Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][N:14]([CH3:16])C)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:21][O:22][C:23]1[CH:28]=C[CH:26]=[C:25](N)[CH:24]=1.Cl>C(O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][NH:14][C:16]2[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH3:21])[CH:28]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: COc1cccc(N)c1
Reactant: CCOC(=O)N1CCN(C(=CN(C)C)C(=O)OC)CC1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)N1CCN(C(=CNc2cccc(OC)c2)C(=O)OC)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product of step (ii) (6.3 g), m-anisidine (2.5 ml), ethanol (65 ml) and concentrated hydrochloric acid (2.2 ml) was stirred at room temperature for 2 hours then evaporated. The residue was basified by careful addition of aqueous sodium carbonate solution. The mixture was extracted with ethyl acetate and the organic extracts were washed with brine, dried (MgSO4) and evaporated to dryness. The residue was purified by flash chromatography on silica by elution with 70% v/v ether/hexane to yield 1-ethoxycarbonyl-4-(1-(3-methoxyphenyl)amino-2-methoxycarbonylethen-2-yl)piperazine (5.15 g) as an off-white solid: m.p. 120°-122° C.; NMR (CDCl3) δ1.28 (3H, t), 2.90 (4H, m), 3.50 (4H, m), 3.71 (3H, s), 3.81 (3H, s), 4.18 (2H, q), 6.52 (3H, m), 7.21 (1H, t), 7.39 (1H, d), 7.80 (1H, d); m/Z 364 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7](Cl)[C:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)=[C:5]2[Cl:25].[CH3:26][O-:27].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7]([O:27][CH3:26])[C:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)=[C:5]2[Cl:25]
Reactant: Cc1cc(Br)cc2c(Cl)c(-c3ccc(OC(F)(F)F)cc3)c(Cl)nc12
Reactant: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1nc2c(C)cc(Br)cc2c(Cl)c1-c1ccc(OC(F)(F)F)cc1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-bromo-2,4-dichloro-8-methyl-3-(4-(trifluoromethoxy)phenyl)quinoline (1.97 g, 4.367 mmol, Intermediate 58, step c) and sodium methoxide (1.18 g, 21.837 mmol) in toluene (20 mL) was heated in a sealed tube at 110° C. for 24 hours, cooled to RT, diluted with DCM, stirred at room temperature for 30 min, and filtered through Celite® rinsing several times with DCM. The solvents were removed under reduced pressure and the off-white solid product precipitated from MeOH, filtered and dried to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[CH:21](=[C:16]1/[C:17](=[O:18])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:20])[CH:12]=2)[C:14](=[O:19])[NH:15]/1)\[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1noc(C)c1Cn1cc(N2C(=O)N/C(=C\c3ccccc3)C2=O)cn1
Yield: 47.6 %

Procedure:
3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) (275 mg, 1 mmol), benzaldehyde (140 mg, 1.3 mmol), and sodium acetate (205 mg, 2.5 mmol), in glacial acetic acid (3 mL) were irradiated in the microwave reactor for 7 hours at 185° C. Upon cooling the mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (3×, 50 mL). The combined organic extracts were washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate, filtered and concentrated. the solid product was triturated with ethyl acetate/hexanes (1/1) and dried under high vacuum to afford (Z)-5-benzylidene-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (173 mg, 48%) as a light yellow solid. 1H NMR (DMSO-d6, 400 MHz): δ 2.14 (s, 3H), 2.40 (s, 3H), 6.59 (s, 1H), 5.20 (s, 2H), 7.33-7.40 (m, 3H), 7.66 (s, 2H), 7.81 (s, 1H), 8.21 (s, 1H), 11.01 (bs, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.34 μM.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[C:16](Cl)(=[O:20])[CH2:17][CH2:18][CH3:19].C(Cl)(Cl)Cl.O>N1C=CC=CC=1>[C:16]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: O=C(O)CCCCCCCCCCCO
Reactant: CCCC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCC(=O)OCCCCCCCCCCCC(=O)O
Reaction time: 4 h
Yield: 96.7 %

Procedure:
12-Hydroxydodecanoic acid (1 g) was dissolved in pyridine, and butyroyl chloride (0.59 g) was added to the solution in an ice bath. After 4 hours of stirring, the reaction mixture was distributed into chloroform and water, and the chloroform layer was concentrated to give 12-butyryloxydodecanoic acid (1.28 g).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[CH3:12][C@H:13]1[C:21]2[C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:19][CH:18]=[N:17][C:16]=2[CH2:15][S:14]1.[C:28]([O:32][C:33]([N:35]([CH:48]([CH3:50])[CH3:49])[CH2:36][CH:37]([C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=1)[C:38](O)=[O:39])=[O:34])([CH3:31])([CH3:30])[CH3:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CCOC(C)=O>[F:47][C:44]1[CH:45]=[CH:46][C:41]([CH:37]([C:38]([N:25]2[CH2:26][CH2:27][N:22]([C:20]3[C:21]4[C@H:13]([CH3:12])[S:14][CH2:15][C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:23][CH2:24]2)=[O:39])[CH2:36][N:35]([CH:48]([CH3:49])[CH3:50])[C:33](=[O:34])[O:32][C:28]([CH3:30])([CH3:29])[CH3:31])=[CH:42][CH:43]=1
Reactant: CC(C)N(CC(C(=O)O)c1ccc(F)cc1)C(=O)OC(C)(C)C
Reactant: C[C@@H]1SCc2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(CC(C(=O)N1CCN(c2ncnc3c2[C@H](C)SC3)CC1)c1ccc(F)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.7 %

Procedure:
DIPEA (0.089 mL, 0.51 mmol) was added to a stirred suspension of (S)-5-methyl-4-(piperazin-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidine dihydrochloride (40 mg, 0.13 mmol), 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-fluorophenyl)propanoic acid (50 mg, 0.15 mmol) and O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (58 mg, 0.15 mmol) in DCM (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hours, diluted with EtOAc, washed with saturated aqueous bicarbonate and then 1N HCl. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (75% EtOAc/hexanes) to give tert-butyl 2-(4-fluorophenyl)-3-(4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (50 mg, 72% yield) as a mixture of 2 diastereomers. LCMS (APCI+) [M-Boc+H]+ 444.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C(=O)C)=[CH:11][CH:10]=1)=[O:5])[CH3:2].[O-]CC.[Na+]>C(O)C>[CH2:1]([O:3][C:4]([NH:6][CH:7]=[CH:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)NC=Cc1ccc(OC(C)=O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)NC=Cc1ccc(O)cc1
Temperature: 50 °C

Procedure:
5.0 g (0.02 mol) of p-(2-ethoxycarbonylaminovinyl)-acetoxybenzene, after dissolving in 75 ml of absolute ethanol, addition of a solution of 1.36 g (0.02 mol) of sodium ethoxide in 10 ml of absolute ethanol, 15 minutes' heating to 50° C. and subsequent evaporation to dryness in vacuo, yield the crude sodium salt of p-(2-ethoxycarbonylaminovinyl)-phenol. This is heated with 20 ml of epichlorohydrin to the boil for 24 hours under a reflux condenser and whilst stirring. Thereafter, the excess epichlorohydrin is removed by vacuum distillation. The residue is partitioned between water and methylene chloride and the organic phase is separated off, dried over sodium sulphate and evaporated. 1-[p-(2-Ethoxycarbonylaminovinyl)-phenoxy]-2,3-epoxy-propane of melting point 112° -113° C. (from ether) is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[N:13]=[C:14]([CH3:18])[N:15]=[C:16](Cl)[C:11]=2[CH:10]=[CH:9]1)[CH3:2].[C:20]([O:24][C:25](=[O:40])[C@@H:26]([NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:27][NH2:28])([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C>CN1CCCC1=O>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[N:13]=[C:14]([CH3:18])[N:15]=[C:16]([NH:28][CH2:27][C@H:26]([NH:29][C:30]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:31])[C:25]([O:24][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:40])[C:11]=2[CH:10]=[CH:9]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Reactant: CCOC(=O)CCCn1ccc2c(Cl)nc(C)nc21
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCn1ccc2c(NC[C@H](NC(=O)OCc3ccccc3)C(=O)OC(C)(C)C)nc(C)nc21
Temperature: 100 °C
Reaction time: 36 h

Procedure:
To a solution of 1000 mg (3.5 mmol) of 4-(4-chloro-2-methyl-pyrrolo[2,3-d]pyrimidin-7-yl)-butyric acid ethyl ester (example 2a) in 7 ml N-methylpyrrolidone were added 1590 mg (5.4 mmol) of (2S)-3-amino-2-benzyloxycarbonylamino-propionic acid tert-butyl ester and 5.9 ml triethylamine and the reaction was stirred at 100° C. for 36 h. The reaction was diluted with 85 ml EE and extracted with water, aqueous citric acid and again with water. The organic phase was dried over MgSO4 filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with DCM/EE (2:1). Yield: 719 mg.
Reaction SMILES: [CH2:1]([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7]O)C.[CH2:10]1[CH2:15]O[CH:13]=[CH:12][CH2:11]1.CC1(C)C2([CH2:25][S:26]([OH:29])(=[O:28])=[O:27])C(CC1CC2)=O>N1C=CC=CC=1>[CH2:5]1[CH2:4][O:3][CH:1]=[CH:7][CH2:6]1.[CH3:1][C:11]1[CH:12]=[CH:13][C:25]([S:26]([OH:29])(=[O:28])=[O:27])=[CH:15][CH:10]=1
Reactant: CCOC(=O)CCCO
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: C1=COCCC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O)cc1

Procedure:
Scheme 7 depicts the synthesis of intermediate 11e wherein R3 and Y2 are the same and X═Br. Thus, commercially-available 4-hydroxy-butanoic acid ethyl ester 37 is treated with DHP and CSA, or with DHP, TsOH, and pyridine to provide ester 38. Reduction with LiAlD4 affords deuterated alcohol 39, which is treated with either triphenyl phosphine in CCl4 (Sabitha, G et al., Tetrahedron Letters, 2006, (volume date 2007), 48(2): 313-315) or with methanesulfonyl chloride, lithium chloride, and 2,6-lutidine in DMF (Blaszykowski, C et al., Organic Letters, 2004, 6(21): 3771-3774) to afford chloride 40. Following the same methods as in Scheme 6, chloride 40 may be converted to 11e.
Reaction SMILES: O.[N:2](=[CH:4][C:5](=[O:17])[CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[OH:3].[CH2:18](O)[CH2:19][OH:20].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1C=CC=CC=1>[CH2:19]1[O:20][C:5]([CH:4]=[N:2][OH:3])([CH2:6][C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[O:17][CH2:18]1
Reactant: OCCO
Reactant: O=C(C=NO)CC(=O)OCc1ccccc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: c1ccccc1
Product: O=C(CC1(C=NO)OCCO1)OCc1ccccc1
Yield: 35 %

Procedure:
In a two liter flask fitted with a Dean Stark water separator and a condenser were placed 186.5 g. (0.85 mole) of benzyl oximino-acetoacetate (17), 62 g. (1 mole) of ethylene glycol, 800 ml. of benzene (reagent grade) and 2 g. of toluenesulfonic acid. The reaction mixture was boiled at reflux until 15 ml. of water was removed (3 hours). The benzene solution was washed once with saturated sodium bicarbonate solution and once with brine. After drying over anhydrous sodium sulfate, the benzene solution was evaporated, leaving 212 g. (94%) of 17 as a light yellow oil. Its NMR spectrum was consistent with the assigned structure. Generally the compound was used as such in subsequent reaction but one of the isomers can be crystallized in 35% yield from toluene-petroleum ether, m.p. 52° C. ##STR144##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][NH:5][C:6](=[O:20])[C@H:7]([CH2:16][CH2:17][S:18][CH3:19])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C[I:23]>>[I-:23].[CH3:17][SH2+:18].[CH3:1][O:2][C:3](=[O:21])[CH2:4][NH:5][C:6](=[O:20])[C@H:7]([CH2:16][CH2:17][S:18][CH3:19])[NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10]
Reactant: CI
Agent: COC(=O)CNC(=O)[C@H](CCSC)NC(=O)OC(C)(C)C
Product: C[SH2+]
Product: [I-]
Reaction time: 6.5 h

Procedure:
The compound of Example 19 (960 mg, 3 mmole) was dissolved with stirring in 6 mL of methyl iodide at room temperature. The reaction mixture was stirred for 6.5 hours over which time a gummy solid had separated. The supernatant was drawn off and the residue was dried under vacuum to give 1.41 g (100%) of the title compound as a hygroscopic foam.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:9]([F:19])[C:8](Cl)=[C:7]([C:21]#[N:22])[N:6]=1)=[O:4].[K].CC(=[N:27][NH2:28])C.CC(=NO)C>>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:9]([F:19])[C:8]2[C:7](=[C:21]([NH2:22])[NH:27][N:28]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(C#N)c(Cl)c(F)c1Nc1ccccc1F
Reactant: CC(C)=NN
Agent: CC(C)=NO
Agent: [K]
Product: COC(=O)c1nc2c(N)[nH]nc2c(F)c1Nc1ccccc1F

Procedure:
The title compound is prepared from 5-chloro-6-cyano-4-fluoro-3-(2-fluorophenylamino)-pyridine-2-carboxylic acid methyl ester (prepared in Example 9) and the potassium salt of acetone hydrazone in place of the potassium salt of acetone oxime by the method previously described in step H of Example 8.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[O:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][C:41]=2[NH:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH2:36][CH2:35]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:43]4[CH:44]=[CH:45][C:40]([N:37]5[CH2:36][CH2:35][O:34][CH2:39][CH2:38]5)=[C:41]([NH:55][S:56]([CH3:59])(=[O:57])=[O:58])[CH:42]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:25])=[O:26])[CH:9]=2)[CH:12]=[N:13]1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)c(NS(C)(=O)=O)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCOCC5)c(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 90.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine Compound of step-I in Example 9) (200 mg, 0.3809 mmol) was coupled with N-(2-morpholino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methane sulfonamide (Intermediate 20) (220 mg, 0.5714 mmol), Pd(PPh3)2Cl2 (13.5 mg, 0.01904 mmol), Toluene/ethanol/water (20/10/4 ml) to afford 240 mg (90.2% yield) of the titled compound.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH2:20][C:21]4[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:27]=1.BrC1C=CC2C3CC(C3)N3C(C(O)C4N(C)N=CC=4)=C(C(OC)=O)N=C3C=2C=1.CS(Cl)(=O)=O.[H][H]>[Pd]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH2:20][C:21]4[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:27]=1
Reactant: COC(=O)c1nc2n(c1Cc1ccnn1C)C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: [H][H]
Agent: [Pd]
Agent: COC(=O)c1nc2n(c1C(O)c1ccnn1C)C1CC(C1)c1ccc(Br)cc1-2
Agent: CS(=O)(=O)Cl
Product: COC(=O)c1nc2n(c1Cc1ccnn1C)C1CC(C1)c1ccc(Br)cc1-2

Procedure:
methyl 10-bromo-3-((1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was prepared similarly to methyl 10-bromo-9-fluoro-3((1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate. Methyl 10-bromo-3-(hydroxy(1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with methanesulfonyl chloride followed by palladium on carbon and hydrogen to afford 140 mg (98% crude yield) of the titled crude product which was carried forward without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([Cl:12])=[CH:4][C:3]=1[NH:13][C:14]1[N:19]=[CH:18][C:17](C(O)C)=[CH:16][CH:15]=1.[C:23](O)(=O)[CH2:24][CH3:25].[C:28]([O:32][C:33](=O)[CH2:34]C)(=[O:31])[CH2:29][CH3:30]>>[Cl:12][C:5]1[C:6]([C:8]([F:9])([F:11])[F:10])=[CH:7][C:2]2[N:1]=[C:23]([CH2:24][CH3:25])[N:13]([C:14]3[N:19]=[CH:18][C:17]([CH2:34][CH2:33][O:32][C:28](=[O:31])[CH2:29][CH3:30])=[CH:16][CH:15]=3)[C:3]=2[CH:4]=1
Reactant: CCC(=O)O
Reactant: CCC(=O)OC(=O)CC
Reactant: CC(O)c1ccc(Nc2cc(Cl)c(C(F)(F)F)cc2N)nc1
Product: CCC(=O)OCCc1ccc(-n2c(CC)nc3cc(C(F)(F)F)c(Cl)cc32)nc1
Temperature: 120 °C
Reaction time: 15 h

Procedure:
To (6-{[2-amino-5-chloro-4-(trifluoromehyl)phenyl]amino}-3-pyridinyl}ethanol (787 mg, 2.37 mmol, from step 5) was added propionic acid and propionic anhydride and stirred at 120° C. for 15 h. The mixture was quenched with NaOH and extracted with dichloromethane (3×30 ml). The organic layer was washed with brine, dried (MgSO4) and concentrated to give 5.26 g of title compound as orange oil.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[C:9]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH3:22])[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:25][Si:26]([CH2:29][CH2:30][O:31][CH2:32]Cl)([CH3:28])[CH3:27]>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[C:9]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH3:22])[CH:12]=3)[N:8]([CH2:32][O:31][CH2:30][CH2:29][Si:26]([CH3:28])([CH3:27])[CH3:25])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1ccc2c(c1)c(-c1cc3nc(Br)cnc3[nH]1)cn2C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3nc(Br)cnc3n1COCC[Si](C)(C)C)cn2C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.4 %

Procedure:
2-Bromo-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazine (0.500 g, 1.40 mmol) in DMF (15 mL) was cooled to about 0° C. then treated with NaH (60% dispersion in mineral oil, 0.112 g, 2.80 mmol). The mixture was stirred for about 15 min, SEM-Cl (0.372 mL, 2.10 mmol) was added, and the mixture was warmed to ambient temperature for about 15 min. The mixture was concentrated and purified by silica gel chromatography (40 g silica column) eluting with DCM to give 2-bromo-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (0.61 g, 89%): LC/MS (Table 2, Method a) Rt=3.88 min; MS m/z: 489 (M+H)+.
Reaction SMILES: Br[CH:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[CH2:3]1.[C:16]1([NH:22][CH2:23][CH2:24][NH2:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])(O)=O.[Na+]>CN(C)C=O>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:15])([CH3:14])[CH2:3][CH:2]([NH:25][CH2:24][CH2:23][NH:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[CH:8]=1)#[N:13]
Reactant: NCCNc1ccccc1
Reactant: CC1(C)CC(Br)c2cc(C#N)ccc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC(NCCNc2ccccc2)c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 409.3 %

Procedure:
A solution of 4-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (0.75 g, 2.82 mmole, from Example 8, part B) and N-phenylethylenediamine (8.84 g, 10 eq.) containing NaHCO3 (2.40 g, 5 eq.) in N,N-dimethylformamide (15 ml) was stirred for 48 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and distilled H2O. The organic phase was washed with distilled H2O, saturated NaCl solution, dried over Na2SO4 and evaporated in vacuo to obtain 3.71 g of an orange gum. The crude product was chromatographed on silica eluting with 3:2 hexane/ethyl acetate to obtain 0.36 g (40%) of the title compound as a colorless gum which solidified upon standing. 1H NMR (CDCl3) δ 7.91 (s. 1H), 7.38 (dd, J=2.34 and 8.79 Hz, 1H), 7.19 (m, 2H), 6.79 (d, J=8.21 Hz, 1H), 6.70 (m, 3H), 3.87 (dd, J=5.86 and 11.14 Hz, 1H), 3.26 (m, 2H), 3.10 (m, 1H), 2.86 (m, 1H), 2.20 (dd, J=5.87 and 12.90 Hz, 1H), 1.58 (d, J=12.30 Hz, 1H), 1.45 (s, 3H), 1.27 (s, 3H); 13C NMR (CDCl3) δ 157.63, 148.16, 132.40, 132.09, 129.21, 125.32, 119.56, 118.09, 117.52, 112.97, 102.89, 76.83, 49.24, 44.89, 44.00, 39.25, 29.69, 24.96; MS: (M+H)+ @322.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[N:4][C:5]([CH2:9]Br)=[CH:6][C:7]=1[CH3:8].CCCC[N+](CCCC)(CCCC)CCCC.[F-:29]>>[Br:1][C:2]1[C:3]([CH3:11])=[N:4][C:5]([CH2:9][F:29])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(CBr)nc(C)c1Br
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: Cc1cc(CF)nc(C)c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-bromo-6-(bromomethyl)-2,4-dimethylpyridine obtained in Preparation Example 30(1) (2.00 g) and TBAF (35.8 mL, 1 M solution in THF) was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 0% to 50%) to give the title compound (572 mg). 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.44 (s, 3H), 2.67 (s, 3H), 5.28-5.47 (m, 2H), 7.14-7.19 (m, 1H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@H:18]3[CH2:20][O:19]3)=[CH:12][CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:35][NH:36][CH3:37]>C1COCC1>[CH2:1]([C:5]1[N:6]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:25][CH:26]=2)[CH:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][C@H:18]([OH:19])[CH2:20][N:36]([CH3:37])[CH3:35])=[CH:14][CH:15]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(OC[C@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: CCCCc1nc(-c2ccc(OC[C@H](O)CN(C)C)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A solution of 2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-((R)-1-oxiranylmethoxy)-phenyl]-1H-imidazole (100 mg, 2.1 mmol, from intermediate A2) in 3 mL of dimethylamine in THF (2M) was stirred at 76° C. for 1 h in a microwave reactor. Upon completion (determined by LC/MS), the reaction was evaporated in vacuo and purified by silica gel flash column chromatography using a gradient of EtOAc to 96% EtOAc/(2M NH3/MeOH) as an eluent to afford (R)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-dimethylamino-propan-2-ol.