Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC(C(O[CH:11]2[CH:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:15]([CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:14]([CH2:33][O:34][C:35](=[O:45])[C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)[CH2:13][O:12]2)=O)=CC=1)([O-])=O.[F:48][C:49]([F:64])([F:63])[C:50]1[CH:51]=[C:52]([C@H:60]([OH:62])[CH3:61])[CH:53]=[C:54]([C:56]([F:59])([F:58])[F:57])[CH:55]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[N+:42]([C:39]1[CH:38]=[CH:37][C:36]([C:35]([O:34][CH2:33][C@@H:14]2[C@@H:15]([CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:16]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C@@H:11]([O:62][C@@H:60]([C:52]3[CH:51]=[C:50]([C:49]([F:63])([F:64])[F:48])[CH:55]=[C:54]([C:56]([F:57])([F:58])[F:59])[CH:53]=3)[CH3:61])[O:12][CH2:13]2)=[O:45])=[CH:41][CH:40]=1)([O-:44])=[O:43]
Reactant: C[C@@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(OCC1COC(OC(=O)c2ccc([N+](=O)[O-])cc2)C(c2ccc(F)cc2)C1COCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@H](O[C@H]1OC[C@H](COC(=O)c2ccc([N+](=O)[O-])cc2)[C@@H](COCc2ccccc2)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -25 °C

Procedure:
The intermediate from example 1 step G (10.95 g, 17.0 mmol) was combined with (1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (4.39 g, 17.0 mmol) and dissolved in 170 mL DCM. The vessel was cooled to −25° C. followed by the addition boron trifluoride etherate (0.48 g, 3.4 mmol). The reaction vessel was maintained at −25° C. for 1 hr. The reaction was quenched by the addition of a saturated solution of NaHCO3 and the mixture was allowed to warm to ambient temperature. The aqueous mixture was extracted several times with EtOAc and washed with brine, dried over Na2SO4, filtered through a fritted funnel and concentrated in vacuo. The crude residue was purified on silica gel and eluted toluene. The first component collected off the column was the unwanted diastereomer. The second component collected was the desired diastereomer and was determined to be 85% pure as determined by 1HNMR. The product was recrystallized from cold methanol to provide the pure title compound. 1H-NMR (CDCl3): δ 1.41 (d, 3H, J=6.5 Hz), 1.76-1.84 (m, 1H), 2.50-2.62 (m, 1H), 3.02 (dd, 1H, J=9.0, 12.0 Hz), 3.07 (dd, 1H, J=3.0, 9.5 Hz), 3.41 (dd, 1H, J=2.5, 10.0 Hz), 3.54 (dd, 1H, J=11.5, 11.5 Hz), 4.26-4.36 (m, 5H), 4.56 (dd, 1H, J=3.5, 11.0 Hz), 4.99 (q, 1H, J=6.5 Hz), 6.92-7.06 (m, 4H), 7.20-7.36 (m, 7H), 7.71 (s, 1H), 8.19 (d, 2H, J=9.0 Hz), 8.31 (d, 2H, J=9.0 Hz) ppm.
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])[CH3:2].C([Cu])#N.[C:9]1([C:15]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:19]3[O:27][CH2:28][O:29][C:18]3=[CH:17][C:16]=2[CH2:30][C@@H:31]2[O:33][CH2:32]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCCCCC>CCCCC.C1COCC1>[CH3:2][C:1]([CH3:4])([CH3:3])[CH2:32][C@@H:31]([OH:33])[CH2:30][C:16]1[CH:17]=[C:18]2[O:29][CH2:28][O:27][C:19]2=[C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: [Li]C(C)(C)C
Reactant: c1ccc(-c2c(C[C@H]3CO3)cc3c(c2-c2ccccc2)OCO3)cc1
Agent: N#C[Cu]
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)C[C@@H](O)Cc1cc2c(c(-c3ccccc3)c1-c1ccccc1)OCO2
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
t-Butyl lithium (21.4 mL of a 1.7M solution in pentane, 36.4 mmol) was added dropwise to a suspension of CuCN (1.63 g, 18.2 mmol) in 120 mL of THF at -78° C. The mixture was stirred for 30 min and allowed to warm to -10° C. A soultion of 8.01 g (2S)-3-(2,3-diphenylmethylenedioxyphenyl)-1,2-epoxypropane (24.2 mmol) of (from step 3 above) in 20 mL of THF was added dropwise. The reactions was stirred for 18 hr, then quenched by addition of 100 mL of 9:1 saturated NH4Cl: conc. NH4OH. The mixture was stirred vigorously for 30 min and partitioned between 50 mL of water and 150 mL of ether. The aqueous phase was extracted twice with 50 mL of ether, and the combined layers were washed with water and saturated NH4Cl and dried over MgSO4. The solvents were removed under vacuum to give an amber oil. The oil was purified by flash chromatography over silica gel, eluting with 20% ethyl acetate:hexane to afford 5.95 g (63% yield) of the title compound as a yellow oil. MS (DCI/NH3) M/Z: 389 (M+H)+, 406 (M+NH4)+. 1H NMR (CDCl3, 300 MHz) δ: 0.95 (s, 9H), 1.45 (m, 2H), 2.73 (dd, 1H), 2.85 (dd, 1H), 4.08 (m, 1H), 6.65-6.8 (m, 3H), 7.37 (m, 6H), 7.57 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3[N:7]=[C:8]([C:14]#[N:15])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.C[O-].[Na+].CO[CH:23](OC)[CH2:24][NH2:25].C(O)(=O)C.Cl>CO.O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[NH:25][CH:24]=[CH:23][N:15]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: N#Cc1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: COC(CN)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: Brc1ccc2c(c1)OCCc1sc(-c3ncc[nH]3)nc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonitrile (0.100 g, 0.326 mmol;) in 1.0 ml of Methanol was added 25% Sodium methoxide (0.020 mL, 0.087 mmol;) in Methanol. The reaction was stirred 1 h rt. Aminoacetaldehyde dimethyl acetal (0.0390 mL, 0.358 mmol;) was added to the reaction mixture followed by Acetic acid (0.0370 mL, 0.651 mmol;). The reaction was heated at 50° C. for 1 h and then cooled to rt. Methanol (0.650 mL, 16.0 mmol;) and 6.00 M of Hydrogen chloride in Water (0.163 mL) were added, the reaction was heated 100 for 12 h. The reaction mixture was concentrated then added EtOAc and water. The combined organic layers was concentrated to give 8-Bromo-2-(1H-imidazol-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene. MS: (ESI+)=349.1
Reaction SMILES: C1COCC1.[CH2:6]([N:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C@H:15]2[C:27]([O:29]CC)=[O:28])=[CH:10][C:9]1=[O:32])[CH3:7].[OH-].[Li+]>CO>[CH3:24][C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][C@@H:14]([C:11]2[CH:12]=[CH:13][N:8]([CH2:6][CH3:7])[C:9](=[O:32])[CH:10]=2)[C@H:15]([C:27]([OH:29])=[O:28])[CH2:16]1)=[O:21])([CH3:25])[CH3:26]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1ccn(CC)c(=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCn1ccc([C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2C(=O)O)cc1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 3:2 (v/v) THF:MeOH solution (0.07 M) of trans-1-(1,1-dimethylethyl) 3-ethyl 4-(1-ethyl-2-oxo-1,2-dihydro-4-pyridinyl)-1,3-piperidinedicarboxylate (1 eq.) from the previous step was added lithium hydroxide (1 M aq. solution, 3.1 eq.). The resulting cloudy solution was stirred vigorously at RT for 18 h. The volatiles were then removed in vacuo and the residue was partitioned between EtOAc and 10% aq. HCl. The aqueous layer was separated and back-extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a white solid.
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[NH2:37][C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1>ClCCl>[CH2:7]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:37][C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1)=[O:20])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: Nc1ccncc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccncc1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 50 °C

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (51.5 mg, 0.186 mmol) in dry dichloromethane (5 mL) was added triethylamine (0.065 mL, 0.466 mmol), 2-chloro-1-methylpyridinium iodide (63.4 mg, 0.248 mmol), and 4-aminopyridine (19.2 mg, 0.204 mmol) sequentially at room temperature under nitrogen. The reaction was then heated to 50° C. for 1.5 hours. LC/MS showed reaction complete. The reaction mixture was concentrated and purified by HPLC on a 30×100 mm Waters Sunfire column to afford the title compound as an orange solid after lyophilization.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][C:12]3[O:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[NH2:26]>CN1CCCC1=O.C(=O)([O-])O.[Na+]>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[C:3]3[N:10]([CH2:11][C:12]4[O:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:13]=4)[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1
Reactant: CCOC(=O)c1ccc(Cn2ccc3ncnc(Cl)c32)o1
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1ccc(Cn2ccc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c32)o1
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
To a solution of ethyl 5-[(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]-2-furoate (300 mg) in 1-methyl-2-pyrrolidone (2.0 mL) was added 3-chloro-4-(pyridin-2-ylmethoxy)aniline (360 mg), and the mixture was heated to 140° C. and stirred for 1.5 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (30 mL) and extracted with a mixed solvent (45 mL×3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluent:ethyl acetate/methanol=10/0→8/2). The object fraction was concentrated under reduced pressure. Chloroform/diisopropyl ether (1/9) was added to the residue, and the resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (440 mg) as pale-yellow powder crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH:14]=1
Reactant: CN1CCCCC1=O
Reactant: Brc1ccc2[nH]ccc2c1
Product: CN1CC=C(c2c[nH]c3ccc(Br)cc23)CC1
Yield: 100.1 %

Procedure:
Following the procedure described in detail in Example 1, 30.0 gm (0.153 mole) 5-bromoindole and 38 mL (0.306 mole) 1-methylpiperidone were reacted together to prepare 44.6 gm (100%) of the desired compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[N:15]=[C:16]([S:19][CH2:20][C:21]([OH:23])=O)[NH:17][CH:18]=2)[CH:9]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:24]1([C:21](=[O:23])[CH2:20][S:19][C:16]2[NH:17][CH:18]=[C:14]([C:10]3[CH:9]=[N:8][CH:13]=[CH:12][CH:11]=3)[N:15]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)CSc1nc(-c2cccnc2)c[nH]1
Reactant: C1CCNCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(CSc1nc(-c2cccnc2)c[nH]1)N1CCCCC1

Procedure:
32 mg (0.069 mmol) of (4-(pyridin-3-yl)-1H-imidazol-2-ylsulfanyl)-acetic acid trifluoroacetic acid salt from step (b), 8.8 mg (0.1 mmol) of piperidine, 24.9 mg (0.076 mmol) TOTU and 15.9 mg (0.138 mmol) NEM in 4 ml of DMF were stirred at room temperature for 4 h. After evaporation, water and dichloromethane were added, the organic phase was separated, washed with water, dried, evaporated, and the product was purified by RP18 chromatography. Yield: 7 mg.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH:14]1([O:19][C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[CH:23]=O)[CH2:18][CH2:17][CH2:16][CH2:15]1>C1COCC1.CCOCC>[CH:14]1([O:19][C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[CH:23]=[CH:5][C:3]#[N:4])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C=CC#N)cc1OC1CCCC1
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a slurry of NaH (1.1 g, 27.5 mmol) in 80 mL of THF at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (4.42 g, 24.9 mmol) in 20 mL of THF. The mixture was stirred for 30 min, and a solution of 3-cyclopentoxy-4-methoxybenzaldehyde (5.0 g, 22.7 mmol) in 20 mL of THF was then added dropwise. The mixture was for 2 hr and then diluted with ether. The mixture was washed with 1M H3PO4, H2O, and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to yield 3-cyclopentoxy-4-methoxycinnamonitrile (4.8 g, 87%) as a yellow oil, which was carried on without further purification. 1H-NMR (300 MHz): δ 3.89 (s, 3), 5.69 (d, 1, J=16.6).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH2:5][CH2:6]2)=O.[C:10]([CH2:12]C(O)=O)#[N:11].[OH-].[NH4+].CN(C)C=O>C1C=CC=CC=1>[C:10]([CH2:12][CH:1]=[C:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH2:5][CH2:6]2)#[N:11]
Reactant: O=CC1CC2CCC1C2
Reactant: N#CCC(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: N#CCC=C1CC2CCC1C2
Yield: 78.7 %

Procedure:
A stirred solution of 95 g (0.77 mol) of 2-formylbicyclo[2.2.1]heptane, 65 g (0.76 mol) of cyanoacetic acid, 2 ml of ammonium hydroxide (58%), 132 ml of dimethylformamide, and 170 ml benzene was heated to reflux and the water removed with a Dean-Stark trap. The reaction was allowed to continue until the evolution of carbon dioxide ceased (approx. 24 hrs.). Upon completion, the reaction was cooled and the solvent removed under reduced pressure. The residual oil was distilled under vacuum to give 88 g (79% yield) of 2-(2-cyanoethylidene)-bicyclo[2.2.1]heptane: b.p. 72°-80° C./1 mm; ir 2960, 2870, 2260, 1685, 1450, 1420, 1305, 920; nmr 1.15-2.8 (10H, m), 2.96 (2H, m), 4.9-5.4 (1H, m); ms 147.
Reaction SMILES: C([BH3-])#N.[Na+].C[Si](Cl)(C)C.[CH2:10]([S:12][C:13]1[N:14]([CH3:31])[N:15]=[C:16]2[C:21]=1[CH:20]=[CH:19][CH:18]=[C:17]2[C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=1[CH3:30])[CH3:11].[OH-:32].[Na+].C1C[O:37]CC1>>[CH2:10]([S:12]([C:13]1[N:14]([CH3:31])[N:15]=[C:16]2[C:21]=1[CH:20]=[CH:19][CH:18]=[C:17]2[C:22]1[C:23]([CH3:30])=[CH:24][C:25]([CH3:29])=[CH:26][C:27]=1[CH3:28])(=[O:37])=[O:32])[CH3:11]
Reactant: C1CCOC1
Reactant: CCSc1c2cccc(-c3c(C)cc(C)cc3C)c2nn1C
Reactant: [OH-]
Agent: C[Si](C)(C)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCS(=O)(=O)c1c2cccc(-c3c(C)cc(C)cc3C)c2nn1C
Yield: 41 %

Procedure:
A mixture of sodium cyanoborohydride (0.276 g, 4.39 mmol), 5 mL of THF, and TMSCl (0.56 mL, 4.4 mmol) was stirred for 10 m, then 45 (0.780 g, 3.67 mmol) in 10 mL of THF was slowly added. The mixture was stirred for 1 h, then 15 mL of a 2 M aqueous NaOH solution were added. The mixture was extracted with 40 mL of diethyl ether, and the organic layer was washed with two 20 mL portions of a saturated aqueous NaCl solution, dried over Na2SO4, filtered, and concentrated. Column chromatography (0→20% EtOAc/hexanes) afforded N′-cyclopropylmethyl-N-ethyl-hydrazinecarboxylic acid tert-butyl ester (46; 0.323 g; 41%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=3)[C:21]([O:23]CC)=[O:22])=[CH:14][C:12]=2[CH:13]=1.[OH-].[Na+]>C(O)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=3)[C:21]([OH:23])=[O:22])=[CH:14][C:12]=2[CH:13]=1
Reactant: CCOC(=O)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H]1CCCN1CCc1cc2cc(-c3cccc(C(=O)O)c3)ccc2o1
Temperature: 55 °C

Procedure:
The product from Example 143C (755 mg, 2 mmol) was dissolved into ethanol (20 mL) and treated with 2 M aqueous NaOH (2 mL). The mixture was heated at 55° C. for 40 minutes, cooled to room temperature, concentrated, and partitioned between isopropanol and a mixture of 1 M aqueous potassium dihydrogen phosphate and brine. The aqueous phase was separated and extracted with isopropanol, and the combined organic phases were washed with a mixture of pH 6 potassium phosphate buffer and brine. The aqueous phase was separated and extracted with isopropanol, and the combined organic phases were washed with brine. Again, the aqueous phase was separated and extracted with isopropanol, and the combined organic phases were diluted with EtOAc, and filtered. The filtrate was dried (Na2SO4) and concentrated. The residue was chromatographed on silica with 50% EtOAc/CH2Cl2, followed by 10% MeOH/45% EtOAc/CH2Cl2, followed by 30% MeOH/CH2Cl2. The appropriate fractions were concentrated and the residue dissolved into EtOAc/CH2Cl2, and the solids which precipitated were washed with additional EtOAc/CH2Cl2 to provide the title compound as a white powder. MS (ESI APCI) m/z 350 (M+H)+; 1HNMR (300 MHz, CD3OD) δ 1.39 (s, 3 H), 1.58-1.76 (m, 1 H), 1.91-2.10 (m, 2 H), 2.16-2.31 (m, 1 H), 2.89-3.04 (m, 1 H), 3.08-3.3 (m, 4 H), 3.50-3.71 (m, 2 H), 6.70 (s, 1 H), 7.39-7.59 (m, 3 H), 7.69 (d, 1 H), 7.79 (s, 1 H), 7.92 (d, 1 H), 8.23 (s, 1 H).]
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].Cl[CH2:25][C:26]1[O:30][C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][CH:27]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:14]([CH2:25][C:26]3[O:30][C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][CH:27]=3)[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Reactant: CCOC(=O)c1ccc(CCl)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Cn2c(N3CCCN(C(=O)OCC)CC3)nc3ccccc32)o1
Reaction time: 72 h

Procedure:
Combine 1-ethoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane (10 mmol) and sodium hydride (10 mmol) in dimethylformamide (20 mL). After gas evolution ceases, add ethyl 5-chloromethyl-2-furoate (10 mmol) and stir. After 3 days, evaporate in vacuo to give a residue. Combine the residue and ethyl acetate. Extract with water and brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give 1-ethoxycarbonyl-4-(1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:7]=[C:8](Br)[CH:9]=[C:10]3[C:14]=2[NH:13][N:12]=[CH:11]3)=[CH:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2.C(N(CC)CC)C.[CH3:27][OH:28].CN(C)[CH:31]=[O:32]>>[CH3:27][O:28][C:31]([C:8]1[CH:9]=[C:10]2[C:14](=[C:6]([C:5]3[S:1][C:2]4[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=4[CH:4]=3)[CH:7]=1)[NH:13][N:12]=[CH:11]2)=[O:32]
Reactant: CN(C)C=O
Reactant: CO
Reactant: Brc1cc(-c2cc3ccccc3s2)c2[nH]ncc2c1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(-c2cc3ccccc3s2)c2[nH]ncc2c1
Temperature: 90 °C
Yield: 80 %

Procedure:
A solution of 7-benzo[b]thiophen-2-yl-5-bromo-1H-indazole (Preparation #26, 4.5 g, 13.7 mmol) in N,N-dimethylformamide (100 mL) was degassed and purged with carbon monoxide. Triethylamine (4.1 g, 41 mmol), methanol (13.1 g, 410 mmol) and dichloro[bis(triphenylphosphine)]palladium (II) (1.45 g, 2.05 mmol) were added and the mixture was heated to about 90° C. for about 15 hours. The mixture was cooled and the solvent was removed under reduced pressure. The residue was triturated with ethyl acetate (75 mL) and water (35 mL) then further purified by flash chromatography over silica gel using dichloromethane/ethyl acetate (95:5) as the eluent to give methyl-7-benzo[b]thiophen-2-yl-1H-indazole-5-methanoate (3.37 g, 80%).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].Br[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:24][C:25]([F:28])([F:27])[F:26])[C:19]=2[F:23])[CH:14]=1.C1(C)C=CC=CC=1>CN(C)C=O.[Cu](I)I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:19]1[C:20]2[C:15](=[CH:14][C:13]([C:11]#[C:10][C:7]3[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=3)=[CH:22][CH:21]=2)[CH:16]=[CH:17][C:18]=1[O:24][C:25]([F:28])([F:27])[F:26]
Reactant: Fc1c(OC(F)(F)F)ccc2cc(Br)ccc12
Reactant: C#Cc1ccc(CCC)cc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCc1ccc(C#Cc2ccc3c(F)c(OC(F)(F)F)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 36.6 %

Procedure:
10 g of 4-propyl-1-ethynylbenzene and 19.5 g of 2-bromo-5-fluoro-6-trifluoromethoxynaphthalene were dissolved in 50 ml of N,N-dimethylformamide (DMF). To the solution wore then added 50 mg of copper iodide (I) and 100 mg of tetrakis(triphenylphosphine)palladium (0). The reaction mixture was then stirred at room temperature for 5 hours. To the reaction solution was then added toluene. Insoluble matters were removed by filtration. The residue was then washed with water and saturated brine. The solvent was then distilled off. The residue was purified through silica gel column chromatography (hexane/ethyl acetate 9/1), and then recrystallized from ethanol to obtain 8.6 g of 1-fluoro-2-trifluoromethoxy-6-[(4-propylphenyl)ethynyl]naphthalene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([Cl:13])=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[C:14]([O:19]CC)(=[O:18])/[CH:15]=[CH:16]/[CH3:17].CC(C)([O-])C.[K+].Cl>CN1CCCC1=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:17][CH:16]=[CH:15][C:14]([OH:19])=[O:18])[C:8]([Cl:13])=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: C/C=C/C(=O)OCC
Reactant: COc1cc(Cl)c(C=O)cc1OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc(Cl)c(C=CC=CC(=O)O)cc1OC

Procedure:
To a solution containing 10.0 g 3,4 dimethoxy-6-chlorobenzaldehyde and 8 mlof ethyl crotonate in 60 ml of N-methylpyrrolidone 6.0 g of potassium tert.-butoxide was added while stirring. The solution was stirred for 0.5 h more at 20° C. and poured then to a mixture of ice and hydrochloric acid. The solution was extracted with ether. The ether solution was washed with water and extracted with 2.5 N NaOH-solution. Theaqueous phase was acidified with hydrochloric acid and the semisolid product was separated. Yield 10.8 g (81%).
Reaction SMILES: CN(C)C([Cl:5])=O.ClC1C=CC(N[C:13]2[C:22]3[C:17](=[CH:18][C:19](OCCNC)=[C:20](OC)[CH:21]=3)[N:16]=[CH:15][N:14]=2)=C(F)C=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:5].[N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[N:14][CH:15]=1
Reactant: CN(C)C(=O)Cl
Reactant: CNCCOc1cc2ncnc(Nc3ccc(Cl)cc3F)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cl
Product: c1ccc2ncncc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 120 %

Procedure:
Dimethylcarbamyl chloride (38 μl, 0.42 mmol) was added to a solution of 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methylaminoethoxy)quinazoline (150 mg, 0.4 mmol), (prepared as described for the starting material in Example 60), and triethylamine (61 μl, 0.44 mmol) in methylene chloride (4 ml). The mixture was stirred for 2.5 hours at ambient temperature, the resulting precipitate was collected by filtration and washed with ether. The solid was purified by column chromatography, eluting with methylene chloride/methanol (92/8). The purified product was dissolved in methylene chloride/methanol (1/1), 2.9M ethereal hydrogen chloride (1 ml) was added and the volatiles were removed by evaporation. The residue was triturated with ether and the solid product collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-N′,N′,N′-trimethylureido)ethoxy)quinazoline hydrochloride (80 mg, 41%).