Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[S:13][CH:14]=[C:15]([CH3:17])[N:16]=1)[C:5]([O:7]C)=[O:6].[OH-].[Li+]>O1CCOCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[S:13][CH:14]=[C:15]([CH3:17])[N:16]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(-c2nc(C)cs2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1csc(-c2ccc(C(=O)O)cc2C)n1

Procedure:
To a solution of methyl 3-methyl-4-(4-methylthiazol-2-yl)benzoate (Step A, 6.0 g, 22.96 mmol) in 1,4-dioxane (5 mL) was added lithium hydroxide (1.65 g, 68.9 mmol) in water (5 mL). Once the reaction was deemed complete by LCMS, it was concentrated in vacuo. The residual white solid was washed with a mixture of dichloromethane/methanol (1/1), and filtered. The filtrate was concentrated to give the title compound as a white solid which was used in the next step without further purification. LCMS (M+H)+: 234.1
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.C1(C)C=CC=CC=1.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>ClCCl>[N:25]([C:24]1[CH:26]=[CH:27][CH:28]=[C:22]([C:21]([F:20])([F:29])[F:30])[CH:23]=1)=[C:5]=[O:11]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C=Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Triphosgene (0.75 g) was added to anhydroue toluene (10 ml) under nitrogen protection, and then a solution of 3-trifluoromethylaniline (0.8 g) in dichloromethane (15 ml) was added dropwise in an ice-bath. After addition, the reaction mixture was stirred at room temperature for 15 min, and then heated to 80° C. for 6 h. The completion of the reaction was indicated by TLC. The reaction mixture was concentrated under reduced pressure to give the product as oil, which then was solidified.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.O.[B-](F)(F)(F)[F:19].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[F:19]
Reactant: COC(=O)c1cc(-c2ccnn2C)c(Cl)s1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(-c2c(F)cnn2C)c(Cl)s1
Reaction time: 12 h
Yield: 24.3 %

Procedure:
To a solution of methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (250 mg, 0.974 mmol)[prepared according to the procedure in Example 95] in acetonitrile (4.864 ml) and H2O (486 μl) was added selectfluor (449 mg, 1.27 mmol). The resulting solution was stirred at 70° C. in a sealed tube for 1 h after which additional selectfluor (449 mg, 1.266 mmol) was added in one portion. After stirring 12 h, the solution was partitioned between H2O-DCM. The aqueous phase was washed several times with DCM-THF and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 10% EtOAc in hexanes) affording methyl 5-chloro-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (65 mg, 0.237 mmol, 24.30% yield) as a yellow solid; LCMS (ES) m/z 274, 276 (M, M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[C:16]([CH:18]([O:21][CH3:22])[C:19]#[CH:20])[CH:15]=[C:14]([O:23][CH3:24])[C:13]=1[O:25][CH3:26]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:20]#[C:19][CH:18]([O:21][CH3:22])[C:16]2[CH:15]=[C:14]([O:23][CH3:24])[C:13]([O:25][CH3:26])=[C:12]([O:11][CH3:10])[CH:17]=2)=[CH:4][N:3]=1
Reactant: C#CC(OC)c1cc(OC)c(OC)c(OC)c1
Reactant: Nc1ncc(I)c(N)n1
Product: COc1cc(C(C#Cc2cnc(N)nc2N)OC)cc(OC)c1OC
Yield: 90 %

Procedure:
2,4-Diamino-5-iodopyrimidine (236 mg) was allowed to react with 1,2,3-Trimethoxy-5-(1-methoxyprop-2-ynyl)benzene (473 mg) as per the general procedure to afford 2,4-Diamino-5-(3-methoxy-3-(3,4,5-trimethoxyphenyl)prop-1-ynyl)pyrimidine as an orange powder (310 mg, 90%): Rf=0.31 (9:1, CHCl3:MeOH); mp=184-186° C.; 1H NMR (DMSO-d6) δ 7.91 (s, 1H), 6.82 (s, 2H), 6.40 (s, 2H), 5.30 (s, 1H), 3.79 (s, 6H), 3.66 (s, 3H), 3.35 (s, 3H); 13C NMR (DMSO-d6) δ 163.8, 162.3, 159.7, 152.8, 137.2, 134.8, 104.6, 92.6, 89.1, 81.9, 73.0, 60.0, 55.9, 55.4; Anal. (C17H20N4O4) C, H, N.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][C:6](=[O:8])[NH:5][C:4]=1[C:9]([OH:11])=O)[CH3:2].[CH3:12][C:13]1[N:14]([C:18]2[CH:26]=[CH:25][C:21](C(O)=O)=[CH:20][CH:19]=2)[CH:15]=[CH:16][N:17]=1>>[CH2:1]([C:3]1[NH:7][C:6](=[O:8])[NH:5][C:4]=1[C:9](=[O:11])[C:21]1[CH:25]=[CH:26][C:18]([N:14]2[CH:15]=[CH:16][N:17]=[C:13]2[CH3:12])=[CH:19][CH:20]=1)[CH3:2]
Reactant: CCc1[nH]c(=O)[nH]c1C(=O)O
Reactant: Cc1nccn1-c1ccc(C(=O)O)cc1
Product: CCc1[nH]c(=O)[nH]c1C(=O)c1ccc(-n2ccnc2C)cc1

Procedure:
In a manner similar to Example I react 2,3-dihydro-5-ethyl-2-oxo-1H-imidazole-4-carboxylic acid with 4-(2-methyl-1H-imidazol-1-yl)benzoic acid to produce the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([OH:15])=[O:14])=[C:8]([OH:16])[CH:7]=[CH:6]2)#[N:2].C(#N)C.[CH3:20][N:21]([CH3:26])[C:22]([CH2:24]Br)=[O:23]>C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([O:15][CH2:24][C:22](=[O:23])[N:21]([CH3:26])[CH3:20])=[O:14])=[C:8]([OH:16])[CH:7]=[CH:6]2)#[N:2]
Reactant: CN(C)C(=O)CBr
Reactant: N#Cc1ccc2c(C(=O)O)c(O)ccc2c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C)C(=O)COC(=O)c1c(O)ccc2cc(C#N)ccc12
Temperature: 70 °C
Reaction time: 24 h
Yield: 78.5 %

Procedure:
To 28.4 g of 6-cyano-1-carboxy-2-naphthol were added 350 ml of acetonitrile, 18 ml of triethylamine and 33.2 g of dimethylcarbamoylmethyl bromide, followed by stirring for 24 hours at 70° C. and further 24 hours at room temperature. The resulting precipitate was collected by filtration and washed with water to obtain 31.2 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=O)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:15][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(C(=O)N3CCOCC3)CCOCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccc(C2(CN3CCOCC3)CCOCC2)cc1
Yield: 87 %

Procedure:
The title compound (2.48 g, 87%) was prepared using 4-{[4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl]carbonyl}morpholine and lithium aluminium hydride similarly to the procedure used for example 142. HRMS ESI+ m/z 292.1897 [MH]+.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]2[C:7]3=[CH:11][S:12][C:13]([N:14]4C(=O)C5C(=CC=CC=5)C4=O)=[C:6]3[C:5](=[O:25])[C:4]=2[CH:3]=1.O.NN.[CH2:29](O)C>>[NH2:14][C:13]1[S:12][CH:11]=[C:7]2[C:8]3[C:9]([CH3:29])=[CH:10][CH:2]=[CH:3][C:4]=3[C:5](=[O:25])[C:6]=12
Reactant: CCO
Reactant: O=C1c2cc(Cl)ccc2-c2csc(N3C(=O)c4ccccc4C3=O)c21
Agent: NN
Solvent: O
Product: Cc1cccc2c1-c1csc(N)c1C2=O
Temperature: 25 °C

Procedure:
To a suspension of 2-(6-chloro-8-oxo-8H-2-thia-cyclopenta[a]inden-1-yl)-isoindole-1,3-dione (0.45 mmol, Example 10, Part E) in absolute ethanol (5 mL) is added hydrazine hydrate (0.5 mmol). The mixture is heated to reflux for one hour, cooled to room temperature, concentrated in vacuo, and the residue dissolved in methylene chloride. The solution is chilled to 5° C. for one hour, during which time the phthaloyl hydrazide precipitates. The precipitate is removed by filtration, the filtrate concentrated in vacuo, and the residue purified by column chromatography on silica gel, eluting with a 4:1 mixture of petroleum ether and ethyl acetate. Fractions containing the product are collected, evaporated, and the product recrystallized.
Reaction SMILES: O[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.O=S(Cl)[Cl:12]>C(Cl)Cl>[Cl:12][CH2:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ncccc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ncccc1CCl
Reaction time: 4 h

Procedure:
To a stirred solution of 3-hydroxymethyl-2-methylpyridine (1.00 g, 8.13 mmol) from step 1 above in CH2Cl2 (40 mL) at ambient temperature was added SOCl2 (9.5 g, 80 mmol). The mixture was stirred for 4 h, and the solvent and excess SOCl2 were evaporated under reduced pressure. The residue was partitioned between CH2Cl2 (50 mL) and saturated aqueous NaHCO3 (100 mL). The organic layer was separated, and the aqueous layer was washed with additional CH2 Cl2 (2×40 mL). The combined organic layers were evaporated under reduced pressure to give 3-chloromethyl-2-methyl-pyridine as a solid which was used in the next step without purification (TLC: Rf = 0.85 (95:5 CH2Cl2 :MeOH); FAB MS m/z 142 (M+ +H)).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](=[O:33])[CH2:11][C@H:12]1[C:16]2[CH:17]=[CH:18][C:19]([O:21][C@H:22]3[C:30]4[C:25](=[C:26]([OH:32])[CH:27]=[CH:28][C:29]=4[F:31])[CH2:24][CH2:23]3)=[CH:20][C:15]=2[O:14][CH2:13]1.[C:34]1(B(O)O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH3:8][O:9][C:10](=[O:33])[CH2:11][C@H:12]1[C:16]2[CH:17]=[CH:18][C:19]([O:21][C@H:22]3[C:30]4[C:25](=[C:26]([O:32][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH:27]=[CH:28][C:29]=4[F:31])[CH2:24][CH2:23]3)=[CH:20][C:15]=2[O:14][CH2:13]1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccccc5)ccc(F)c43)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Triethylamine (0.4 mL) is added to a mixture of {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (0.15 g), phenylboronic acid (0.10 g), freshly activated molecular sieves 4A (1.0 g), copper(II) acetate (78 mg) and dichloromethane (8 mL) at room temperature. The flask is purged with O2 and sealed. The mixture is stirred under O2 atmosphere (1 bar) at room temperature for 16 h. The mixture is diluted with dichloromethane, filtered and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→80:20) to give the title compound. LC (method 3): tR=0.81 min; Mass spectrum (ESI+): m/z=435 [m+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([C:8]([CH3:11])=[CH:9][CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:17])=O.N1C=CC=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([C:8]([CH3:11])=[CH:9][CH:10]=1)[C:5]([Cl:17])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C)c([N+](=O)[O-])c1C(=O)O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(C)c([N+](=O)[O-])c1C(=O)Cl

Procedure:
3,6-Dimethyl-2-nitrobenzoic acid in an amount of 9.6 g (51 mmol) was dissolved in 100 ml benzene and then followed by an addition of thionyl chloride in an amount of 8.8 g (74 mmol) and pyridine in an amount of 0.1 lg. The mixture was then heated for 2 hours under reflux, and the solvent therein was distillated out under reduced pressure to obtain 3,6-dimethyl-2-nitrobenzoyl chloride in an amount of 10.3 g.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH3:8])=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:5][CH:4]=1)[CH3:2].[CH3:14][CH:15]1OC(C)OC(C)O1>>[CH2:14]([C:4]1[NH:5][C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([CH3:8])[C:3]=1[CH2:1][CH3:2])[CH3:15]
Reactant: CCOC(=O)c1[nH]cc(CC)c1C
Reactant: CC1OC(C)OC(C)O1
Product: CCOC(=O)c1[nH]c(CC)c(CC)c1C

Procedure:
As in Example 32 but using 3-ethyl-4-methyl-5-carbethoxy-pyrrole and paraldehyde. Colourless prisms (64%), m.p. 71°-73° (lit. 8) 73°-74°). Anal. Calc. for C12H19NO2 : C, 68.86; H, 9.15; N, 6.67. Found: C, 68.71; H, 9.11; N, 6.84.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=2)[N:9]=1.C(N(CC)CC)C.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>O1CCCC1>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([N:40]3[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]3)=[O:26])=[CH:22][CH:21]=2)[N:9]=1
Reactant: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(C(=O)c2ccc(-n3nc(-c4ccccc4O)nc3-c3ccccc3O)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3 g of 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-benzoic acid (Example 5) and 1.25 ml of 1-chloro-N,N-2-trimethyl-1-propen-1-amine are stirred for 2 h in 50 ml of tetrahydrofuran. 2.2 ml of triethylamine and 1 ml of N-methylpiperazine are added and the mixture is stirred at room temperature for 48 h. It is poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying, {4-[3,5-bis(2-hydroxy-phenyl)-[1,2,4]triazol-1-yl]-phenyl}-(4-methylpiperazin-1-yl)methanone remains as colorless crystals of m.p. 226-229° C.
Reaction SMILES: [NH:1]([C:5]1[NH:6][CH2:7][CH2:8][N:9]=1)[N+]([O-])=O.N[CH2:11][CH:12]([OH:20])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1>C1(C)C(C)=CC=CC=1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH:12]([OH:20])[CH2:11][NH:1][C:5]2[NH:6][CH2:7][CH2:8][N:9]=2)=[CH:14][CH:15]=1
Reactant: NCC(O)c1ccc(Cl)cc1
Reactant: O=[N+]([O-])NC1=NCCN1
Solvent: Cc1ccccc1C
Product: OC(CNC1=NCCN1)c1ccc(Cl)cc1

Procedure:
To 5.2 parts of 2-(nitramino)-2-imidazoline is added a solution of 7.5 parts of α-(aminomethyl)-p-chlorobenzyl alcohol in 40 parts of xylene while heating. Upon completion, stirring is continued while heating in an oil-bath at 150°-160°C. and while the xylene is partly distilled off (till gas evolution ceases). The residue is cooled and after the addition of a few parts of acetone, the produce is allowed to crystallize. It is filtered off, washed successively with acetone and diisopropylether, dried and the product is recrystallized from 4-methyl-2-pentanone, yielding p-chloro-α-(2-imidazolin-2-ylaminomethyl)benzyl alcohol; m.p. 156°-158°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:17][C:18]4[C:23]([N:24]=3)=[CH:22][C:21]([C:25]([O:27]C)=[O:26])=[CH:20][CH:19]=4)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:17][C:18]4[C:23]([N:24]=3)=[CH:22][C:21]([C:25]([OH:27])=[O:26])=[CH:20][CH:19]=4)[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4ccc(OC)cc4)CC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C2CCN(c3nc4cc(C(=O)O)ccc4nc3-c3ccccc3)CC2)cc1

Procedure:
To a solution of methyl 3-(4-(4-methoxyphenyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylate (179.6 mg, 0.36 mmol, 1.00 equiv, 90%) in methanol (17 mL) was added a solution of sodium hydroxide (80 mg, 2.00 mmol, 5.00 equiv) in water (2 mL) dropwise with stirring. The resulting solution was stirred for 7 h at 50° C. in an oil bath, then the pH of the solution was adjusted to 3-4 with 1N hydrochloric acid. The resulting mixture was concentrated under vacuum, followed by washing with methanol yielding 81.9 mg (50%) of 3-(4-(4-methoxyphenyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH2:8][O:9][CH3:10])[NH:5][C:6]=1[I:7].[H-].[Na+].[C:13]([NH:20][CH2:21][CH2:22]Br)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O>CN(C=O)C>[C:16]([O:15][C:13](=[O:14])[NH:20][CH2:21][CH2:22][N:3]1[C:2]([I:1])=[C:6]([I:7])[N:5]=[C:4]1[CH2:8][O:9][CH3:10])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: COCc1nc(I)c(I)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1nc(I)c(I)n1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4,5-diiodo-2-methoxymethyl-1H-imidazole (3.000 g; 8.244 mmol) in anhydrous DMF (35 ml) was added portionwise, at rt, 55-65% sodium hydride moistened with oil (395 mg; 9.895 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 20 min. The mixture was then heated to 100° C., and a colorless homogeneous solution of 2-(Boc-amino)-ethylbromide (2.032 g; 9.068 mmol) in anhydrous DMF (30 ml) was added dropwise, over 15 min., with an addition funnel. After completion of the addition, the resulting dark-orange homogeneous mixture was further heated at 100° C. for 1 h45. The reaction mixture was cooled to rt, and water (175 ml) was added slowly. This mixture was extracted with ether (4×120 ml). The combined organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. The crude was purified by FC (DCM/MeOH=50/1) to give the pure product [2-(4,5-diiodo-2-methoxymethyl-imidazol-1-yl)-ethyl]-carbamic acid tert-butylester as a pale yellow solid which was further dried under HV (3.050 g; 73%). LC-MS: tR=0.87 min.; [M+H]+=508.16 g/mol.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)[CH2:20]1>CS(C)=O>[C:33]([C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH2:25][N:21]2[CH2:22][CH2:23][CH2:24][C@@H:20]2[CH2:19][N:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=3[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]2=3)=[CH:32][CH:31]=1)#[N:34]
Reactant: c1ccc2c(c1)COc1ccccc1N2
Reactant: N#Cc1ccc(CCN2CCC[C@H](Cl)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1ccc(CCN2CCC[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 14.4 %

Procedure:
Three-hundred milligrams (7.5 mmols) of 60% sodium hydride were washed with petroleum ether, and then suspended in 30 ml of dimethyl sulfoxide. To the suspension were added 1.4 g (7.1 mmols) of 5,11-dihydrodibenzo[b,e][1,4]oxazepine. The mixture was stirred in a nitrogen atmosphere at room temperature for 40 minutes. To this reaction solution was added dropwise a solution of 1.7 g (6.8 mmols) of (S)-(+)-3-chloro-1-(4-cyanophenethyl)piperidine [[α]D25=+16.7° (c=0.5, ethanol)] in 10 ml of dimethyl sulfoxide, and the mixed solution was stirred at room temperature for 17 hours and at 40° C. for 6 hours. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water and with a saturated aqueous solution of sodium chloride in this order, and dried. Subsequently, the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography, and eluted with a mixed solvent of ethyl acetate and hexane at a ratio of 1:2. This mixed solvent was distilled off under reduced pressure to give 0.4 g of (R)-(+)-5,11-dihydro-5-[1-(4-cyanophenethyl)-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]oxazepine as a pale yellow oil in a yield of 14%.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([F:28])([F:27])[C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[CH:5]=[CH:4][C:3]=1[C:29]1[CH:34]=[CH:33][C:32]([C:35]([OH:37])=[O:36])=[CH:31][CH:30]=1.[F:38][C:39]([F:92])([F:91])[C@H:40]([O:47][C:48]([C:50]1[CH:55]=[CH:54][C:53](OC(C2C=CC(C3C=CC(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)=C(F)C=3F)=CC=2)=O)=[CH:52][CH:51]=1)=[O:49])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>>[F:38][C:39]([F:91])([F:92])[C@H:40]([O:47][C:48]([C:50]1[CH:51]=[CH:52][C:53]([O:36][C:35]([C:32]2[CH:33]=[CH:34][C:29]([C:3]3[CH:4]=[CH:5][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([F:27])([F:28])[C:17]([F:25])([F:26])[C:18]([F:23])([F:24])[C:19]([F:22])([F:20])[F:21])=[C:7]([F:8])[C:2]=3[F:1])=[CH:30][CH:31]=2)=[O:37])=[CH:54][CH:55]=1)=[O:49])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCC[C@@H](OC(=O)c1ccc(OC(=O)c2ccc(-c3ccc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c3F)cc2)cc1)C(F)(F)F
Reactant: O=C(O)c1ccc(-c2ccc(OCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c2F)cc1
Product: CCCCCC[C@@H](OC(=O)c1ccc(OC(=O)c2ccc(-c3ccc(OCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c3F)cc2)cc1)C(F)(F)F

Procedure:
2′,3′-Difluoro-4′-(7,7,8,8,9,9,10,10,10-nonafluoro-decyloxy)-biphenyl-4-carboxylic acid 4-[(R)-1-trifluoromethyl-heptyloxycarbonyl]-phenyl ester (15B) was prepared from 2′,3′-difluoro-4′-(7,7,8,8,9,9,10,10,10-nonafluoro-decyloxy)-biphenyl-4-carboxylic acid (14B) as described in the preparation 2′,3′-difluoro-4′-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-biphenyl-4-carboxylic acid 4-[(R)-1-trifluoromethyl-heptyloxycarbonyl]-phenyl ester (15A) yielding 2′,3′-difluoro-4′-(7,7,8,8,9,9,10,10,10-nonafluoro-decyloxy)-biphenyl-4-carboxylic acid 4-[(R)-1-trifluoromethyl-heptyloxycarbonyl]-phenyl ester (15B)) as a white solid (88%).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[Cl:23]>>[Cl:16][C:17]1[CH:18]=[C:19]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 3,4-dichlorophenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C16H10Cl2N4, 330. Found, 329, 331.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)([OH:3])=O.O>S1(CCCC1)(=O)=O>[CH3:18][C:15]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:1](=[O:3])[C:17]=2[CH:16]=1
Reactant: Cc1ccc(C=Cc2ccccc2C(=O)O)cc1
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: Cc1ccc2c(c1)C(=O)c1ccccc1CC2
Yield: 87.2 %

Procedure:
The acid from Step A (37.5 g) in sulfolane (200 ml) was heated to 110° C. and polyphosphoric acid (150 ml) added. After 1.5 hr at 110° C. the mixture was poured into water (500ml). extracted with hexane (3×200 ml) and the extract washed, dried, diluted with an equal volume of ether and percolated through silica (200 g). The eluate Was evaporated to afford 3-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one (30.5 g) as an oil. 60MHz NMR in deuterochloroform 2.35 (CH3), 3.20 ppm [(CH2)2 ].
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10]CC)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C=CC=CC=1.[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>>[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:8](=[O:10])[CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: Nc1ccccc1Cl
Reactant: CCOC(=O)C(C)C(=O)OCC
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1ccccc1Cl

Procedure:
The ester was prepared according to Procedure A using diethyl 2-methylmalonate (6.1 mL, 35.3 mmol), pyridine (3.80 mL, 47.0 mmol) and 2-chloroaniline (3.00 g, 23.52 mmol). The reaction mixture was heated for 6 days. The residue was purified by column chromatography on silica gel (0-30% EtOAc/hexanes) to give ethyl 3-(2-chlorophenylamino)-2-methyl-3-oxopropanoate. Mass Spectrum (ESI) m/e=256.1 (M+1).