:8][C:9]2=O)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=2)[C:6]([O:13][CH3:14])=[CH:7][N:8]=1
Reactant: COc1c[nH]c(=O)c2cc(F)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cnc(Cl)c2cc(F)ccc12
Yield: 24 %

Procedure:
A solution of 7-fluoro-4-methoxyisoquinolin-1(2H)-one (11 g, 56.9 mmol) in POCl3 (100 ml) was refluxed for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The combine organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (20% ethyl acetate in pet ether) to get desired compound (2.9 g, 24%) as off-white solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.36-8.32 (m, 1H), 7.93-7.90 (m, 1H), 7.88 (s, 1H), 7.70-7.65 (m, 1H), 4.11 (s, 3H); MS: MS m/z 212.1 (M++1).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.O>CC1C=CC(C)=CC=1>[CH2:12]([C:7]1[CH:8]=[C:2]([C:1]([O:10][CH3:11])=[O:9])[C:3]([NH2:4])=[CH:5][CH:6]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ccccc1
Reactant: COC(=O)c1ccccc1N
Agent: Cl
Solvent: Cc1ccc(C)cc1
Solvent: O
Product: COC(=O)c1cc(Cc2ccccc2)ccc1N
Reaction time: 3 h
Yield: 4.4 %

Procedure:
Methyl anthranilate (30.9 g; 205 mmols) and benzyl alcohol (4.43 g; 40,9 mmols) were dissolved in 50 mL of p-xylene. Montmorillonite (1.3 g), activated with hydrochloric acid, was added to the reaction mixture, which was then heated to boiling. The water produced during the reaction was collected using a Dean-Starck-apparatus. After three hours the solvent and the excess of methyl anthranilate were distilled off at reduced pressure. Chromatography using silica gel 60 and heptane/ethyl acetate (19/1->9/1) as eluent afforded 430 mg (4.4%) of the desired methyl 5-benzylanthranilate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)#[N:15].[OH-].[K+].O>C1COCC1.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:13][CH2:12][C:4]1[CH:3]=[C:2]([C:19]2[CH:20]=[CH:21][C:16]([C:14]#[N:15])=[CH:17][CH:18]=2)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: OCc1cc(Br)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(-c2cc(CO)cc(C(F)(F)F)c2)cc1
Temperature: 120 °C
Yield: 50.7 %

Procedure:
A solution of (3-bromo-5-(trifluoromethyl)phenyl)methanol (3.0 g, 11.8 mmol), 4-cyanophenyl boronic acid (5.2 g, 35 mmol), tetrakis(triphenylphosphine) palladium(0) (2.7 g, 2.4 mmol), and aqueous potassium hydroxide (41 mL, 1N, 41 mmol) in THF (80 mL) was degassed with nitrogen for 10 minutes and then heated at 120° C. for 18 hours. The reaction was cooled to ambient temperature and poured into water (100 mL), then was diluted with ethyl acetate (100 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×20 mL) and the combined organic layers were dried with MgSO4 and evaporated. The residue was purified by chromatography on SiO2 with a gradient of ethyl acetate/hexanes of 5%-40%. The product 3′-(hydroxymethyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile (1.66 g, 51%) was obtained as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 7.65-7.80 (m, 7H), 4.85 (s, 2H), 1.90 (bs, 1H). Mass spec.: 278.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:9])=[N:6][C:7]=1[CH3:8].C(N(CC)CC)C.[CH3:17][C:18]1[N:22]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)[N:21]=[CH:20][C:19]=1[C:33](Cl)=[O:34]>O1CCCC1>[Br:9][C:5]1[N:6]=[C:7]([CH3:8])[C:2]([NH:1][C:33]([C:19]2[CH:20]=[N:21][N:22]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][N:24]=3)[C:18]=2[CH3:17])=[O:34])=[CH:3][CH:4]=1
Reactant: Cc1nc(Br)ccc1N
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(C(F)(F)F)cn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(Br)ccc1NC(=O)c1cnn(-c2ccc(C(F)(F)F)cn2)c1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.6 %

Procedure:
To a solution of 5-amino-2-bromo-6-picoline (701 mg) and triethylamine (1.57 ml) in tetrahydrofuran (20 ml) was added 5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid chloride (1.34 g) described in Reference Example 180 under ice-cooling, and stirred at room temperature for 1.5 hours. After completion of the reaction, the solvent was evaporated, and saturated sodium bicarbonate water was added thereto. The insoluble matter was collected by filtration, washed with water, and then dried in vacuo to give the titled compound as a pale yellow solid (1.66 g). MS (ESI) m/z: 440 (M+H)+.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([OH:17])=[C:12]([Cl:18])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][CH2:21]Cl.C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl>[Cl:18][C:12]1[CH:11]=[C:10]([O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:15]=[C:14]([CH3:16])[C:13]=1[O:17][CH2:19][O:20][CH3:21]
Reactant: Cc1cc(OC(=O)c2ccccc2)cc(Cl)c1O
Reactant: COCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1c(C)cc(OC(=O)c2ccccc2)cc1Cl
Temperature: 0 °C
Yield: 93.9 %

Procedure:
Then, 25 g of 4-benzoyloxy-2-chloro-6-methylphenol was dissolved in 250 ml of chloroform, to which 12 g of chloromethyl methyl ether was added, while stirring at 0° C., and 21 g of N-ethyldiisopropylamine was added dropwise. After heating under reflux for 1 hour, the chloroform layer was washed with water, and concentrated. The residue was subjected to silica gel chromatography, which afforded 27.4 g of 3-chloro-4-methoxymethoxy-5-methyl-1-benzoyloxybenzene (96% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:6][C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O=[C:23]([CH2:27][CH2:28][CH3:29])[C:24]([OH:26])=[O:25]>C(O)C.[Pd]>[CH2:8]([C:7]1[C:2]([NH:1][CH:23]([CH2:27][CH2:28][CH3:29])[C:24]([OH:26])=[O:25])=[N:3][CH:4]=[C:5]([C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)[N:6]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCCC(=O)C(=O)O
Reactant: Nc1ncc(-c2ccc(O)cc2)nc1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCCC(Nc1ncc(-c2ccc(O)cc2)nc1Cc1ccccc1)C(=O)O
Temperature: 65 °C
Reaction time: 4 h
Yield: 51.5 %

Procedure:
4-(5-amino-6-benzylpyrazin-2-yl)phenol (100 mg, 0.36 mmol) was mixed with 2-Oxovaleric acid (84 mg, 0.72 mmol) in ethanol (20 mL). Pd/C (10% Palladium in active carbon, 40 mg) was added, and the reaction mixture heated to 65° C. Air was bubbled out by N2 gas, and a hydrogen balloon applied to the reaction flask. The reaction was continuously stirred for 4 hrs. After cooling down, it was filtered, and the resulting solution purified by flash chromatography (eluting solvent: 50% EtOAc in heptanes) to give the product as a yellow powder (70 mg, 52%). 1H NMR (300 MHz, CD2Cl2, δ): 8.31 (s, 1H), 7.82 (d, 2H, J=9.0 Hz), 7.31 (m, 5H), 6.92 (d, 2H, J=9.0 Hz), 5.34 (s, 2H), 4.20 (m, 1H), 1.10 (m, 2H), 0.98 (m, 2H), 0.87 (t, 3H); MS (ESI) m/z 378.3 (M+1).