Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[C@@H:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH2:25][CH2:26][CH3:27])[CH:22]=2)[C@H:17]([C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[C@H:16]1[C:37]([O:39]C)=[O:38])([O:3]C)=[O:2].[OH-].[Na+:42]>C(O)(C)C.O>[Na+:42].[Na+:42].[C:1]([CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[C@@H:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH2:25][CH2:26][CH3:27])[CH:22]=2)[C@H:17]([C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[C@H:16]1[C:37]([O-:39])=[O:38])([OH:3])=[O:2].[C:1]([CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[C@@H:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH2:25][CH2:26][CH3:27])[CH:22]=2)[C@H:17]([C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[C@H:16]1[C:37]([O-:39])=[O:38])([OH:3])=[O:2]
Reactant: CCCOc1ccc2c(c1)[C@@H](c1ccc(OC)cc1OCC(=O)OC)[C@H](C(=O)OC)[C@H]2c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCOc1ccc2c(c1)[C@@H](c1ccc(OC)cc1OCC(=O)O)[C@H](C(=O)[O-])[C@H]2c1ccc2c(c1)OCO2
Reaction time: 16 h

Procedure:
To a solution of (+) Methyl (1S,2R,3S)-3-(2-carbomethoxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (49.2 g) in isopropanol (1000 mL) and water (48 mL) was added a 50% aqueous solution of sodium hydroxide (179.4 g). The mixture was stirred under nitrogen for 16 hours then concentrated to approximately 200 mL. Water (400 mL) was added and the solution was extracted with t-butyl methyl ether (300 mL). The aqueous layer was acidified with dilute HCl and extracted twice with 300 mL portions of TBNE. The organic layer was washed 4 times with water (4×200 mL), then concentrated under reduced pressure. Absolute ethanol was added (400 mL) and the solution was further concentrated to approximately 150 mL. The solution was diluted to 800 mL with absolute ethanol and 60 mL of water. The solution was titrated to pH=11-12 with 1.25 N sodium hydroxide solution then after stirring for 15 minutes, concentrated to an oil. Absolute ethanol (250 mL) was added and the solution reconcentrated to a solid which was triturated with hexane, and filtered. The solid was dried to a constant weight to afford (+) (1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid disodium salt.
Reaction SMILES: [N+](C1C=CC(N2CCNCC2)=CC=1)([O-])=O.[N+:16]([C:19]1[CH:20]=[C:21]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1)([O-])=O.CS(C1N=CC2=CC=C([C:43]3C=CC=[CH:45][C:44]=3[O:49]C)N2N=1)=O.[Cl:51][C:52]1[CH:53]=[C:54]([C:58]2[N:66]3[C:61]([CH:62]=[N:63][C:64](S(C)=O)=[N:65]3)=[CH:60][CH:59]=2)[CH:55]=[CH:56][CH:57]=1>>[Cl:51][C:52]1[CH:53]=[C:54]([C:58]2[N:66]3[C:61]([CH:62]=[N:63][C:64]([NH:16][C:19]4[CH:20]=[C:21]([N:25]5[CH2:30][CH2:29][N:28]([CH2:43][C@@H:44]([OH:49])[CH3:45])[CH2:27][CH2:26]5)[CH:22]=[CH:23][CH:24]=4)=[N:65]3)=[CH:60][CH:59]=2)[CH:55]=[CH:56][CH:57]=1
Reactant: CS(=O)c1ncc2ccc(-c3cccc(Cl)c3)n2n1
Reactant: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Agent: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Product: C[C@H](O)CN1CCN(c2cccc(Nc3ncc4ccc(-c5cccc(Cl)c5)n4n3)c2)CC1

Procedure:
The compound was prepared in an analogous fashion to Example 69 replacing 1-(4-Nitro-phenyl)-piperazine with 1-(3-Nitro-phenyl)-piperazine and 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine with 7-(3-Chloro-phenyl)-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine to afford 28.66 mg of (S)-1-(4-{3-[7-(3-Chloro-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperazin-1-yl)-propan-2-ol as a lyophilized powder. (M+H)=463.12. 1H NMR (400 MHz, DMSO, d6) δ 9.41 (s, 1H), 9.02 (s, 1H), 8.39 (m, 1H), 8.06 (d, 1H, J=7.85 Hz), 7.48 (m, 3H), 7.26 (m, 3H), 6.98 (d, 1H, J=4.81 Hz), 6.67 (dd, 1H, J=2.00, 6.16 Hz), 4.12 (m, 2H), 3.66 (m, 2H), 3.53 (m, 2H), 3.17 (m, 3H), 3.11 (m, 2H), 1.14 (d, 3H, J=6.16 Hz).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[C:3]1=[O:16].Br[C:18]1[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=[C:22]([Br:24])[N:23]=1.C(N(CC)CC)C>CC(O)C>[Br:24][C:22]1[N:23]=[C:18]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([C@H:4]3[C:3](=[O:16])[N:2]([CH3:1])[CH2:7][CH2:6][N:5]3[CH3:8])=[CH:10][CH:11]=2)[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: CN1CCN(C)C(c2ccc(N)cc2)C1=O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CN1CCN(C)[C@@H](c2ccc(Nc3nc(Br)cn(C)c3=O)cc2)C1=O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a single-necked 250 mL round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged (−)-1,4-dimethyl-3-(4-aminophenyl)piperazin-2-one (8.2 g, 37.3 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (10.0 g, 37.3 mmol), and i-PrOH (100 mL). Triethylamine (5.72 mL, 41 mmol, 1.1 eq) was then added and the resulting suspension was heated at 80° C. for 16 hrs. A thick slurry was observed the following day. The reaction was cooled to room temperature then concentrated in vacuo to ˜20 mL total volume. At that point 20 mL of 2M Na2CO3 solution was added followed by 100 mL of water. The mixture was then allowed to slurry for 2 hrs at room temperature. The off-white solid was then collected on a fritted funnel and allowed to air dry for ˜1 hr. The solids were returned to the reaction flask and 100 mL of diethyl ether/hexanes (1:1) was added and the suspension was triturated at room temperature for 1 hr. The white solid was then collected on a fritted funnel, dried on the filter with vacuum for 1 hr, then transferred to a round-bottomed flask and vacuum-dried overnight. White solids were obtained, 12.88 g (85%).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[NH:10][C:9]2=[N:11][C:12]([CH2:14][CH3:15])=[CH:13][C:8]2=[C:7]([Cl:16])[N:6]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br>O1CCCC1.C(Cl)Cl>[CH3:3][S:4][C:5]1[N:6]=[C:7]([Cl:16])[C:8]2[CH:13]=[C:12]([CH2:14][CH3:15])[N:11]([CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[C:18]([Cl:17])[CH:19]=3)[C:9]=2[N:10]=1
Reactant: Clc1cccc(CBr)c1
Reactant: CCc1cc2c(Cl)nc(SC)[nH]c-2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1cc2c(Cl)nc(SC)nc2n1Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
To a suspension of 48 mg (2.00 mmol) of sodium hydride in 4.0 mL of tetrahydrofuran was added 227 mg (1.00 mmol) of 2-(methylthio)-4-chloro-6-ethyl-1H-pyrrolo[2,3-d]pyrimidine and 410 mg (2.00 mmol) of 3-chlorobenzyl bromide. The reaction was stirred at ambient temperature for 18 hours then diluted with 30 mL of methylene chloride and washed with 20 mL of saturated sodium bicarbonate solution. The organic phase was dried with sodium sulfate and concentrated. The crude product was purified by flash chromatography (25 g silica, methylene chloride-heptane gradient 1:1 to 100:0) to provide 350 mg (99%) of 2-(methylthio)-4-chloro-6-ethyl-7-[(3-chlorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidine as a white solid. nmr (500 MHz, CDCl3) δ1.33 (t, J=7.4 Hz, 3H), 2.58 (s, 3H), 2.59 (q, J=7.4 Hz, 2H), 5.30 (s, 2H), 6.29 (s, 1H), 6.92 (d, J=7.4 Hz, 1H), 7.09 (s, 1H), 7.23 (m, 2H)
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-:28][Si](C)(C)C)(C)C.[Li+].[NH2:34][C:35]1[C:40]([C:41]([C:43]2[CH:44]=[N:45][C:46]([F:49])=[CH:47][CH:48]=2)=O)=[CH:39][C:38]([Br:50])=[CH:37][N:36]=1.C([Mg]Cl)(C)(C)C>C1COCC1>[Br:50][C:38]1[CH:39]=[C:40]([C:41]([C:43]2[CH:44]=[N:45][C:46]([F:49])=[CH:47][CH:48]=2)=[CH:2][O:3][CH3:4])[C:35]([NH:34][NH2:28])=[N:36][CH:37]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Nc1ncc(Br)cc1C(=O)c1ccc(F)nc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC=C(c1ccc(F)nc1)c1cc(Br)cnc1NN
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of (methoxymethyl)triphenylphosphonium chloride (1.16 g, 3.38 mmol) in THF (4 ml) at 0° C. under nitrogen was added dropwise a 1M solution of lithium bis(trimethylsilyl)amide in THF (3.4 ml, 3.4 mmol). The resulting dark red mixture was stirred at 0° C. for 10 minutes to generate the ylide reagent. To a solution of (2-amino-5-bromo-pyridin-3-yl)-(6-fluoro-pyridin-3-yl)-methanone (400 mg, 1.35 mmol) in THF (6 ml) was added dropwise a 1M solution of tert-butylmagnesium chloride in THF (1.35 ml) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 5 minutes, then the ylide reagent was added dropwise in 5 minutes. The reaction mixture was allowed to warm up to room temperature in 45 minutes before quenching with a saturated aqueous solution of ammonium chloride (50 ml) at 0° C. The mixture was stirred vigorously for 1.5 hours at room temperature. Water was added, followed by extracting ethyl acetate (three times). The combined organic layers were washed with brine, and directly adsorbed on silica gel. Purification on silica gel with a gradient of ethyl acetate/hexane afforded the title compound (single isomer) as a dark foam (220 mg, 50% yield). 1H NMR (DMSO-d6): δ 8.15 (d, J=2.5 Hz, 1H), 8.00 (d, J=2.5 Hz, 1H), 7.78 (dt. J=2.5, 8.5 Hz, 1H), 7.48 (d, J=2.5 Hz, 1H), 7.10 (dd, J=3.0, 8.5 Hz, 1H), 6.61 (s, 1H), 5.73 (broad s, 2H), 3.80 (s, 3H); MS: m/z 324, 326 [MH]+.
Reaction SMILES: [H-].[Na+].C1COCC1.[C:8]([CH:12]([C:29]([O:31][CH3:32])=[O:30])[C:13]1[CH:14]=[CH:15][N:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:17]2=[O:28])([O:10][CH3:11])=[O:9].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>O>[C:8]([C:12]([C:13]1[CH:14]=[CH:15][N:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:17]2=[O:28])([C:29]([O:31][CH3:32])=[O:30])[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])([O:10][CH3:11])=[O:9]
Reactant: CCOC(=O)c1ccc2cc(C(C(=O)OC)C(=O)OC)ccn2c1=O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(C(=O)OC)(C(=O)OC)c1ccn2c(=O)c(C(=O)OCC)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
An oven-dried 50 ml three-necked round-bottom flask equipped with a reflux condenser was charged with NaH (160 mg, 60% suspension in oil, 4 mmol, washed with hexane) and 10 ml THF. Ethyl 8-(dicarbomethoxymethyl)-4-oxo-4H-quinolizine-3-carboxylate (19) (700 mg, 2 mmol) was added in three portions and stirring was continued for 1 h, followed by addition of ethyl bromoacetate (0.5 ml, 5.3 mmol). The reaction mixture was refluxed overnight, cooled to room temperature and poured into 100 ml water. The aqueous layer was extracted three times with 100 ml dichloromethane. The organic solvent was evaporated and the crude product was purified by flash chromatography (ethyl acetate) to give a yellow viscous oil (630 mg, 74%). 1H NMR (δ, CDCl3): 1.24 (t, J=7 Hz, 3H), 1.42 (t, J=7 Hz, 3H), 3.39 (s, 2H), 3.84 (s, 6H), 4.14 (q, J=7 Hz, 2H), 4.41 (q, J=7 Hz, 2H), 6.63 (d, J=8 Hz, 1H), 7.14 (dd, J=2 Hz, J=7 Hz, 1H), 7.61 (d, J=2 Hz, 1H), 8.40 (d, J=8 Hz, 1H), 9.29 (d, J=8 Hz, 1H). MS: m/z 433.1363; required for C21H21NO9: 433.1372.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:16][Si:17](Cl)([CH3:24])[C:18]([CH:21]([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(Cl)Cl.CN(C)C1C=CN=CC=1.CCCCCC>[Br-:1].[CH3:16][Si:17]([CH3:24])([C:18]([CH3:20])([CH3:19])[CH:21]([CH3:23])[CH3:22])[O:8][C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)C(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc(Br)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC(C)C(C)(C)[Si](C)(C)Oc1ccccc1
Product: [Br-]
Reaction time: 1.5 h
Yield: 94.8 %

Procedure:
To a stirred solution of 3-bromophenyl alcohol (5.0 g, 26.7 mmol) and triethylamine (3.25 g, 32.1 mmol) in anhydrous CH2Cl2 (125 mL) at room temperature under argon was added dropwise dimethylthexyl-silylchloride (5.26 g, 29.4 mmol). After 1.5 hours, 4-dimethylaminopyridine (0.50 g) was added and the stirring was continued for an additional 3 hours. The reaction mixture was diluted with hexane (200 mL) and the precipitate was filtered off. The filtrate was concentrated, partitioned between hexane (200 mL) and lN aqueous HCl (3×40 mL), and the organic layer was washed with saturated aqueous NaHCO3 (2×40 mL). The organic layer was dried (MgSO4), filtered and concentrated to yield title bromide (8.01 g, 91%).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[CH:21]1[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH:24]=[CH:23][C:22]=1[OH:31].[OH-].[Na+]>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:31][C:22]2[CH:23]=[CH:24][C:25]3[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=3[CH:21]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: Oc1ccc2c(c1)CCCC2
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc3c(c2)CCCC3)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 5,6,7,8-Tetrahydro-naphthalen-2-ol under the Standard Procedure J. The compound thus obtained was allowed to react under Standard Hydrolysis Procedure C (NaOH) to give the title compound. MS(ES) for C23H28NO5 [M+Na]+: 407, [M+H]+: 385.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:31]([O:32][CH3:33])=[CH:30][C:6]2[CH2:7][C:8](=O)[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:28])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:43]2)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:31]([O:32][CH3:33])=[CH:30][C:6]2[CH2:7][C:8](=[S:43])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:28])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc(CCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=S)cc1OC

Procedure:
2.28 gm (0.005 mol) of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-N-(2-{3,4-dimethoxy-phenyl}-ethyl)-amino]-propane were dissolved in 10 ml of absolute toluene, and the solution was refluxed for 50 minutes with 1.0 gm (0.0025 mol) of 2,4-bis-(4-methoxy-phenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide. After the solvent had been removed in vacuo in a rotary evaporator, the residue was purified on aluminium oxide with methylene chloride plus 2% ethanol as the eluant.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[NH:20][C:19](=[O:21])[C:18]([C:22]#[N:23])=[C:17]([S:24]([CH3:26])=[O:25])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:28][C:29]([NH2:31])=[O:30].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[C:19]([O:21][CH2:28][C:29]([NH2:31])=[O:30])[C:18]([C:22]#[N:23])=[C:17]([S:24]([CH3:26])=[O:25])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)CBr
Reactant: CS(=O)c1cc(-c2ccccc2OCc2ccccc2)[nH]c(=O)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)c1cc(-c2ccccc2OCc2ccccc2)nc(OCC(N)=O)c1C#N
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 60.8 %

Procedure:
A mixture of 6-[2-(benzyloxy)phenyl]-4-(methylsulfinyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (2.97 g, 8.16 mmol), bromoacetamide (1.27 g, 9.21 mmol), and K2CO3 (1.43 g, 10.4 mmol) in DMF (30 mL) was stirred at 60° C. for 1.5 hrs. The reaction mixture was poured into water, and the resulting precipitates were collected by filtration. The solid obtained was washed with acetone to give 2-{[6-[2-(benzyloxy)phenyl]-3-cyano-4-(methylsulfinyl)-2-pyridinyl]oxy}acetamide as a solid (2.09 g, yield; 61%).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]=1.N1C=C(B(O)[OH:39])C=NC=1>>[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@@H:9]4[CH2:12][C@H:11]([N:13]5[CH2:17][CH2:16][CH2:15][C@H:14]5[CH2:18][OH:39])[CH2:10]4)[S:8][C:4]=3[CH:3]=2)=[CH:25][N:24]=1
Reactant: COc1ncc(B(O)O)cn1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: OB(O)c1cncnc1
Product: COc1ncc(-c2ccc3nc([C@H]4C[C@@H](N5CCC[C@H]5CO)C4)sc3c2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, substituting the product of Example 36A for the product of Example 1E and substituting 2-methoxypyrimidine-5-boronic acid for pyrimidine-5-boronic acid. 1H NMR (400 MHz, CDCl3) δ ppm 8.77 (s, 2H) 8.06 (d, J=8.59 Hz, 1H) 7.98 (d, J=1.53 Hz, 1H) 7.59 (dd, J=8.59, 1.84 Hz, 1H) 4.08 (s, 3H) 3.55-3.68 (m, J=7.67 Hz, 2H) 3.36-3.47 (m, 1H) 3.25-3.35 (m, 1H) 3.03-3.14 (m, 1H) 2.72-2.87 (m, 2H) 2.61-2.72 (m, 1H) 2.40-2.54 (m, 3H) 1.87-2.01 (m, 1H) 1.69-1.85 (m, 2H) 1.51-1.70 (m, 1H). MS: (M+H)+=397.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1.[OH:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][C:20]#[N:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][O:14][C:15]2[CH:23]=[CH:22][C:18]([CH2:19][C:20]#[N:21])=[CH:17][CH:16]=2)=[CH:6][CH:5]=1
Reactant: N#CCc1ccc(O)cc1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: N#CCc1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1
Yield: 89.5 %

Procedure:
A mixture of 4-(trifluoromethoxy)benzyl bromide (2.5 g, 10 mmol), 4-hydroxybenzyl cyanide (1.1 g, 8 mmol) and potassium carbonate (1.4 g, 10 mmol) in acetone (25 mL) was heated to reflux for 7 hours. The mixture was then diluted with H2O (100 mL) and extracted with EtOAc (2×150 mL). Organics portions were combined and washed with brine and then dried with Na2SO4. The mixture was then filtered and the solvent was removed in vacuo affording 2.5 g of crude product. Purification by flash chromatography eluting with 30 percent ether/pentane over silica gel yielded 2.2 g of a white solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][NH:16][CH:17]=O)[CH:11]=[CH:12][CH:13]=1>CCCCCC>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:11](=[CH:12][CH:13]=1)[CH:17]=[N:16][CH2:15][CH2:14]2
Reactant: COc1cccc(CCNC=O)c1
Solvent: CCCCCC
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)CCN=C2
Temperature: 25 °C
Yield: 67.5 %

Procedure:
Phosphorus oxychloride (80 mL, 0.85 mol) was added dropwise to N-[2-(3-methoxy-phenyl)-ethyl]-formamide (41.1 g, 0.24 mol) and refluxed for 1 hour. The reaction mixture was cooled to room temperature, and hexane (3×500 mL) was added and decanted off three times. To the dark oily solution was added slowly water (200 mL) while stirring. The mixture was basified with NaOH to pH>13, extracted with ethyl acetate, dried (Na2SO4) and concentrated to afford the desired product (26.1 g, 67%). MS: 162.1 (M+1+).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]3[CH:33]=[CH:32][C:18]4/[C:19](=[CH:28]\[C:29](O)=O)/[C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5O[CH2:23][C:17]=4[CH:16]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH2:34].[NH2:35][NH2:36].[OH2:37]>C1COCC1.ClCCl>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]3[CH:33]=[CH:32][C:18]4/[C:19](=[CH:28]\[C:29]([NH:35][NH2:36])=[O:37])/[C:20]5[CH:21]=[CH:24][CH:25]=[CH:26][C:27]=5[O:34][CH2:23][C:17]=4[CH:16]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: NN
Reactant: CCCc1nc2c(C)cccc2n1Cc1ccc2c(c1)COc1ccccc1/C2=C/C(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCc1nc2c(C)cccc2n1Cc1ccc2c(c1)COc1ccccc1/C2=C/C(=O)NN
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
[step 1] (E)-2-[8-(4-Methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]acetic acid (300 mg, 0.68 mmol) obtained in Example 105, step 1 was dissolved in THF (6.8 mL) and dichloromethane (6 mL), N,N′-carbonyldiimidazole (444 mg, 2.74 mmol) was added, and the mixture was stirred at room temperature for 4 hr. To the mixture was added hydrazine monohydrate (0.33 mL, 6.84 mmol), and the mixture was stirred at room temperature for 5 hr. Water was added to the mixture, and the mixture was extracted with chloroform (70 mL). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 85/15) to give (E)-2-[8-(4-methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]acetohydrazide (309 mg, 100%). [step 2] (E)-2-[8-(4-Methyl-2-propylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]acetohydrazide (118 mg, 0.25 mmol) obtained in step 1 was dissolved in dichloromethane (2.5 mL), N,N′-carbonyldiimidazole (120 mg, 0.74 mmol) was added, and the mixture was stirred at room temperature for 3 hr. Water was added to the mixture, and the mixture was extracted with ethyl acetate (80 mL). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 93/7) to give the title compound (compound 106) (30 mg, 25%).
Reaction SMILES: [C:1]([CH2:5][C:6]1([CH2:13][CH3:14])[C:11](=[O:12])[CH:10]=[CH:9][CH2:8][CH2:7]1)([O:3][CH3:4])=[O:2].S(C)C.[CH:18]([Mg]Br)=[CH2:19]>C1COCC1>[C:1]([CH2:5][C:6]1([CH2:13][CH3:14])[CH2:7][CH2:8][CH:9]([CH:18]=[CH2:19])[CH2:10][C:11]1=[O:12])([O:3][CH3:4])=[O:2]
Reactant: C=C[Mg]Br
Reactant: CCC1(CC(=O)OC)CCC=CC1=O
Solvent: CSC
Solvent: C1CCOC1
Product: C=CC1CCC(CC)(CC(=O)OC)C(=O)C1
Yield: 69 %

Procedure:
The enone, 6-carbomethoxymethyl-6-ethyl-2-cyclohexen-1-one, prepared by the process of Step (c) (58.1 mmol, 11.4 g), 5.81 mmol (1.194 g) of CuBr.Me2S and 11.7 ml of Me2S were stirred in 176 ml of THF at -40° C. under nitrogen and treated with 58.1 mmol (58.1 ml of 1M solution in THF) of vinylmagnesium bromide added dropwise over 45 minutes. The reaction was then quenched with 200 ml of 1M HCl (aq.) and extracted with 5×100 ml of petroleum ether. Drying (MgSO4) and flash chromatography afforded 8.96 g (39.9 mmol, 69% pale yellow oil) of product as a mixture of diastereomers. The diastereomers (56:44 ratio) were separated by preparative HPLC on a Prep 500A using a brand of silica gel available from Waters Associates, Milford, Ma., and designated "more polar isomer" and "less polar isomer."
Reaction SMILES: [C:1](N1C=CN=C1)(=[O:3])[CH3:2].[F:9][C:10]([F:32])([F:31])[O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]3[CH:23]=[C:24]([C:27]([NH:29][NH2:30])=[O:28])[CH:25]=[CH:26][C:21]=3[N:20]=[CH:19]2)=[CH:14][CH:13]=1>O1CCCC1>[C:1]([NH:30][NH:29][C:27]([C:24]1[CH:25]=[CH:26][C:21]2[N:20]=[CH:19][N:18]([C:15]3[CH:14]=[CH:13][C:12]([O:11][C:10]([F:9])([F:31])[F:32])=[CH:17][CH:16]=3)[C:22]=2[CH:23]=1)=[O:28])(=[O:3])[CH3:2]
Reactant: NNC(=O)c1ccc2ncn(-c3ccc(OC(F)(F)F)cc3)c2c1
Reactant: CC(=O)n1ccnc1
Solvent: C1CCOC1
Product: CC(=O)NNC(=O)c1ccc2ncn(-c3ccc(OC(F)(F)F)cc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
A mixture of N-acetylimidazole (264 mg, 2.4 mmol), 1-[4-(trifluoromethoxy)phenyl]-1H-benzimidazole-6-carbohydrazide (672 mg, 2.0 mmol) and tetrahydrofuran (20 mL) was stirred overnight at room temperature, and at 50° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the precipitate was collected by filtration to give the title compound (614 mg, yield 81%) as colorless crystals.