Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=[C:13]2[OH:24].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:32][C:33]#[N:34]>CC(C)=O.CCOC(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]([F:22])([F:21])[F:23])[CH:14]=[C:13]2[O:24][CH2:32][C:33]#[N:34]
Reactant: Oc1cc(C(F)(F)F)nc2ccc(-c3cc4ccccc4o3)cc12
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: N#CCOc1cc(C(F)(F)F)nc2ccc(-c3cc4ccccc4o3)cc12
Reaction time: 18 h
Yield: 82.5 %

Procedure:
To a stirred solution of 6-(1-benzofuran-2-yl)-4-hydroxy-2-(trifluoromethyl)quinoline (0.770 g, 2.34 mmol) in acetone (40 mL) at room temperature was added Cs2CO3 (0.839 g, 2.57 mmol) followed by bromoacetonitrile (0.326 mL, 4.68 mmol) dropwise. The reaction was stirred at this temperature for 18 hours and then diluted with EtOAc (200 mL). The organic layer was washed with 1 N HCl (20 mL), sat. aq. NaHCO3 (20 mL), and brine (20 mL) and then dried (MgSO4). After concentration, the residue was recrystallized from EtOAc:Hexane to afford the product (0.711 g, 82%) as a off-white solid, mp 174-176° C. Mass spectrum (+APCI, [M+H]+) m/z 369. 1H NMR (500 MHz, DMSO-d6): δ 8.61 (d, 1H, J=2.0), 8.48 (dd, 1H, J=2.0, 8.8 Hz), 8.23 (d, 1H, J=8.8 Hz), 7.78 (s, 1H), 7.70-7.75 (m, 2H), 7.67 (s, 1H), 7.39 (t, 1H, J=7.2 Hz,), 7.30 (t, 1H, J=7.6 Hz), and 5.70 ppm (s, 2H), Elemental analysis for C20H11F3N2O2: Calculated: C, 65.22; H, 3.01; N, 7.61. Found: C, 65.02; H, 2.87; N, 7.51.
Reaction SMILES: CO[C:3](=[O:20])[C@@H:4]([N:6]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:7][CH:8]=O)[CH3:5].Cl.[CH3:22][O:23][C:24](=[O:30])[CH2:25][C@H:26]([OH:29])[CH2:27][NH2:28]>>[CH2:13]([O:12][C:10]([N:6]1[CH2:7][CH2:8][N:28]([CH2:27][C@@H:26]([OH:29])[CH2:25][C:24]([O:23][CH3:22])=[O:30])[C:3](=[O:20])[C@@H:4]1[CH3:5])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)C[C@H](O)CN
Reactant: COC(=O)[C@H](C)N(CC=O)C(=O)OCc1ccccc1
Agent: Cl
Product: COC(=O)C[C@H](O)CN1CCN(C(=O)OCc2ccccc2)[C@@H](C)C1=O
Yield: 59 %

Procedure:
In analogy to the procedure described in Example 12D, (S)-2-[benzyloxycarbonyl-(2-oxo-ethyl)-amino]-propionic acid methyl ester (intermediate 12C) and (S)-4-amino-3-hydroxy-butyric acid methyl ester, hydrochloride (intermediate 24) gave the titled compound in 59% yield as light yellow oil. MS: 365.17 (MH+).
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].C[O-].[Na+].Cl.Cl[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>CO>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][S:3][C:2]1[NH:1][CH2:7][C:5](=[O:6])[N:4]=1
Reactant: ClCc1ccccn1
Reactant: O=C1CNC(=S)N1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C1CNC(SCc2ccccn2)=N1

Procedure:
Initially, 1 g of 2-thiohydantoin and 2.5 g of sodium methylate were dissolved in 50 mL of methanol (MeoH), and 1.5 g of 2-chloromethylpyridine hydrochloride was added to the solution. The reaction mixture was stirred under reflux for one and a half hour and concentrated in vacuo. To the residue, there was added 50 mL of chloroform (CHCl3), and the mixture was washed with 50 mL of water. Then, the CHCL3 layer was dried over magnesium sulfate (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography [using a developing solvent consisting of CHCl3 :MeOH=50:1 (volume ratio, v/v)]. Recrystallization from diethylether gave the desired compound in the form of a needle-like crystal. The yield of this compound was 1.2 g with a yield ratio of 67.2%, and its melting point was 105°-107° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](O)=[CH:5][CH:4]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:41])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[CH:13][CH:12]=1.Cl>>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]([O:41][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:38])[CH3:39])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[CH:15][CH:16]=1
Reactant: COc1ccc(O)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(F)cc3)CC2)c1
Agent: Cl
Product: COc1ccc(OC(CCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(F)cc2)cc1

Procedure:
Prepared by Procedure A and Scheme AN using 4-methoxyphenol and N-(3-{1-(6-(4-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.11 (s, 1H), 7.65–6.84 (m, 12H), 5.21–5.10 (m, 1H), 3.66–3.56 (m, br, 2H), 3.02–2.82 (br, 2H), 2.82–2.56 (m, br, 4H), 2.54 (s, 3H), 2.53–2.32 (m, br, 2H), 2.02–1.70 (m, br, 6H), 1.64–1.48 (m, br, 1H), 1.48–1.34 (br, 3H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 547.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:11]2[CH:16]=[CH:15][C:14]([CH2:17]Br)=[CH:13][N:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:19]([O:21][C:22]([C:24]1[NH:25][C:26]([CH2:30][CH2:31][CH2:32][CH3:33])=[N:27][C:28]=1[Cl:29])=[O:23])[CH3:20]>>[CH2:19]([O:21][C:22]([C:24]1[N:25]([CH2:17][C:14]2[CH:13]=[N:12][C:11]([C:6]3([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][CH2:9][CH2:8][CH2:7]3)=[CH:16][CH:15]=2)[C:26]([CH2:30][CH2:31][CH2:32][CH3:33])=[N:27][C:28]=1[Cl:29])=[O:23])[CH3:20]
Reactant: CCOC(=O)C1(c2ccc(CBr)cn2)CCCC1
Reactant: CCCCc1nc(Cl)c(C(=O)OCC)[nH]1
Product: CCCCc1nc(Cl)c(C(=O)OCC)n1Cc1ccc(C2(C(=O)OCC)CCCC2)nc1

Procedure:
Alkylation was carried out on 1-(5-bromomethylpyridin-2-yl)cyclopentane-carboxlic acid ethyl ester (45) as described in Example 1, Step 5, using 2-butyl-5-chloro-3H-imidazole-4-carboxylic acid ethyl ester (69) to produce the title compound (82).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11](OS(C)(=O)=O)[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[CH:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:38]([OH:41])[CH2:39][CH3:40]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:41][CH2:38][CH2:39][CH3:40])[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[CH:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: C#CCOc1ccc(CCN(OS(C)(=O)=O)C(=O)Cc2ccc(Cl)cc2)cc1OC
Reactant: CCCO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C#CCOc1ccc(CCNC(=O)C(OCCC)c2ccc(Cl)cc2)cc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-(4-chloro-phenyl)-N-mesyloxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-acetamide (452 mg, 1 mmol) in a mixture of 6 ml acetonitrile and 6 ml n-propanol during a period of 12 hours a solution of triethylamine (0.146 ml, 1.05 mmol) in 12 ml of acetonitrile is added dropwise. The mixture is stirred for 20 hours at room temperature. The solvent and excess n-propanol is removed under reduced pressure and the residue was diluted with ethyl acetate (30 ml), washed with water, 1N HCl, and brine, and dried with Na2SO4. After evaporation of the solvent the product is purified by flash chromatography (ethyl acetate:hexane, 1:2) to yield 2-(4-chloro-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-propoxy-acetamide in form of an oil. 1H-NMR (300 MHz, CDCl3): 0.89(t, 3H, CH3), 1.58(q, 2H, CH2), 2.50(t, 1H, C≡CH), 2.79(t, 2H, CH2CH2), 3.35(t, 2H, OCH2), 3.52(dt, 2H, CH2CH2), 3.83(s, 3H, OCH3), 4.63(s, 1H, CHOH), 4.74(d, 2H, OCH2), 6.67-7.30(m, 8H, CH arom., NH).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:28][C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28]([S:33]([CH3:32])(=[O:35])=[O:34])[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: C[C@H]1CCCN1CCCOc1cnc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: C[C@H]1CCCN1CCCOc1cnc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2S(C)(=O)=O
Yield: 52 %

Procedure:
The title compound was synthesized in analogy to example 18 from (4,4-difluoro-piperidin-1-yl)-{5-[3-((S)-2-methyl-pyrrolidin-1-yl)-propoxy]-1H-pyrrolo[2,3-b]pyridin-2-yl}-methanone (example 11), sodium hydride and methanesulfonyl chloride, to give the desired product as a light yellow oil (52%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=O)=[CH:11][CH:10]=2)[CH:6]=[N:7][CH:8]=1)#[N:2].[CH3:21][CH:22](C)[C@H:23]([NH2:25])[CH3:24]>>[C@H:23]([NH:25][C:16](=[O:18])[C:15]([C:12]1[CH:11]=[CH:10][C:9]([C:5]2[CH:6]=[N:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)=[CH:14][CH:13]=1)([CH3:20])[CH3:19])([CH2:22][CH3:21])[CH3:24]
Reactant: CC(C)(C(=O)O)c1ccc(-c2cncc(C#N)c2)cc1
Reactant: CC(C)[C@@H](C)N
Product: CC[C@@H](C)NC(=O)C(C)(C)c1ccc(-c2cncc(C#N)c2)cc1
Yield: 48 %

Procedure:
Prepared in a similar manner to Example 3 from 2-(4-(5-cyanopyridin-3-yl)phenyl)-2-methylpropanoic acid (example 21a) and (R)-3-Methyl-2-butylamine. Yield 48%. 1H NMR (400 MHz, DMSO): δ 0.71-0.73 (d, 3H), 0.74-0.76(d, 3H), 0.91-0.93 (d, 3H), 1.46 (s, 3H), 1.47 (s, 3H), 1.59 (m, 1H), 3.58 (m, 1H), 6.98-7.01 (d, 1H), 7.42-7.44 (d, 2H), 7.77-7.79 (d, 2H), 8.64 (s, 1H), 8.98 (s, 1H), 9.17 (s, 1H). MS (M+H, 336).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:31](O)[CH2:32][CH2:33][OH:34].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([C:8]2([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)[O:34][CH2:33][CH2:32][CH2:31][O:9]2)[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: COc1ccc(C(=O)c2cccc(C)n2)cc1OC
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C2(c3cccc(C)n3)OCCCO2)cc1OC
Reaction time: 17 h

Procedure:
About 77.1 g. of (3,4-dimethoxyphenyl) (6-methyl-2-pyridyl) ketone, 74.1 g. of p-toluenesulfonic acid and 22.8 ml of 1,3-propanediol in 600 ml of toluene were heated under reflux with stirring for 17 hours. The water evolved during the reaction was neutralized with 500 ml of saturated sodium bicarbonate. Two phases formed and the phases were separated. The organic layer was washed with saturated sodium bicarbonate solution and dried over magnesium sulfate. Removal of the desiccant and solvent gave a solid residue which, on recrystallization from a mixture of acetone and petroleum ether (b.p. 60°-80°C.), yielded 2-(3,4-dimethoxyphenyl)-2-(6-methyl-2-pyridyl)-1,3-dioxane, m.p. 124°-126°C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH:10]([S:13]([C:16]2[CH:25]=[CH:24][C:19]3[NH:20][C:21](=[O:23])[O:22][C:18]=3[CH:17]=2)(=[O:15])=[O:14])[CH2:9]1.[C:26]1([CH2:32][CH2:33][CH2:34][CH:35]=O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([CH2:32][CH2:33][CH2:34][CH2:35][N:8]2[CH2:12][CH2:11][CH:10]([S:13]([C:16]3[CH:25]=[CH:24][C:19]4[NH:20][C:21](=[O:23])[O:22][C:18]=4[CH:17]=3)(=[O:15])=[O:14])[CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=CCCCc1ccccc1
Reactant: O=c1[nH]c2ccc(S(=O)(=O)C3CCNC3)cc2o1
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2ccc(S(=O)(=O)C3CCN(CCCCc4ccccc4)C3)cc2o1

Procedure:
The title compound, MS: m/e=401.4 (M+H+) was prepared from (RS)-6-(pyrrolidine-3-sulfonyl)-3H-benzooxazol-2-one trifluoroacetic acid and 4-phenyl-butyraldehyde.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.Cl[C:9]1[C:13]2[CH:14]=[C:15]([CH:27]=[O:28])[C:16]([N:19]3[CH2:24][C@@H:23]([CH3:25])[O:22][C@H:21]([CH3:26])[CH2:20]3)=[C:17]([F:18])[C:12]=2[O:11][N:10]=1>CN(C=O)C.C(Cl)Cl>[CH3:26][C@@H:21]1[CH2:20][N:19]([C:16]2[C:15]([CH:27]=[O:28])=[CH:14][C:13]3[C:9]([N:3]4[CH:7]=[N:6][CH:5]=[N:4]4)=[N:10][O:11][C:12]=3[C:17]=2[F:18])[CH2:24][C@@H:23]([CH3:25])[O:22]1
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(Cl)noc3c2F)C[C@@H](C)O1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H]1CN(c2c(C=O)cc3c(-n4cncn4)noc3c2F)C[C@@H](C)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60% dispersion) (0.288 g, 7.19 mmol) was added to a solution of 1H-1,2,4-triazole (0.530 g, 7.67 mmol) and 3-chloro-6-((2R,6R)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-5-carbaldehyde (Intermediate 535, 1.5 g, 4.80 mmol) in DMF (10 ml), and the mixture was stirred at room temperature overnight. The mixture was quenched with aqueous NH4Cl and diluted with water before being extracted with CH2Cl2 5 times. The combined extracts were dried (MgSO4) and concentrated to give a solid that was taken up in CH2Cl2. Insoluble solids were filtered off and rinsed with additional CH2Cl2. The solids were dried in vacuo and were consistent with desired product. The filtrate was concentrated and chromatographed on silica gel (100% CH2Cl2 followed by gradient elution to 50% EtOAc in CH2Cl2) to give additional desired product. Total of 866 mg.
Reaction SMILES: [O:1]=[S@:2]1[N:6]2[CH2:7][CH2:8][CH2:9][CH:5]2[CH2:4][O:3]1.C(OCC)(=[O:12])C>O>[O:1]=[S:2]1(=[O:12])[N:6]2[CH2:7][CH2:8][CH2:9][C@@H:5]2[CH2:4][O:3]1
Reactant: CCOC(C)=O
Reactant: O=[S@@]1OCC2CCCN21
Solvent: O
Product: O=S1(=O)OC[C@H]2CCCN21
Reaction time: 1 h

Procedure:
The (R)-1-oxo-3a,4,5,6-tetrahydropyrrolo[1,2-c][1,2,3]oxathiazolidine, from the previous step, and 20 mL ethyl acetate were added to a 50 mL round bottom flask equipped with a magnetic stirrer. A catalytic amount of RuCl3.3H2O (a few mg) was added, followed by NaIO4 (3.17 g; 14.82 mmol) in 10 mL water. The mixture was stirred vigorously for one hour. The phases were separated, and the aqueous phase was extracted with three portions (10 mL each) ethyl acetate. The combined organic phases were washed with 10 mL aqueous sodium thiosulfate, 10 mL half-saturated brine, and 10 mL brine, and then dried over MgSO4. The solvent was removed on a rotary evaporator with a 40° C. water bath to yield 0.65 g (3.98 mmol) of (R)-1,1-dioxo-3a,4,5,6-tetrahydropyrrolo[1,2-c][1,2,3]oxathiazolidine as a colorless oil which crystallized spontaneously.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH:20]=2)=[CH:15][C:14]=1[N+:32]([O-:34])=[O:33]>CS(C)=O>[N+:32]([C:14]1[CH:15]=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:31])[C:27]([F:28])([F:29])[F:30])[CH:20]=2)[CH:17]=[CH:18][C:13]=1[CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])([O-:34])=[O:33]
Reactant: O=C(Nc1cccc(-c2ccc(F)c([N+](=O)[O-])c2)c1)C(F)(F)F
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1ccc(-c2cccc(NC(=O)C(F)(F)F)c2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
Dimethyl malonate (9.6 mL) was added dropwise to a stirred suspension of 3.2 g of 60% sodium hydride in mineral oil in 40 mL anhydrous dimethylsulfoxide under nitrogen. The mixture was stirred for 10 minutes and 2-fluoro-5-(3-trifluoroacetamidophenyl)nitrobenzene in 20 mL dimethylsulfoxide was added. The resulting dark red mixture was heated to 100° C. for 2 hours. The reaction was quenched by pouring into 100 mL of saturated ammonium chloride solution and extracted twice with 50 mL of ethyl acetate. The organic phase was washed with 50 mL each of saturated ammonium chloride solution, water, and brine, dried over anhydrous sodium sulfate and concentrated to a yellow oil. The oil was chromatographed on a column of silica gel (ethyl acetate:hexane (1:4)) to give 4.4 g (50% yield) of dimethyl 2-[2-nitro-4-(3-trifluoroacetamidophenyl)phenyl]malonate as a pale yellow solid.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[F:16][C:17]([F:29])([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[C:18]([F:21])([F:20])[F:19].[CH2:30]([C@H:35]1[CH2:40][CH2:39][C@H:38]([C@H:41]2[CH2:46][CH2:45][C@H:44]([C:47](O)=[O:48])[CH2:43][CH2:42]2)[CH2:37][CH2:36]1)[CH2:31][CH2:32][CH2:33][CH3:34].CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH2:30]([C@H:35]1[CH2:40][CH2:39][C@H:38]([C@H:41]2[CH2:42][CH2:43][C@H:44]([C:47]([O:28][C:25]3[CH:26]=[CH:27][C:22]([C:17]([F:29])([F:16])[C:18]([F:20])([F:19])[F:21])=[CH:23][CH:24]=3)=[O:48])[CH2:45][CH2:46]2)[CH2:37][CH2:36]1)[CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)O)CC2)CC1
Reactant: Oc1ccc(C(F)(F)C(F)(F)F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)Oc3ccc(C(F)(F)C(F)(F)F)cc3)CC2)CC1

Procedure:
0.1 mol of dicyclohexylcarbodiimide (DCC) in 30 ml of CH2Cl2 is added with stirring at about 10° to a mixture of 0.1 mol of 4-(pentafluoroethyl)-phenol (preparation analogously to Bull. Chem. Soc. Japan, 57 (1984) 3361), 0.1 mol of trans-4-(trans-4-pentylcyclohexyl)-cyclohexanecarboxylic acid and 0.01 mol of dimethylamino-pyridine and 150 ml of CH2Cl2, and the mixture is then stirred for 15 hours at room temperature. It is filtered over silica gel, the solvent is evaporated and further purification gives 4-(pentafluoroethyl)-phenyl trans-4-(trans-4-pentylcyclohexyl)-cyclohexanoate.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[NH:20][N:19]=3)[N:16]=2)[N:11]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:10]=1)=[O:8])[CH3:5].[H-].[Na+].Br.[CH3:39][N:40]([CH2:42][CH2:43]Br)[CH3:41]>CN(C=O)C>[CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[N:20]([CH2:43][CH2:42][N:40]([CH3:41])[CH3:39])[N:19]=3)[N:16]=2)[N:11]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])[CH:10]=1)=[O:8])[CH3:5]
Reactant: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Reactant: CN(C)CCBr
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCN(C)C)c4cc(Cl)ccc34)nc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53.3 %

Procedure:
2-(6-Chloro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide (80 mg, 0.16 mmol) was combined with DMF (8 mL) at 0° C. to give a yellow solution. Sodium hydride (60% in mineral oil, 19 mg, 0.47 mmol) was added and the reaction was stirred at 0° C. for 10 min. Dimethylaminoethyl bromide hydrobromide (54 mg, 0.23 mmol) was added and the reaction was stirred at 0° C. for 30 min, then allowed to warm to room temperature and stirred for 2 h. The reaction mixture was quenched with 5 mL of brine and 10 mL of water, then extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with water and brine, then dried and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-10% methanol in dichloromethane) to afford 50 mg (55%) of 2-[6-chloro-1-(2-dimethylamino-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as a foaming solid. MS: (M+H)+=587.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[C:12]([CH3:17])[CH:11]=1)(=[O:9])=[O:8].[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[C:12]([CH3:17])[CH:11]=1)(=[O:9])=[O:8]
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1cc(S(=O)(=O)NCCCCO)ccc1Br
Product: Cc1cc(S(=O)(=O)NCCCCO)ccc1-c1ccc(F)cc1

Procedure:
Using a method analogous to that described in Example 40, 4-bromo-3-methylphenyl-sulfonic acid-(4-hydroxybutyl)-amide and 4-fluorophenyl boronic acid were reacted to give the title compound as a thick oil. δC (CDCl3, 62.9 MHz): 20.6, 26.4, 29.6, 43.1, 62.2, 115.4 (d, J 21.5), 124.5, 128.8, 130.5, 130.6, 136.1 (d, J 2.9), 136.9, 138.6, 145.3 and 162.4 (d, J 247.1).
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[O:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:31])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17]([CH3:18])=[O:31])[O:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2ccc(Cn3cnc4cc(Br)ccc43)cc2o1
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3cnc4cc(Br)ccc43)cc2o1
Yield: 75.4 %

Procedure:
A solution of 6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]oxazole (327 mg, 0.87 mmol) and m-CPBA (226 mg, 1.31 mmol) in DCM (6 mL) was stirred at 0° C. for 3.5 h. The mixture was washed with aq Na2S2O3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:5 petroleum ether/ethyl acetate to give 6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (256 mg, 75.52%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.97 (s, 1H), 7.87-7.89 (m, 2H), 7.57 (d, J=9.0 Hz, 1H), 7.46 (d, J=9.6 Hz, 1H), 7.36 (d, J=6.6 Hz, 1H), 5.68 (s, 2H), 3.18 (s, 3H). LCMS (ESI) m/z 391 (M+H)+.
Reaction SMILES: C(O[C:4](=O)[CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[CH3:12])C.[Br:14][C:15]1[CH:16]=[C:17]([NH2:22])[C:18]([NH2:21])=[CH:19][CH:20]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>CS(O)(=O)=O>[Br:14][C:15]1[CH:20]=[CH:19][C:18]2[NH:21][C:4]([CH2:5][CH2:6][N:7]3[CH2:11][CH2:10][CH2:9][C@H:8]3[CH3:12])=[N:22][C:17]=2[CH:16]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: CCOC(=O)CCN1CCC[C@H]1C
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: C[C@@H]1CCCN1CCc1nc2cc(Br)ccc2[nH]1
Temperature: 110 °C
Yield: 40 %

Procedure:
In a round-bottom flask was charged 3-(2-(R)-methyl-pyrrolidin-1-yl)-propionic acid ethyl ester (5.6 g, 30 mmol), 4-bromo-benzene-1,2-diamine (5.6 g, 30 mmol) and 56 mL of 5% P2O5 in CH3SO3H (Eaton's reagent). After briefly stirring, the homogeneous solution was heated to 110° C. for approximately 24-48 h. The reaction mixture was quenched with ice (˜50 g) and then the pH slowly adjusted to pH>11 with 50% NaOH. The product was extracted with isopropyl acetate (100 mL). The organic layer was then extracted with 5% NaHCO3, H2O and then distilled to dryness. The crude product was purified by column chromatography to provide the title compound (3.7 g). 1H NMR (500 MHz, [(CD3)2SO] δ 1.00 (d, 3H), 1.27 (m, 1H), 1.63 (m, 2H), 1.85 (m, 1H), 2.11 (m, 1H), 2.31 (m, 1H), 2.45 (m, 1H), 2.91-2.99 (m, 2H), 3.09 (m, 1H), 3.19 (m, 1H), 7.24 (m, 1H), 7.43 (d, 1H), 7.66 (s, 1H), some protons were not readily identified due to exchange broadening. 13C NMR (500 MHz, [(CD3)2SO+2 drops DCI] δ 15.3, 21.0, 23.2, 31.0, 48.3, 52.3, 64.3, 115.9, 116.6, 117.9, 128.8, 130.2, 132.2, 151.1 (some 13C peaks were not readily identified due to exchange broadening at 25° C., but were observed under acidic conditions, 2 drops DCI). APPI-MS: (M+1)+ at 308 m/z.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:22][CH3:23])=[C:4]([CH:8]=[C:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Br:1][C:2]1[C:3]([CH2:22][CH3:23])=[C:4]([CH:8]=[C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1c(Br)cccc1C=C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1c(Br)cccc1C=C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[(3-bromo-2-ethylphenyl)methylidene]-1-piperidinecarboxylate (D136) (3 g, 7.89 mmol) in Dichloromethane (DCM) (100 mL) was added TFA (6.08 mL, 79 mmol). The reaction solution was stirred at room temperature for 2 hours. The solvent was evaporated in vacuo to afford 4-[(3-bromo-2-ethylphenyl)methylidene]piperidine (D137) (1.9 g), which was used directly without further purification. MS (ES): C14H18BrN requires 279.1. found 280.1 (M+H+).