Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]C(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(NC(C)C)(C)C.[F:20][C:21]([F:64])([F:63])[C:22]1[CH:23]=[C:24]([C@H:32]2[O:36][C:35](=[O:37])[N:34]([CH2:38][C:39]3[C:44]([N:45]([CH2:48][C@H:49]4[CH2:54][CH2:53][C@H:52]([CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH2:51][CH2:50]4)[CH2:46][CH3:47])=[CH:43][CH:42]=[CH:41][N+:40]=3[O-])[C@H:33]2[CH3:62])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:20][C:21]([F:64])([F:63])[C:22]1[CH:23]=[C:24]([C@H:32]2[O:36][C:35](=[O:37])[N:34]([CH2:38][C:39]3[C:44]([N:45]([CH2:48][C@H:49]4[CH2:54][CH2:53][C@H:52]([CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH2:51][CH2:50]4)[CH2:46][CH3:47])=[CH:43][CH:42]=[C:41]([Cl:1])[N:40]=3)[C@H:33]2[CH3:62])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1
Reactant: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc[n+]([O-])c2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc(Cl)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Triphosgene (360 mg, 1.21 mmol) and diisopropylamine (123 mg, 170 μL, 1.21 mol) were added successively to a stirred solution of ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-1-oxidopyridin-3-yl](ethyl)amino]methyl}cyclohexyl)acetate (156.6 mg, 0.243 mmol) in dry CH2Cl2 (9 mL) at −20° C. under N2. The reaction was stirred at room temperature for 6 h. Additional triphosgene (360 mg, 1.21 mmol) and diisopropylamine (123 mg, 170 μL, 1.21 mmol) were added successively and the reaction was stirred at room temperature overnight. The reaction was diluted with saturated NaHCO3 (10 mL) and extracted with CH2Cl2 (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 25×160 mm, 0-60% EtOAc in hexanes gradient) to afford ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-chloropyridin-3-yl](ethyl)amino]methyl}cyclohexyl)acetate. Rf=0.32 (20% EtOAc/hexanes). LCMS calc.=664.2; found=664.4 (M+1)+. 1H NMR (500 MHz, CDCl3): δ 7.87 (s, 1 H); 7.81 (s, 2 H); 7.41 (d, J=8.4 Hz, 1 H); 7.19 (d, J=8.4 Hz, 1 H); 5.83 (d, J=8.4 Hz, 1 H); 4.97 (d, J=16.9 Hz, 1 H); 4.47-4.43 (m, 1 H); 4.29 (d, J=16.9 Hz, 1 H); 4.12-4.06 (m, 2 H); 2.98-2.88 (m, 2 H); 2.81-2.74 (m, 2H); 2.13 (d, J=6.8 Hz, 2 H); 1.84-1.68 (m, 5 H); 1.36-1.24 (m, 1 H); 1.22 (t, J=7.1 Hz, 3 H); 0.99 (t, J=7.0 Hz, 3 H); 0.95-0.81 (m, 4 H); 0.73 (d, J=6.6 Hz, 3 H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([Cl:12])[CH:4]=1.[CH3:13]O>C(OCC)C>[Br:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:13])=[O:8])=[C:5]([Cl:12])[CH:4]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: CO
Agent: Cl
Solvent: CCOCC
Product: COC(=O)c1ccc(Br)cc1Cl
Yield: 94 %

Procedure:
Hydrochloric acid (gas) was bubbled through a solution of 10 g (42.5 mmol) of 4-bromo-2-chloro benzoic acid in 100 ml of methanol until reflux occurred. The resulting reaction mixture was allowed to react overnight. When the reaction was substantially complete, as indicated by TLC, the reaction mixture was concentrated in vacuo to provide a residue. This residue was redissolved in diethyl ether and washed sequentially with water (twice) and a saturated sodium chloride solution, dried over sodium sulfate, filtered and then concentrated in vacuo to provide 10 g of a light tan oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:25])=O.[NH2:26][C:27]([NH2:29])=[S:28]>CCO>[CH3:24][O:23][CH2:22][CH2:21][CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:26]=[C:27]([NH2:29])[S:28][CH:2]=3)=[C:6]([CH3:25])[CH:7]=2)=[CH:14][CH:15]=1
Reactant: COCCCOc1ccc(Oc2cc(C)c(C(=O)CBr)c(C)c2)cc1
Reactant: NC(N)=S
Solvent: CCO
Product: COCCCOc1ccc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)cc1
Yield: 88.8 %

Procedure:
A mixture of 2-bromo-1-{4-(4-(3-methoxypropoxy)phenoxy)-2,6-dimethylphenyl}ethanone (21-4, 0.34 g, 0.82 mmol) and thiourea (0.07 g, 0.96 mmol) in 95% EtOH (5.0 mL) was heated at reflux for 2.0 h. The solution was concentrated and added with water (10 mL) and saturated aqueous Na2CO3 (1.0 mL). The resultant precipitate was filtered and washed with hot water. The solids were filtered and dried under vacuum to give 4-{4-(4-(3-methoxypropoxy)phenoxy)-2,6-dimethylphenyl}thiazol-2-amine (21-5, 0.28 g) as yellow solids in 90% yield, which was used directly for the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C[Si](C)(C)N[Si](C)(C)C.[Li].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.C(OCC)(=O)C>[C:26]1([NH:25][C:2]2[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Reactant: Nc1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(F)(F)F)nc1Nc1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
In a 50 mL round-bottomed flask, 2-chloro-6-(trifluoromethyl)-nicotinic acid (5 g, 22.2 mmol) was combined with THF (20 mL) to give a dark red solution. The reaction solution was cooled to −78° C., lithium hexamethyldisilazane (LiHMDS, 1.0 M in THF) (66.5 mL, 66.5 mmol) was added and stirred for 2 hr. A solution of aniline (19.6 g, 19.2 mL, 210 mmol) in THF (20 mL) was added dropwise to the reaction and the reaction was allowed to gradually warm at room temperature. The resultant reaction was stirred overnight. The reaction mixture was diluted with ethyl acetate (250 mL). The organic layers were combined, washed with saturated aqueous NaHCO3 (2×150 mL), H2O (1×50 mL), and brine (1×50 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The compound was triturated in ether to give of 2-phenylamino-6-trifluoromethyl-nicotinic acid (6.19 g, 98.9%) as a light brown solid. The material was not further purified.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5]1[N:9]([CH3:10])[C:8]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:7][N:6]=1.Cl[CH:18]([C:20]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[O:22][N:21]=1)[CH3:19]>CN(C=O)C.[Cl-].[Na+].O>[Cl:31][C:27]1[CH:26]=[C:25]([C:23]2[O:22][N:21]=[C:20]([CH:18]([N:4]([CH3:3])[C:5]3[N:9]([CH3:10])[C:8]([C:11]4[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=4)=[N:7][N:6]=3)[CH3:19])[N:24]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CNc1nnc(-c2cccnc2)n1C
Reactant: CC(Cl)c1noc(-c2cccc(Cl)c2)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(c1noc(-c2cccc(Cl)c2)n1)N(C)c1nnc(-c2cccnc2)n1C
Temperature: 60 °C
Yield: 43.5 %

Procedure:
NaH (14 mg, 0.35 mmol) was added to N,4-dimethyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-amine (33 mg, 0.18 mmol) in DMF (3 mL). After 30 min 3-(1-chloroethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole (80 mg, 0.18 mmol) in DMF (1 mL) was added to the mixture and the reaction was stirred at 60° C. o.n. Brine was added and the mixture was extracted with EA. The organic phase was dried and concentrated. The product was purified by column chromatography (DCM to DCM-MeOH 30:1) to give 31 mg (43%) of the title compound. 1H NMR: 1.71 (d, 3H) 2.97 (s, 3H) 3.67 (s, 3H) 4.88 (q, 1H) 7.46 (m, 2H) 7.56 (d, 1H) 8.00 (d, 1H) 8.10 (d, 2H) 8.71 (bs, 1H) 8.92 (bs, 1H)
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[CH3:12][Si:13](Cl)([CH3:15])[CH3:14]>CCOCC.CCCCCC>[CH3:12][Si:13]([CH3:15])([CH3:14])[C:2]1[S:3][CH:4]=[CH:5][N:6]=1
Reactant: C[Si](C)(C)Cl
Reactant: Brc1nccs1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: C[Si](C)(C)c1nccs1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 8.28 g of 2-bromothiazole in 100 ml of ether at -78° C., under argon, was added 21.7 ml of n-butyl lithium in hexane. The mixture was stirred at -78° C. for 45 minutes then 6.8 ml of trimethylsilyl chloride was added. This mixture was stirred at -78° C. for 1 hour, warmed to -30° C. over 1 hour, then 0° C. over 1/2 hour and kept at 0° C. for 1 hour. The reaction was quenched with 50 ml of 50% saturated sodium bicarbonate and then diluted with 50 ml of ether. The ether solution was washed with 50 ml of brine, dried, filtered and evaporated, giving 10.81 g of 2-trimethylsilylthiazole as an amber colored oil.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:9][C:10]([CH2:13][CH3:14])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][CH3:33])[CH2:28][CH2:27][C:26]([N+:34]([O-:36])=[O:35])=[CH:25]2>C1COCC1>[C:1]([NH:5][C:6]([C:8]1[S:9][C:10]([CH2:13][CH3:14])=[CH:11][C:12]=1[C@@H:25]1[C:24]2[C:29](=[CH:30][C:31]([O:32][CH3:33])=[C:22]([O:21][CH3:20])[CH:23]=2)[CH2:28][CH2:27][C@H:26]1[N+:34]([O-:36])=[O:35])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(cc1OC)CCC([N+](=O)[O-])=C2
Reactant: CCc1ccc(C(=O)NC(C)(C)C)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc([C@@H]2c3cc(OC)c(OC)cc3CC[C@H]2[N+](=O)[O-])c(C(=O)NC(C)(C)C)s1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 50.1 %

Procedure:
To a solution of 5.4 g (25.5 mmol) of 5-ethyl-2-thiophenecarboxylic acid, N-t-butyl amide, from step 3b above, in 80 mL of THF cooled to -78° C. was added 20.4 mL (51.1 mmol) of n-butyllithium (2.5M in hexane). The solution was then stirred at 0° for 40 min, then re-cooled to -78° C., and a solution of 6.0 g of 1,2-dihydro-6,7-dimethoxy-3-nitronaphthalene, from Example 1 b above, in 100 mL of THF cooled to -78° C. was added via cannula. The solution was stirred at -78° C. for 1 hour and at 0° C. for 1 hour. The reaction was quenched with saturated NH4Cl, diluted with water, and extracted with methylene chloride. The extract was washed with brine, dried and concentrated. The residue was dissolved in 30 mL of acetonitrile, 1 mL of triethylamine was added, and the reaction was stirred for 16 hours. The solvent was evaporated, and the residue was purified by flash chromatography, eluting with 6:1 hexane:ethyl acetate to afford 5.7 g of the title product. MS 447 (M+H)+, 464 (M+NH4)+. NMR (CDCl3), δ:6.48 (s, 1H), 6.37 (s, 1H), 6.30 (s, 1H), 5.70 (bs, 1H, 5.47 (d, 1H, J=8 Hz), 5.05 (m, 1H), 3.85 (s, 3H) 3.69 (s, 3H), 3.2-2.88 (m, 2H), 2.72 (q, 2H, J=7 Hz), 2.5-2.35 (m, 2H), 1.42 (s, 3H), 1.23 (t, 3H, J=7 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12]1([CH3:21])[C:13]([N:18]=[C:19]=[O:20])=[CH:14][CH:15]=[CH:16][CH:17]=1>>[C:12]1([CH3:21])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=[O:20])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: Cc1ccccc1N=C=O
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1

Procedure:
4-o-Tolylureidophenylacetic acid was prepared using procedure C with 4-amino-phenylacetic acid and o-tolyl isocyanate: 1H NMR (CD3SOCD3, 300 MHz, ppm) 8.97 (s, 1H), 7.88 (s, 1H), 7.83 (d, 1H), 7.38 (d, 2H), 7.17-7.09 (m, 4H), 6.92 (t, 1H), 3.48 (s, 2H), 2.23 (s, 3H); m/z 285.
Reaction SMILES: [CH2:1]1[N:12]2[C:13]3[C:9]([C@@H:10]4[CH2:17][NH:16][CH2:15][CH2:14][C@@H:11]42)=[CH:8][C:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=2[C:26](=[O:28])[CH3:27])=[CH:6][C:5]=3[CH2:4][O:3][CH2:2]1.[BH4-].[Na+]>CO.C(OCC)(=O)C>[CH2:1]1[N:12]2[C:13]3[C:9]([C@@H:10]4[CH2:17][NH:16][CH2:15][CH2:14][C@@H:11]42)=[CH:8][C:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=2[CH:26]([OH:28])[CH3:27])=[CH:6][C:5]=3[CH2:4][O:3][CH2:2]1
Reactant: CC(=O)c1cc(C)ccc1Nc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCOC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(Nc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)c(C(C)O)c1
Temperature: 25 °C

Procedure:
To a solution of 1-{2-[(7bR,11aS)-1,2,7b,8,9,10,11,11a-octahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indol-6-ylamino]-5-methylphenyl} ethanone from EXAMPLE 116 (20 mg, 0.05 mmol) in 5 ml methanol at 0° C. was added sodium borohydride (5.5 mg, 0.15 mmol). The solution was stirred with warming to room temperature for 2 h. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4) and concentrated. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and the product containing fractions were concentrated, free-based with aq ammonium hydroxide, extracted with chloroform, washed with brine, dried (K2CO3) and concentrated to afford the title compound of EXAMPLE 117 as a mixture of diastereomers at the alcohol center. LRMS (ES)+: 380.3 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH:13]1[CH2:16][CH:15]([C:17]#[N:18])[CH2:14]1.CCN(C(C)C)C(C)C>C(#N)C>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:12][CH:13]2[CH2:16][CH:15]([C:17]#[N:18])[CH2:14]2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: N#CC1CC(N)C1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1CC(Nc2cc(F)ccc2[N+](=O)[O-])C1
Yield: 67.3 %

Procedure:
2,4-Difluoro-1-nitrobenzene (0.38 g, 2.4 mmol), 3-aminocyclobutanecarbonitrile (0.23 g, 2.4 mmol) and then DIPEA (0.425 mL, 2.4 mmol) were added to acetonitrile (10 mL) and the resultant mixture stirred at 20° C. for 16 hours under a nitrogen atmosphere. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (Si—PPC; eluting with ethyl acetate in cyclohexane 0-50%) to give the title compound as a yellow solid (0.38 g, 68%). 1H NMR (CDCl3) δ: 8.23 (1H, dd, J=9.2, 5.8 Hz), 8.20 (1H, br s), 6.41-6.49 (1H, m), 6.29 (1H, dd, J=11.0, 2.7 Hz), 4.30-4.43 (1H, m), 3.20-3.31 (1H, m), 2.87-2.98 (2H, m), 2.42-2.55 (2H, m)
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[OH:14])=[O:4].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]2[NH:5][C:3](=[O:4])[CH2:2][O:14][C:7]=2[CH:8]=1
Reactant: COc1ccc(NC(=O)CCl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc2c(c1)OCC(=O)N2
Reaction time: 5 h
Yield: 86 %

Procedure:
A reaction mixture was prepared from 19.6 g of N-chloroacetyl-2-hydroxy-4-methoxyaniline, 13.8 g of potassium carbonate and 500 ml of acetone. The mixture was refluxed with stirring for about 5 hours and was then cooled. Inorganic salts were separated by filtration, and the solvent removed from the filtrate in vacuo. The resulting residue was dissolved in methylenedichloride. The methylenedichloride solution was washed with saturated aqueous sodium chloride and then dried. Fourteen grams of 3,4-dihydro-7-methoxy-2H-[1,4]benzoxazin-3-one were obtained. NMR indicated complete cyclization to the lactam. Recrystallization from ethyl acetate/hexane yielded product melting at 164°-165° C.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[OH:10][CH2:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)=[O:13].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([O:10][CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=2)=[O:13])[N:7]=1
Reactant: O=C(CO)Nc1cccc(C(F)(F)F)c1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(COc1nc(Cl)nc(Cl)n1)Nc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
To a 200 mL recovery flask was added cyanuric chloride (504 mg, 2.73 mmol, 1.0 eq.) and CH2Cl2 (50 mL). The solution was cooled to 0° C. In a separate flask, a solution of 2-hydroxy-N-(3-trifluoromethyl-phenyl)-acetamide (599 mg, 2.73 mmol, 1.0 eq.) and i-Pr2NEt (524 μL, 2.00 mmol, 1.1 eq.) in 10 mL was prepared and then slowly added to the reaction flask. The reaction was stirred for 2 h while warming to room temperature. The reaction was quenched with H2O (50 mL). The organic phase washed with brine (1×50 mL). The combined aqueous phases were extracted with CH2Cl2 (2×25 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give an off-white solid. The crude material was purified via flash chromatography (1:4 EtOAc/Hexanes) to give 2-(4,6-dichloro-[1,3,5]triazin-2-yloxy)-N-(3-trifluoromethyl-phenyl)-acetamide as a white solid (600 mg, 60%). LC/MSD (HP Series 1100 MSD) Expected MW: 365.99, Observed M+H: 367.0, Retention time: 1.59. 1H-NMR, DMSO-d6, Varian 400 MHz δ 11.19 (s, 1H), 10.63 (s, 1H), 8.08 (s, 1H), 7.75 (d, 1H), 7.59 (t, 1H), 7.44 (d, 1H), 4.99 (s, 2H) ppm.
Reaction SMILES: [F:1][C:2]([F:7])([CH3:6])[C:3]([OH:5])=[O:4].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)Cl>[F:1][C:2]([F:7])([CH3:6])[C:3]([O:5][C:3](=[O:4])[C:2]([F:7])([F:1])[CH3:6])=[O:4]
Reactant: CC(F)(F)C(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: CC(F)(F)C(=O)OC(=O)C(C)(F)F
Reaction time: 48 h

Procedure:
Synthesis: Step 1: To a solution of 2,2-difluoropropanoic acid (330 mg, 2.97 mmol) in DCM (5 mL) was added P2O5 (3.3 g, 29.7 mmol) at room temperature and the mixture was stirred for 2 days to give 2,2-difluoropropanoic anhydride. To a suspension of Intermediate A-2a (170 mg, 0.59 mmol) in TEA (5 mL) was added dropwise the 2,2-difluoropropanoic anhydride in DCM at 0˜10° C. The mixture was stirred at room temperature for 2 h. The volatiles were evaporated and the residue was purified by prep-TLC (PE:EA=1:1) to afford methyl 4-(2-(1,1-difluoroethyl)-7-hydroxy-4-oxo-4H-chromen-3-yl)benzoate as brown oil (45 mg, 21%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][O:14][C:15]([C:17]1[CH:30]=[CH:29][C:20]2[C@@H:21]3[C@H:26]([CH2:27][CH2:28][C:19]=2[CH:18]=1)[NH:25][CH2:24][CH2:23][CH2:22]3)=[O:16]>>[CH3:13][O:14][C:15]([C:17]1[CH:30]=[CH:29][C:20]2[C@@H:21]3[C@H:26]([CH2:27][CH2:28][C:19]=2[CH:18]=1)[N:25]([C:10]([C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1)=[O:12])[CH2:24][CH2:23][CH2:22]3)=[O:16]
Reactant: COC(=O)c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: COC(=O)c1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Yield: 92 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-8-carboxylic acid methyl ester following a procedure analogous to that described in Example 1. Yield: 92% of theory; LC (method 1): tR=2.57 min; Mass spectrum (ESI+): m/z=390 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[C:30]([F:29])=[CH:37][C:36]([F:38])=[CH:35][C:34]=3[F:39])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1c(F)cc(F)cc1F
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Fc1cc(F)c(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c(F)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2,4,6 trifluorobenzaldehyde. MS (ESI) m/z 523.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9]([NH:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:18][C:19]2=[O:22])=[CH:14][CH:13]=1)=[O:10].[OH-].[Na+]>CN(C=O)C>[N:1]1([CH2:8][C:9]([NH:11][C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[C:17]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[NH:18][C:19]3=[O:22])=[CH:14][CH:13]=2)=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=C(CCl)Nc1ccc2cc(-c3ccccc3)[nH]c(=O)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(CN1CCOCC1)Nc1ccc2cc(-c3ccccc3)[nH]c(=O)c2c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
0.042 ml (0.47 mmol) of morpholine was added to a DMF solution containing 50 mg (0.16 mmol) of the 2-chloro-N-(1-oxo-3-phenyl-1,2-dihydroisoquinolin-7-yl)acetamide obtained in Example 57, and the obtained mixture was then stirred at 100° C. for 30 minutes. Thereafter, 30 ml of a 1 N sodium hydroxide aqueous solution was added to the reaction solution, and the mixture was then extracted with ethyl acetate (50 ml×2). The extract was washed with 30 ml of water, and was then dried over anhydrous magnesium sulfate. Thereafter, the solvent was distilled away under reduced pressure. The precipitated solid was collected by filtration, and the filtrate was then washed with a suitable amount of ether and hexane, so as to obtain 44 mg (76%) of 2-morpholin-4-yl-N-(1-oxo-3-phenyl-1,2-dihydroisoquinolin-7-yl)acetamide in the form of a colorless solid.
Reaction SMILES: C[O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][OH:6].[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C1COCC1>[CH2:12]([O:6][CH2:5][C:4]([CH3:8])([CH3:7])[C:3]([OH:2])=[O:9])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)C(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(COCc1ccccc1)C(=O)O
Temperature: 80 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
3-Hydroxy-2,2-dimethyl-propionic acid methyl ester (3.00 g, 22.7 mmol) in 40 mL of THF at 0° C. was treated with 1.0 g (25 mmol) of 60% NaH in mineral oil for 20 min. Benzyl bromide (2.97 mL, 25.0 mmol) was added dropwise over 10 minutes. The mixture was stirred overnight, 30 mL of water was added, and the mixture was extracted with EtOAc (3×100 mL). The combined extracts were washed with brine, dried with MgSO4, filtered, and concentrated. The residue was dissolved in 40 mL of EtOH, 28 mL of 2M NaOH was added, and the mixture was heated to 80° C. for 12 h. The mixture was cooled, neutralized with 2M HCl, and extracted with EtOAc (3×100 mL). The combined extracts were washed with brine, dried with MgSO4, filtered, concentrated, and chromatographed (10–100% EtOAc in hexanes) to provide 2.4 g of 3-benzyloxy-2,2-dimethyl-propionic acid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].C(N(CC)CC)C.[CH2:18]([NH2:23])[CH2:19][CH:20]([CH3:22])[CH3:21]>O1CCCC1>[CH3:21][CH:20]([CH3:22])[CH2:19][CH2:18][NH:23][C:2](=[O:3])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)CCN
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)CCNC(=O)Oc1ccccc1
Temperature: 25 °C
Yield: 58.1 %

Procedure:
Phenyl chloroformate (14.8 ml, 0.117 mol) was dissolved in tetrahydrofuran (200 ml); triethylamine (18.0 ml, 0.129 mol) and isoamylamine (15.0 ml, 0.129 mol) were added thereto at room temperature while stirring; and the reaction mixture was stirred overnight. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was concentrated and dried under reduced pressure to yield the title compound as crystals (14 g, 0.068 mol, 58%).