Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[N:4]=[CH:3]1.[Br:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15](F)[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:21]([O:11][C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[CH:3]=[N:4][C:5]=3[CH:10]=2)[CH:22]=1
Reactant: Cn1cnc2cc(O)ccc21
Reactant: COC(=O)c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Br)cc1Oc1ccc2c(c1)ncn2C
Temperature: 90 °C

Procedure:
1-methyl-1H-benzo[d]imidazol-5-ol (296 mg), methyl 4-bromo-2-fluorobenzoate (311 mg) and potassium carbonate (553 mg) were combined in dimethylsulfoxide and heated to 90° C. overnight. The reaction mixture was diluted with ethyl acetate and washed thoroughly with water and with brine, dried over MgSO4, filtered and concentrated.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[C:18]([Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[C:17]([F:27])=[CH:16][N:15]=1.[Li+].CC([N-]C(C)C)C.[CH3:36][C:37](N(C)C)=[O:38].Cl>C1COCC1.[Cl-].[Na+].O.COC(C)(C)C.O>[Br:13][C:14]1[N:15]=[C:16]([C:37](=[O:38])[CH3:36])[C:17]([F:27])=[C:18]([Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:19]=1
Reactant: CC(=O)N(C)C
Reactant: CC[Si](CC)(CC)c1cc(Br)ncc1F
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CC(C)NC(C)C
Product: CC[Si](CC)(CC)c1cc(Br)nc(C(C)=O)c1F
Reaction time: 1.17 h
Yield: 91 %

Procedure:
To a solution of diisopropylamine (25.4 g, 251 mmol) in THF (500 ml) was added n-BuLi (100 ml, 2.5 mol/L in hexanes) below −50° C. A solution of 2-bromo-5-fluoro-4-triethylsilanyl-pyridine (56.04 g, 193 mmol) in THF (60 ml) was added to the LDA-solution at −78° C. in a dropwise manner below −65° C. After 70 minutes at −78° C. DMA (23.51 ml, 251 mmol) was added dropwise in a fast manner to the deep red solution keeping the temperature below −57° C. After 15 minutes the cooling bath was removed and the reaction mixture was allowed to reach −40° C. The cold reaction mixture was poured on a mixture of 2M aq. HCl (250 ml)/water (200 ml)/brine (100 ml). Tert.-butyl methyl ether was added and the layers were separated. The organic phase was washed twice with brine, dried over magnesium sulfate, filtered and evaporated to give a yellow oil. The crude product (64.76 g) was chromatographed over silica gel (hexane/TBME) to give the title compound as a yellow liquid: 58.3 g (91% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5](O)=[O:6].[CH3:29][O:30][CH2:31][CH2:32][NH2:33]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:21][CH2:22]1)[N:14]=2)[C:5]([NH:33][CH2:32][CH2:31][O:30][CH3:29])=[O:6]
Reactant: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: COCCN
Product: COCCNC(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
The title compound was synthesized using the procedure described in Example 105 above, with 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzoic acid (97 mg, 0.248 mmol) and 2-methoxyethylamine (26 μl, 0.298 mmol). MS (ESI) m/z: Calculated: 447.1; Observed: 448.1 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[C:34]([C:36]1[CH:37]=[C:38]([S:43](Cl)(=[O:45])=[O:44])[CH:39]=[CH:40][C:41]=1[F:42])#[N:35]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([S:43]([C:38]2[CH:39]=[CH:40][C:41]([F:42])=[C:36]([C:34]#[N:35])[CH:37]=2)(=[O:44])=[O:45])[C:6]=1[CH3:14]
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(F)c(C#N)c2)c2ncccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (0.5 g, 2.45 mmol) in DMF (3 mL) is added BEMP (1.13 mL, 3.92 mmol). After 1 hour, a solution of 3-cyano-4-fluoro-benzenesulfonyl chloride (0.86 g, 3.92 mmol) in DMF (3 mL) is added. The reaction mixture is stirred at room temperature overnight, then concentrated under reduced pressure to a minimum volume. The residue is loaded onto a pre-packed Isolute™ silica column and eluted using a gradient eluent from 100% iso-hexane to 50% EtOAc in iso-hexane to afford [1-(3-cyano-4-fluoro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester; MH+=388.
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]1[C:13]([Cl:14])=[N:12][C:11]([C:15]#[N:16])=[C:10]([C:17]#[N:18])[N:9]=1.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([SH:26])[CH:21]=1>ClCCCl>[Cl:14][C:13]1[N:12]=[C:11]([C:15]#[N:16])[C:10]([C:17]#[N:18])=[N:9][C:8]=1[S:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH3:19])[CH:21]=1
Reactant: N#Cc1nc(Cl)c(Cl)nc1C#N
Reactant: Cc1cccc(S)c1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1cccc(Sc2nc(C#N)c(C#N)nc2Cl)c1
Reaction time: 0.25 h

Procedure:
Pyridine (2.37 g) was mixed rapidly with a solution of 6.00 g of 2,3-dichloro-5,6-dicyanopyrazine in 240 ml of 1,2-dichloroethane. After 15 minutes the well stirred mixture, protected from moisture, was cooled to -30° and 3.72 g of m-thiocresol was added in one portion. The temperature was maintained at -30° for 0.5 hour and then was allowed to return to ambient over the course of 2 hours. The mixture was then washed with water to remove pyridine hydrochloride, dried over MgSO4, and concentrated on a rotary evaporator to a solid residue. The residue was purified by the technique of dry column chromatography using silica gel adsorbent and 1-chlorobutane as solvent and eluent. The yield of pure product was 6.9 g, mp 117°-119°.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19]C(=O)C)=[C:15]([O:23]C(=O)C)[CH:14]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(N(CC)CC)C>[CH2:1]([O:8][C:9](=[O:27])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:23])[CH:14]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Oc1ccc(C[C@H](N)C(=O)OCc2ccccc2)cc1OC(C)=O
Solvent: CCN(CC)CC
Product: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)OCc1ccccc1

Procedure:
First, carbobenzoxyglycyl-3,4-diacetyloxy-L-phenylalanine-benzyl ester was obtained in the manner which follows. Dichloromethane (100 ml) solution containing 0.95 g (9.4 millimole) of triethylamine was permitted to react with 3.64 g (8.92 millimole) of 3,4-diacetyloxy-L-phenylalanine-benzyl ester hydrochloride for 0.3 hours at room temperature. The solution was then concentrated in vacuo at room temperature to dryness. The residue obtained was filtered and washed with ether to give 1.54 g of triethylamine hydrochloride, contaminated with 3,4-diacetyloxy-L-phenylalanine-benzyl ester in various stages of deprotection. For instance, 3,4-dihydroxy-L-phenylalanine-benzyl ester was obtained quantitatively if a large excess of triethylamine was employed to neutralize the hydrochloride. The ether filtrate was concentrated in vacuo at room temperature. The resulting residue was analyzed by nmr and found to be consistent with the proposed structure, 3,4-diacetyloxy-L-phenylalanine-benzyl ester.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@@:15]4([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[C:4]([F:27])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)CCC.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:27][C:4]1[CH:3]=[C:2]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[CH:7]=[CH:6][C:5]=1[C:8]1([C:11]([N:13]2[CH2:17][CH2:16][C@@:15]3([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[C:19](=[O:26])[O:18]3)[CH2:14]2)=[O:12])[CH2:10][CH2:9]1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(Cl)cc4F)CC3)C2)c2ccccc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(-c5ccccn5)cc4F)CC3)C2)c2ccccc21

Procedure:
A mixture of (1R)-1′-{[1-(4-chloro-2-fluorophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (20 mg, purity: 80%, 0.04 mmol), 2-(tributylstannyl)-pyridine (17 mg, 0.046 mmol), Tris(dibenzylideneacetone)dipalladium(0) (2 mg, 0.002 mmol), tri-tert-butylphosphine (0.8 mg, 0.004 mmol), and cesium carbonate (16 mg, 0.05 mmol) in 1,4-dioxane (0.5 ml) was microwave irradiated at 100° C. for 30 minutes. The product was obtained from the mixture by prep-HPLC. LCMS: m/z 429.2 (M+H)+; 451.1 (M+Na)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl.Cl>CO>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: CC(C)N1CCN(c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
1-Isopropyl-4-(4-nitro-phenyl)-piperazine (8.3 g, 33.2 mmol) is dissolved in MeOH (120 mL) and tin (II) dichloride dihydrate (37.4 g, 0.165 mol) is added. The mixture is cooled using a water bath and conc. HCl is added (36 mL). The reaction is stirred at room temperature overnight. After removing the methanol, the resultant solution is basified using conc. NaOH (pH 11). The water phase is extracted with diethyl ether (3×) and the organic layers combined, dried over MgSO4, filtered, concentrated in vacuo to afford the title compound (6.4 g, 88%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: Sc1cccs1
Reactant: O=C(O)CCCCCBr
Product: O=C(O)CCCCCSc1cccs1

Procedure:
Method in which thiophene-2-thiol is reacted with 6-bromo hexanoic acid to obtain 6-(2-thienylsulfanyl)hexanoic acid represented by Chemical Formula [5].
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:27]=1[C:28](O)=[O:29])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[N:43]1(OC(N(C)C)=[N+](C)C)[C:47]2N=CC=C[C:46]=2[N:45]=N1.C(CN)O>CN(C=O)C>[NH2:43][CH2:47][CH2:46][NH:45][C:28]([C:27]1[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:26]=1[CH2:25][NH:24][C:22]([C:10]1[N:11]=[C:12]2[N:17]([C:18](=[O:19])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:16][CH2:15][O:14][C:13]2([CH3:21])[CH3:20])=[O:23])=[O:29]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C(=O)O)c(OCc1ccccc1)c2=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: NCCO
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C(=O)NCCN)c(OCc1ccccc1)c2=O
Reaction time: 0.33 h
Yield: 87 %

Procedure:
A mixture of intermediate 190, 2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorobenzoic acid, (59 mg, 0.12 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, HATU (76 mg, 0.2 mmol; Aldrich) in DMF (1 mL) was stirred for 20 min. To this mixture was added ethanolamine (20 mg, 0.3 mmol) and the stirring continued overnight. The mixture was concentrated in vacuo, dissolved in CH2Cl2, washed with water then dried (MgSO4), filtered, and concentrated to provide 55 mg (Yield 87%) of the title compound: LC/MS m/z 525 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C@@H:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][CH2:8]Cl.[NH4+:19].[OH-].CCO.C(O)(=O)/C=C\C(O)=O>CCOC(C)=O.C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C@@H:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][CH2:8][NH2:19]
Reactant: [NH4+]
Reactant: Fc1cccc(O[C@H](CCCl)c2ccccc2)c1
Agent: O=C(O)/C=C\C(=O)O
Agent: [OH-]
Solvent: CCO
Solvent: CC#N
Solvent: CCOC(C)=O
Product: NCC[C@@H](Oc1cccc(F)c1)c1ccccc1

Procedure:
A solution of (R)-3-(3-fluorophenoxy)-3-phenylpropyl chloride (0.971 g, 3.96 mmol), conc. NH4OH (30 mL), and EtOH (20 mL) were shaken at 90° C. on a Parr apparatus (50–90 psig) for 18 h. The mixture was then evaporated under vacuum and the residue was dissolved in Et2O (100 mL) and washed with H2O (2×25 mL). The organic layer was dried (anh. Na2SO4), filtered, and evaporated under vacuum to provide a yellow oil. This material was then dissolved in EtOAc (50 mL) and filtered. A solution of 30 maleic acid (0.272 g, 2.6 mmol, 0.93 equiv) dissolved in hot EtOAc (5 mL) was added to precipitate the maleate salt (519 mg, 53.5%) as a white solid: TLC Rf 0.25 (1% MeOH—CHCl3); GC, tr 7.37 min; MS, m/z 245 (M+). The synthesis of Compound 187 was accomplished as follows.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[C:6]1(=O)[O:11][C:9](=[O:10])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]2[C:6]1=[O:11])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: CC(C)CN1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of 3.2 cm3 of isobutylamine in 3 cm3 of toluene is added to a suspension of 5.2 g of phthalic anhydride in 50 cm3 of toluene, with stirring. The reaction mixture is heated at a temperature in the region of 60° C. for 1 hour, and then at a temperature in the region of 100° C. for 2 hours. Dean-Stark apparatus is then installed on the reactor and the reaction mixture is heated at a temperature in the region of 130° C. for 2 hours, after which it is cooled to a temperature in the region of 20° C. The reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up in 50 cm3 of saturated sodium bicarbonate solution and extracted twice with 75 cm3 of dichloromethane. The organic extracts are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 20° C. 6.5 g of N-isobutylphthalimide are thus obtained in the form of a white solid melting at 92° C.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23]>C(Cl)Cl>[CH3:20][C:21]([CH3:26])([CH3:25])[C:22]([O:1][NH:2][C:3]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:12])=[O:23]
Reactant: O=C(NO)OCc1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)ONC(=O)OCc1ccccc1

Procedure:
To a solution of benzyl hydroxycarbamate (1 g, 5.98 mmol) in DCM (20 ml) is added triethylamine (0.6 g, 5.98 mmol) and 2,2-dimethylpropanoyl chloride (0.74 ml, 5.98 mmol). After 2 hours the reaction mixture is quenched by the addition of water (10 ml) and the organics are extracted into DCM (2×20 ml), dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as a yellow oil which is used without any further purification. (1.6 g, 100%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.02 (1H, br. s.), 7.29-7.43 (5H, m), 5.22 (2H, s), 1.30 (9H, s).
Reaction SMILES: Cl.[CH2:2]([N:6]([CH3:24])[C:7](=[O:23])[C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][SiH2]C(C)(C)C(C)C)[CH2:3][CH2:4][CH3:5]>>[CH2:2]([N:6]([CH3:24])[C:7](=[O:23])[C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCN(C)C(=O)C#CCCCCCO[SiH2]C(C)(C)C(C)C
Agent: Cl
Product: CCCCN(C)C(=O)C#CCCCCCO
Temperature: 25 °C
Yield: 69 %

Procedure:
1 ml of 2N hydrochloric acid was added to a solution of 1.9 g of the product of Step C and the mixture was maintained for one hour at ambient temperature, then extracted with ethyl acetate. The extracts were washed with water, dried and evaporated to dryness under reduced pressure. The 1.79 g of residue were chromatographed on silica (eluant: ethyl acetate) to obtain 870 mg of the expected product.
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][N:12]1[CH2:13][CH2:14][C@H:9]([O:8][CH2:7][C:6]2[CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=[C:4]([C:3]([F:2])([F:28])[F:29])[CH:5]=2)[C@H:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11]1)[CH3:36]
Reactant: CCOC(=O)CBr
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Product: CCOC(=O)CN1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Yield: 42.8 %

Procedure:
The compound (0.21 g) obtained in Example 1 and ethyl bromoacetate (0.17 g) were reacted and treated in the same manner as in the method described in Example 7 to obtain the title compound as colorless oil (0.10 g, 42%).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30].C(N(CC)CC)C>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:27]=4[O:26][CH3:25])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: COc1cc(Cl)ccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Cl)ccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
As described for Example 9, a mixture of 0.377 g (1 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.295 g of 2-methoxy-4-chlorobenzoyl chloride, and 0.15 g of triethylamine in 10 ml of dichloromethane is stirred at room temperature for 3 hours. An additional 0.148 g of 2-methoxy-4-chlorobenzoyl chloride and 75 mg of triethylamine is added and the mixture stirred overnight. The solution is worked-up as for Example 9 to give 0.38 g of product (crystallized from dichloromethane-hexane) m.p. 237°-239° C.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:28][C:27]3[CH:30]=[CH:31][CH:32]=[C:25]([O:24][CH3:23])[CH:26]=3)[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: COc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(Cn2c(CC(F)(F)F)nc3cc(Cl)c(Cl)cc32)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (368 mg) in DMF (5 mL) was added potassium carbonate powder (567 mg) and 3-methoxybenzyl bromide (825 mg). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes), followed by dissolution in CH2Cl2 and trituration with hexanes to yield the title compound as a peach solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[C:11]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH2:27][C:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH3:39])=[CH:33][CH:32]=2)([CH3:30])[CH3:29])[CH:22]=[CH:23][CH:24]=1)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(OCC)(=O)C>CCOCC>[CH2:11]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH2:27][C:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH3:39])=[CH:33][CH:32]=2)([CH3:30])[CH3:29])[CH:22]=[CH:23][CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOc1ccc(C(C)(C)CC=Cc2cccc(C(=O)c3ccccc3)c2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOc1ccc(C(C)(C)CC=Cc2cccc(Cc3ccccc3)c2)cc1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
To 5 ml of dry ether was added 0.1 g of lithium aluminum hydride, and thereinto was added a solution of 0.7 g of aluminum chloride in 10 ml of dry ether. A solution of 0.54 g of 1-(3-benzoylphenyl)-4-(4-ethoxyphenyl)-4-methyl-1-pentene (prepared according to (1) of Synthesis Example 12) in 2 ml of dry ether was added dropwise into the mixture, and refluxed for 30 minutes. After cooling to room temperature, ethyl acetate was added dropwise into the mixture. And the mixture was poured into ice water, and extracted with benzene. The benzene extract was washed with water and dried, and evaporated under reduced pressure, and purified by column chromatography on silica gel (1:2 mixed solvent of benzene and hexane) to give 0.45 g of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:17][OH:18]>N1C=CC=CC=1>[OH:18][N:17]=[CH:4][C:3]1[CH:6]=[CH:7][C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:9][C:2]=1[OH:1]
Reactant: O=Cc1ccc(N2CCOCC2)cc1O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=Cc1ccc(N2CCOCC2)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.3 %

Procedure:
A solution of 2-hydroxy-4-morpholin-4-yl-benzaldehyde (0.135 g, 0.65 mmol) in pyridine (5 mL) was treated with hydroxylamine hydrochloride (45 mg, 0.65 mmol) and stirred for 30 min at room temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and 5% sodium bicarbonate. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the product as a pale yellow solid (51 mg, 35%).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.[C:22](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:22])=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Temperature: 25 °C

Procedure:
A suspension of 15.07 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 10.10 g of potassium carbonate in 260 ml of acetone is admixed with 5.43 ml of dimethyl sulphate and stirred at reflux over 7 hours. The reaction mixture is cooled to room temperature and concentrated by evaporation. The residue is partitioned between diethyl ether and a 1:1 25% conc. ammonia-water mixture. The organic phase is washed with water, 2N NaOH (2×) and brine, dried over sodium sulphate and concentrated by evaporation. The crude title compound is obtained as a white solid from the residue. Rf=0.30 (1:1 EtOAc-heptane); Rt=4.22.