Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:13]2[CH2:14][CH:10]([CH2:11][N:12]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][CH:8]=1)(=O)=O.C(N(CC)CC)C.[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33]>C1(C)C=CC=CC=1>[CH3:31][Si:32]([C:35]#[C:36][C:7]1[CH:13]2[CH2:14][CH:10]([CH2:11][N:12]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][CH:8]=1)([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CC2CC=C(OS(=O)(=O)C(F)(F)F)C1C2
Reactant: C#C[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2CC=C(C#C[Si](C)(C)C)C1C2
Yield: 58.9 %

Procedure:
To a solution of t-butyl 4-trifluoromethanesulfonyloxy-6-azabicyclo [3.2.1]oct-3-ene-6-carboxylate (1.8 g, 5.0 mmol) in 10 mL of toluene was added 20 mL of triethylamine, followed by trimethylsilylacetylene (0.49 g, 5.0 mmol). The mixture was degassed, placed under a nitrogen atmosphere, and copper iodide (50 mg) and bis (triphenylphosphine)palladium dichloride (100 mg) were added. The reaction mixture was heated under reflux for 16 h, then cooled and concentrated under reduced pressure. The residue was chromatographed on a silica gel column, using 0-50% ethyl acetate in hexane as eluent, to give tert-butyl 4-trimethylsilylethynyl-6-azabicyclo [3.2.1]oct-3-ene-6-carboxylate (900 mg, 58.9%). This was dissolved in 25 mL of methanol and treated with solid potassium carbonate (−1 g) with vigorous stirring. After 4 h, the mixture was concentrated to dryness in vacuo, and the residue was column chromatographed on silica gel, eluting with 2:1 hexane/ethyl acetate, to give a yellow oil (300 mg, 25.8% for two steps).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[C:14]([F:15])=[C:13]([O:16][CH3:17])[C:12]([F:18])=[C:11]([F:19])[C:8]=1C#N.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:17][O:16][C:13]1[C:14]([F:15])=[C:7]([CH:8]=[C:11]([F:19])[C:12]=1[F:18])[NH2:6]
Reactant: COc1c(F)c(N)c(C#N)c(F)c1F
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: COc1c(F)c(N)cc(F)c1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
50 ml of water and 200 ml of concentrated sulfuric acid were added to 84.4 g (0.42 mole) of 2-amino-4-methoxy-3,5,6-trifluorobenzonitrile (XX) [prepared as described in Step (E2) above]. The mixture was then stirred at 100° C. for 1 hour, after which 150 ml of water were added thereto, and the mixture was stirred at 110°-120° C. for a further 2 hours. The reaction mixture was then allowed to stand to cool to room temperature, after which it was poured into ice-water and neutralized with potassium carbonate. The crystalline substance which precipitated was extracted with ethyl acetate; the extract was washed with water and dried over anhydrous sodium sulfate; and the solvent was removed by evaporation under reduced pressure to afford 57.6 g of 3-methoxy-2,4,5-trifluoroaniline (XXIII) as colorless needles melting at 45°-47° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:14][S-:15].[Na+].Cl>CN(C)C=O>[CH3:14][S:15][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Reactant: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(C(F)(F)F)cc1C#N
Yield: 67.1 %

Procedure:
(Step 1) A mixture of 2-fluoro-5-(trifluoromethyl)benzonitrile (10 g) and sodium methanethiolate (4.08 g) was stirred in N,N-dimethylformamide (30 ml) at 80° C. for 14 hr. The reaction solution was treated with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 2-(methylsulfanyl)-5-(trifluoromethyl)benzonitrile (7.71 g) as a solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[C:5]([CH3:25])[N:4]=1.P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C.Cl.[CH2:44]([O:46][C:47](=[O:57])[C@H:48]([CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])[NH2:49])[CH3:45]>CN(C)C=O>[CH2:44]([O:46][C:47](=[O:57])[C@H:48]([CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])[NH:49][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([N:13]2[CH2:12][CH2:11][N:10]([C:6]3[C:7]([NH2:9])=[N:8][C:3]([NH2:2])=[N:4][C:5]=3[CH3:25])[CH2:15][CH2:14]2)=[CH:17][CH:18]=1)[CH3:45]
Reactant: Cc1nc(N)nc(N)c1N1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(N2CCN(c3c(C)nc(N)nc3N)CC2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.8 %

Procedure:
A mixture of 4.27 g (0.01137 mole) of 4-[4-(2,4-diamino-6-methyl-5-pyrimidinyl)-1-piperazinyl]benzoic acid hydrochloride, 6.12 g (0.0375 mole) of diethyl phosphorocyanidate and 7.0 ml (0.050 mole) of triethylamine in 300 ml of previously dried dimethylformamide was stirred at room temperature for five hours and then at 80° C. for five minutes. The solution was cooled to room temperature, and a solution of 3.00 g (0.0125 mole) of L-glutamic acid diethyl ester hydrochloride and 1.74 ml (0.0125 mole) of triethylamine was added. The resulting mixture was stirred for two hours at room temperature. The solvent was removed under high vacuum at 40° C. and the gummy residue partitioned between 500 ml of dichloromethane and 500 ml of 5% sodium bicarbonate solution. The organic layer was separated, washed with water and then with saturated sodium chloride solution and dried over magnesium sulfate. The dried solution was concentrated in vacuo to give a yellow solid. Recrystallization from acetonitrile gave 3.9 g of the product as a tan solid, mp 224° C. (dec.).
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:15]3[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:8][CH:7]=1.[OH-].[K+]>C1COCC1.CO>[CH2:21]([N:17]1[C:18]2[C:14](=[CH:13][C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:41])=[O:2])=[CH:7][CH:8]=3)=[CH:20][CH:19]=2)[C:15]([CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[C:16]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)COc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(-c2ccccc2)n3Cc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(-c2ccccc2)n3Cc2ccccc2)cc1

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 4. Thus, [4-(1,3-dibenzyl-2-phenyl-1H-indol-5-yl)-phenoxy]-acetic acid methyl ester (0.491 g, 0.913 mmol) was reacted with 1N KOH (1.8 ml) in THF/MeOH (6 ml/4 ml) to give the product (0.376 g, 0.713 mmol, 78%) as a white solid, mp 153-155° C. 1H NMR (DMSO-d6) δ 4.08 (s, 2H), 4.68 (s, 2H), 5.35 (s, 2H), 6.89 (d, J=7.2 Hz, 2H), 6.96 (d, J=8.9 Hz, 2H), 7.10-7.25 (m, 8H), 7.35 (dd, J=1.7, 8.5 Hz, 1H), 7.41-7.51 (m, 8H), 7.59 (d, J=1.1 Hz, 1H), 12.95 (broad s, 1H); IR (solid) 3020, 2900, 1750, 1600, 1520, 1470, 1450, 1430, 1350, and 1220 cm−1; [ESI(+)], m/z 524 (M+H)+; Anal. Calcd. for C36H29NO3.0.20H2O: C, 82.01; H, 5.62; N, 2.66; Found: C, 82.08, H, 5.58; N, 2.55.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([NH:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1.C(Cl)Cl.B(Br)(Br)Br>C(OCC)(=O)C>[OH:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([NH:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)(=[O:24])=[O:25])=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc(C(F)(F)F)ccc1-c1ncnc2cc(S(=O)(=O)Nc3nccs3)ccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1nccs1)c1ccc2c(-c3ccc(C(F)(F)F)cc3O)ncnc2c1
Reaction time: 8 h

Procedure:
A vial was charged with 4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide (Example 261; 0.100 g, 0.214 mmol) and DCM (2.144 ml) to give a clear solution. Boron tribromide (0.101 ml, 1.072 mmol) was added in one portion at room temperature to give a dark red suspension. The mixture was stirred overnight. The reaction was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 40 g, gradient elution 0-10% MeOH:DCM) to afford 4-(2-hydroxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=13.02 (s, 1H), 10.65 (s, 1H), 9.49 (s, 1H), 8.41 (d, J=1.5 Hz, 1H), 8.02-7.96 (m, 1H), 7.94-7.88 (m, 1H), 7.63 (d, J=7.7 Hz, 1H), 7.38 (d, J=8.1 Hz, 1H), 7.34 (s, 1H), 7.31 (d, J=4.6 Hz, 1H), 6.90 (d, J=4.5 Hz, 1H). m/z (ESI) 453.2 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)=[O:22])[CH:15]=3)=[CH:10][CH:9]=2)=[N:5][N:4]=1.[CH3:27][O-:28].[Na+]>>[CH:24]1([NH:23][C:21]([C:16]2[CH:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:6]4[O:7][C:3]([CH2:2][O:28][CH3:27])=[N:4][N:5]=4)=[CH:9][CH:10]=3)[C:19]([CH3:20])=[CH:18][CH:17]=2)=[O:22])[CH2:26][CH2:25]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CCl)o2)cc1
Reactant: C[O-]
Agent: [Na+]
Product: COCc1nnc(-c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc2)o1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
4′-[5-(Chloromethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 45) (50 mg) was added to a freshly prepared sodium methoxide solution (0.08M, 12 ml), and the reaction stirred at room temperature for 96 hours. The reaction was partitioned between ethyl acetate and water, the organic phase dried (sodium sulphate) and reduced to dryness under vacuum. The residue was applied to a bond-elut (silica, 5 g) and eluted with an ethyl acetate/cyclohexane gradient. The product fractions were reduced to dryness under vacuum and further purified by HPLC, to give after evaporation of the solvent, N-cyclopropyl-4′-[5-(methoxymethyl)-1,3,4-oxadiazol-2-yl]-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[C:4](=[O:34])[CH2:3]1.[CH3:35][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI.[NH4+].[Cl-]>CN(C=O)C.C1COCC1>[CH3:35][CH:3]1[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[C:4]1=[O:34]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(N(C(=O)CN2C(=O)C(C)C(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.17 h

Procedure:
To a stirring solution of 2.65 g (5.78 mmol) of 2-(2,4-Dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide in 80 mL of DMF at 0° C. is added 6.36 mL (6.36 mmol) of a 1.0M solution of NaN(TMS)2 in THF. The resulting solution is stirred 10 min, then 400 mL (6.36 mmol) of methyl iodide is added neat. The resulting solution is stirred at RT for 45 min then poured into 100 mL NH4Cl. The reaction mixture is concentrated to remove the DMF, diluted with 500 mL of H2O and extracted with EtOAc (3×200 mL). The organics were dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel flash chromatography using EtOAc as eluent afforded 2.52 g of 2-(3-Methyl-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide as a white foam: 1H NMR (CDCl3, 400 MHz) δ8.50 (s, br, 2H), 7.79 (d, 1H, J=8.1), 7.43 (d, 1H, J=8.1), 7.36-6.94 (m, 8H), 6.88 (d, 1H, J=8.8), 4.98 (m, 1H), 4.26 (m, 2H), 3.85 (s, 3H), 3.54 (q, 1H, J=7.1), 1.42 (d, 3H, J=7.1), 1.07 (m, 6H); low resolution MS (FAB)m/e 473 (MH+); Anal. (C27H28N4O4) Calcd. C, 68.63; H, 5.97; N, 11.86 Found C, 66.91; H, 6.13; N, 11.29.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:29][CH3:30])=[N:4][C:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[CH:6][C:7]=1[NH:8][C:9]([C:11]1[N:15]([CH3:16])[N:14]=[C:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]=1[Cl:21])=O>CC(O)=O>[C:17]([C:13]1[C:12]([Cl:21])=[C:11]([C:9]2[NH:1][C:2]3[C:3]([O:29][CH3:30])=[N:4][C:5]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])=[CH:6][C:7]=3[N:8]=2)[N:15]([CH3:16])[N:14]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: COc1nc(-c2ccccc2Cl)cc(NC(=O)c2c(Cl)c(C(C)(C)C)nn2C)c1N
Solvent: CC(=O)O
Product: COc1nc(-c2ccccc2Cl)cc2nc(-c3c(Cl)c(C(C)(C)C)nn3C)[nH]c12
Temperature: 90 °C
Reaction time: 0.03 h

Procedure:
A 2-L four neck round bottom flask equipped with mechanical stirrer, reflux condenser with nitrogen outlet, positive pressure nitrogen inlet and thermocouple was charged with N-(3-amino-6-(2-chlorophenyl)-2-methoxypyridin-4-yl)-3-tert-butyl-4-chloro-1-methyl-1H-pyrazole-5-carboxamide (156.2 g, 0.346 mol) and AcOH (glacial, 780 mL). The resulting mixture was heated to 90° C. for 2 h. The resulting mixture was then was cooled to 50° C., transferred to a one-neck round bottom flask and concentrated on a rotary evaporator (bath at 50° C.). The resulting orange pasty solid was dissolved in EtOAc (1.5 L) and added to a separatory funnel containing saturated aqueous sodium bicarbonate (2 L) and EtOAc (1.5 L). The pH of the aqueous was still acidic, and was adjusted with 50% wt/wt NaOH (˜10 mL) to pH 8-9, then back to neutral with aqueous HCl (2 M, 120 mL) to a final pH of 6-8. The turbid organic layer was separated and the aqueous layer extracted with EtOAc (2×500 mL). The combined turbid organic layers were warmed in a 50° C. bath with gentle stirring and within 1-2 min, a clear orange solution resulted. The warm organic layer was quickly washed with brine (500 mL), dried (MgSO4) with occasional warming throughout the drying process, filtered and the volatiles removed under reduced pressure. The resulting residue crystallized on standing and then redissolved with dichloromethane to yield a turbid mixture. The resulting concentrate was loaded onto BIOTAGE 150M (2.5 kg silica, prewetted with 4 L heptane) and eluted with heptane (4 L), 10% EtOAc in heptane (12 L), and finally 20% EtOAc in heptane (16 L), whereby fractions of suitable purity were collected and concentrated to yield the title compound.
Reaction SMILES: C([O:5][C@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[C:19]([F:20])=[CH:18][N:17]=[C:16]([NH:21][C@H:22]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH3:23])[N:15]=1)[CH3:7])(C)(C)C.Br[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([C:37]([CH3:43])([CH3:42])[C:38]([F:41])([F:40])[F:39])[CH:32]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:20][C:19]1[C:14]([N:9]2[C@@H:8]([C@@H:6]([OH:5])[CH3:7])[CH2:12][O:11][C:10]2=[O:13])=[N:15][C:16]([NH:21][C@H:22]([CH:24]2[CH2:25][CH2:26][N:27]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]([C:37]([CH3:43])([CH3:42])[C:38]([F:41])([F:40])[F:39])[CH:32]=3)[CH2:28][CH2:29]2)[CH3:23])=[N:17][CH:18]=1
Reactant: C[C@H](Nc1ncc(F)c(N2C(=O)OC[C@@H]2[C@H](C)OC(C)(C)C)n1)C1CCNCC1
Reactant: CC(C)(c1cc(Br)ccn1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: C[C@H](Nc1ncc(F)c(N2C(=O)OC[C@@H]2[C@H](C)O)n1)C1CCN(c2ccnc(C(C)(C)C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.1 %

Procedure:
A cloudy solution of (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(5-fluoro-2-(((S)-1-(piperidin-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (21 mg, 0.051 mmol), 4-bromo-2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine (14 mg, 0.051 mmol), Pd(OAc)2 (1 mg, 5 umol), BINAP (3 mg, 5 umol), and Cs2CO3 (25 mg, 0.077 mmol) in 6 mL toluene was heated at 90° C. overnight. The mixture was cooled to room temperature, and filtered through Celite. The celite cake was rinsed with 5 mL EtOAc. The filtrate was poured into 5 mL water. Organic layer was separated, and the aqueous was further extracted with EtOAc (5 mL). The organic extracts were combined and concentrated by rotary evaporation. The resulting crude was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction solution was stirred for 2 hour at room temperature and was concentrated by rotary evaporation. The resulting residue was dissolved in DCM (2 mL) and water (2 mL) and the pH was adjusted to ˜9 with NH4OH. The DCM layer was separated and concentrated by rotary evaporation. The crude was dissolved in a mixture of MeOH (1 mL) and DMSO (1 mL) and purified by reverse phase HPLC. Selected fractions were collected and concentrated by rotary evaporation to afford the title product as a colorless oil (5 mg) (ratio of two peaks with same MS: 93/7% by LC-MS). (400 MHz, CD2Cl2) δ 8.16-8.08 (m, 2H), 6.79-6.75 (m, 1H), 6.57-6.52 (m, 1H), 4.97-4.86 (m, 1H), 4.47-4.39 (m, 2H), 4.33-4.25 (m, 1H), 4.11-4.02 (m, 1H), 3.89-3.75 (m, 3H), 2.97 (br s, 1H), 2.80-2.67 (m, 2H), 1.84-1.67 (m, 2H), 1.67-1.55 (m, 1H), 1.48 (s, 6H), 1.38-1.15 (m, 2H), 1.11 (d, J=5.91 Hz, 3H), 1.07 (d, J=5.91 Hz, 3H), HRMS(C) tR=3.59 min; MS m/z 541.2557 (M+H)+
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([CH:27]=O)[CH:18]=1>>[CH:1]([N:4]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:27]([C:19]2[CH:18]=[N:17][C:26]3[C:21]([CH:20]=2)=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: O=Cc1cnc2ccccc2c1
Reactant: CC(C)N(C(N)=O)c1ccc2c(c1)OCO2
Product: CC(C)N1C(=O)NC(c2cnc3ccccc3c2)c2cc3c(cc21)OCO3
Yield: 14 %

Procedure:
This compound was synthesized from N-isopropyl-N-[3,4-(methylenedioxy)-phenyl]urea (308 mg) and 3-quinolinecarboxaldehyde (243 mg) by the procedure described in example 10 in 14% yield. mp: 202-205° C. 1H NMR (CDCl3): 8.89 (d, J=2.0, 1H), 8.11 (d, J=7.6, 1H), 8.05 (s, 1H), 7.80 (d, J=7.6, 1H), 7.74 (t, J=7.6, 1H), 7.58 (t, J=7.6, 1H), 6.72 (s, 1H), 6.41 (s, 1H), 5.94 (s, 1H), 5.92 (s, 1H), 5.52 (d, J=1.9, 1H), 5.25 (s, 1H), 4.42 (m, 1H), 1.57 (d, J=7.0, 3H), 1.56 (d, J=7.0, 3H).
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl[C:9]([N:11]1[CH2:16][CH:15]([CH2:17][CH3:18])[O:14][C:13]2[CH:19]=[C:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]([CH3:37])([CH3:36])[C:32]([O:34][CH3:35])=[O:33])=[N:27][CH:28]=3)[CH:21]=[CH:22][C:12]1=2)=[O:10].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:17]([CH:15]1[O:14][C:13]2[CH:19]=[C:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]([CH3:37])([CH3:36])[C:32]([O:34][CH3:35])=[O:33])=[N:27][CH:28]=3)[CH:21]=[CH:22][C:12]=2[N:11]([C:9](=[O:10])[NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:16]1)[CH3:18]
Reactant: CCCCCCN
Reactant: CCC1CN(C(=O)Cl)c2ccc(-c3ccc(OCC(C)(C)C(=O)OC)nc3)cc2O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCNC(=O)N1CC(CC)Oc2cc(-c3ccc(OCC(C)(C)C(=O)OC)nc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
n-Hexylamine (23.0 μL, 0.173 mmol) was added dropwise to a solution of methyl 3-(5-(4-(chlorocarbonyl)-2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyridin-2-yloxy)-2,2-dimethylpropanoate B-11 (50.0 mg, 0.115 mmol) and N-ethyl-N,N-diisopropylamine (40.2 μL, 0.231 mmol) in anhydrous methylene chloride (1.10 mL) at 0° C. under an atmosphere of argon. The reaction mixture was slowly warmed to room temperature and stirred for 8 h, then sequentially diluted with methylene chloride (30 mL), quenched with an aqueous pH 7 phosphate buffer solution (15 mL) and decanted. The aqueous layer was extracted with methylene chloride (3×30 mL); the combined extracts were successively washed with an aqueous pH 7 phosphate buffer solution (20 mL), brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. Crude methyl 3-(5-(2-ethyl-4-(hexylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyridin-2-yloxy)-2,2-dimethylpropanoate B-12 (55.2 mg, Yield=96%) was obtained as a light tan solid and was used for the next step without further purification. MS (ESI) [M+1]+ 498.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(Cl)Cl.[CH3:23][C:24]1[CH:41]=[CH:40][CH:39]=[CH:38][C:25]=1[C:26]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)=[O:27]>C(N(CC)CC)C>[CH3:23][C:24]1[CH:41]=[CH:40][CH:39]=[CH:38][C:25]=1[C:26]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([N:7]2[C:8]3[CH:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:34])=[CH:31][CH:30]=1)=[O:27]
Reactant: CCOC(=O)c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2c(c1)Cn1cccc1CN2C(=O)c1ccc(NC(=O)c2ccccc2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.3 %

Procedure:
A solution of 1.2 g of ethyl 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-7-carboxylate in ml of methylene chloride is cooled to 0° C. and 10 ml of triethylamine added followed by 1.5 g of 4-[(2-methylbenzoyl)amino)benzoyl chloride. The reaction mixture is stirred at room temperature for 18 hours and concentrated in vacuo to a residue which is partitioned between water and chloroform. The organic layer is dried over Na2SO4 and concentrated in vacuo to a residue. The residue is purified by column chromatography on silica gel by elution with 40% ethyl acetatehexane to give 1.0 g of the desired product as a solid; mass spectrum (M+ H)494.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[CH2:13]([O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: OCCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(CCOCc2ccccc2)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 2-(4-bromophenyl)ethanol (1.0 g) in N,N-dimethylformamide (25 mL) was added 55% sodium hydride (0.26 g) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. To this mixture was added benzyl bromide (0.77 mL) at the same temperature, and the mixture was stirred at the same temperature for 15 minutes, and stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane-n-hexane/ethyl acetate=20/1) to give 1-[2-(benzyloxy)ethyl]-4-bromobenzene (1.35 g). The title compound was prepared in a similar manner to that described in Step 2 of Reference Example 46 using this material instead of 1-bromo-2-fluoro-4-methoxybenzene.