Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:11]([N:29]=2)=[N:12][C:13]([N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([C:22]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])[CH2:17]2)=[CH:14][CH:15]=3)[CH:5]=[CH:4][CH:3]=1.[CH:30]1([C:33]#[N:34])[CH2:32][CH2:31]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1(C)C=CC=CC=1.C1COCC1>[N:24]1([C:22]([C@@H:18]2[CH2:19][CH2:20][CH2:21][N:16]([C:13]3[N:12]=[C:11]4[N:29]=[C:8]([C:6]5[N:7]=[C:2]([C:30]6([C:33]#[N:34])[CH2:32][CH2:31]6)[CH:3]=[CH:4][CH:5]=5)[NH:9][C:10]4=[CH:15][CH:14]=3)[CH2:17]2)=[O:23])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: N#CC1CC1
Reactant: O=C([C@@H]1CCCN(c2ccc3[nH]c(-c4cccc(Br)n4)nc3n2)C1)N1CCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#CC1(c2cccc(-c3nc4nc(N5CCC[C@@H](C(=O)N6CCCC6)C5)ccc4[nH]3)n2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 7 %

Procedure:
To a stirred solution of (R)-(1-(2-(6-bromopyridin-2-yl)-1H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (300 mg, 0.658 mmol) in toluene was added cyclopropane carbonitrile. The mixture was cooled to 0° C. then a 1M solution of sodium bis(trimethylsilyl)amide in THF was added dropwise. The reaction mixture was stirred for 16 h at room temperature. The mixture was quenched with water and then was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and was concentrated under reduced pressure. The residue was purified via preparative TLC (twice) to afford (R)-1-(6-(5-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)-1H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)cyclopropanecarbonitrile (20 mg, 7%) MS (ES+APCI) (M+H) 442.2; LCMS retention time 2.969 min (Method C1); 1H NMR (400 MHz, CDCl3) δ 1.24-1.31 (m, 4H), 1.65-1.71 (m, 2H), 1.78-2.04 (m, 6H), 2.69 (m, 1H), 3.01 (t, 1H), 3.07-3.18 (m, 1H), 3.43-3.56 (m, 3H), 3.60-3.72 (m, 1H), 4.35 (br s, 1H), 4.54 (d, 1H), 6.72 (d, 1H), 7.48 (d, 1H), 7.79-7.95 (m, 2H), 8.58 (d, 1H), 10.28 (br s, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N+:14]([O-])([OH:16])=[O:15]>>[N+:14]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:5]=1[NH:4][C:1](=[O:3])[CH3:2])[C:9]([OH:11])=[O:10])([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Product: CC(=O)Nc1ccc(C(=O)O)cc1[N+](=O)[O-]

Procedure:
In this reaction sequence, partially described by Kumar et al., J. Med. Chem., 27, pp. 1083-1089 (1984), 4-acetamidobenzoic acid is utilized as a starting material and is nitrated using, for instance, fuming nitric acid at about -10° to about 10° C. for 1-4 hours to afford 3-nitro-4-acetamidobenzoic acid. This compound is then reacted with thionyl chloride in a non-polar, aprotic solvent to afford the corresponding 3-nitro-4-acetamidobenzoyl chloride, which is then further reacted with the R'1 --H amine wherein R'1 is an amino group or a --NR4R5 group, to afford the 3-nitro-4-acetamino compound of formula V.
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[CH:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1CCC[C@H]1C(O)=O>CN(C)C=O.C(OCC)(=O)C>[OH:12][C@H:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C@H:2]([CH3:3])[CH:1]=[O:4]
Reactant: O=Cc1ccccc1
Reactant: CCC=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](C=O)[C@H](O)c1ccccc1
Reaction time: 16 h
Yield: 81 %

Procedure:
A solution of freshly distilled propionaldehyde (72 μL, 1.0 mmol) in 500 μL dimethylformamide pre-cooled to 4° C. was added slowly over the course of 16 h to a stirring suspension of benzaldehyde (1.02 mL, 10 mmol), L-proline (11.5 mg, 0.10 mmol) and 4.5 mL dimethylformamide at 4° C. After 16 hours, the resulting solution was diluted with ethyl acetate and washed successively with water and brine. The combined aqueous layers were back-extracted with 3 portions of dichloromethane. The organic layers were combined, dried over anhydrous Na2SO4, and then concentrated. Flash chromatography (4:1 hexanes:ethyl acetate) afforded the title compound as a clear, colorless oil in 81% yield (132 mg, 0.81 mmol), 99% ee and 3:1 anti:syn. Analytical data for this compound are identical in every respect to that previously reported (Mahrwald, supra) with the exception of optical rotation which has not been reported. [α]D=+9.1 (c=1.0, CHCl3). The product ratios were determined by HPLC analysis of the corresponding alcohol (obtained by NaBH4 reduction) using a Chiracel AD and AD guard column (1.0% isopropanol/hexanes, 1 mL/min); (2S,3S) anti isomer tr=147.5 min, (2R,3R) anti isomer tr, =161.1 min, (2R,3S) and (2S,3R) syn isomers tr=173.0, 200.0 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([N+:13]([O-])=O)[CH:4]=1>CCO>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH2:13])[CH:4]=1
Reactant: COc1cc([N+](=O)[O-])c(C(N)=O)cc1C
Solvent: CCO
Product: COc1cc(N)c(C(N)=O)cc1C

Procedure:
Compound 110 (7.0 g, 33.3 mmol) was hydrogenated in EtOH (200 ml) and raney-ni (5.0 g) overnight at room temperature at 50 psi. The catalyst was filtered off and washed with dioxane and ethanol. The solvent was removed under vacuo and the product was isolated by column chromatography on silica gel eluted with dichloromethane and 3% methanol. Yield: 3.4 g=56%.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]([OH:14])[CH2:7][NH:8][C:9](=[O:13])[C:10]([CH3:12])=[CH2:11])[CH:2]=[CH2:3].[CH3:15][Si:16]([CH3:30])([CH3:29])[O:17][SiH:18]([O:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[O:19][Si:20]([CH3:23])([CH3:22])[CH3:21].[Cl-]>C1(C)C=CC=CC=1>[OH:14][CH:6]([CH2:5][O:4][CH2:1][CH2:2][CH2:3][Si:18]([O:19][Si:20]([CH3:23])([CH3:22])[CH3:21])([O:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[O:17][Si:16]([CH3:29])([CH3:30])[CH3:15])[CH2:7][NH:8][C:9](=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: C=CCOCC(O)CNC(=O)C(=C)C
Reactant: C[Si](C)(C)O[SiH](O[Si](C)(C)C)O[Si](C)(C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)NCC(O)COCCC[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C
Temperature: 96 °C
Reaction time: 16 h

Procedure:
N-(3-Allyloxy-2-hydroxy-propyl)-2-methyl acrylamide made according to Example 9 (18 g, 0.09 mol), platinic chloride (4 mg, 100 ppm), BHT (36 mg, 2000 ppm) and toluene (90 mL) were charged into a 500 mL three-neck flask, equipped with a condenser with a nitrogen inlet and outlet, and a thermocouple connected to a temperature controller. Tris(trimethylsiloxy)silane (26.8 g, 0.09 mol) was added dropwise to the above mixture at 96–97° C. After stirred at about 96° C. for 16 hours, additional platonic chloride (4 mg, 100 ppm) was added to the reaction solution. The reaction was monitored by gas chromatography. After stirred for 47 hours, the reaction solution was washed with 0.5 N aqueous sodium hydroxide solution and twice with 2.5% aqueous sodium chloride solution. This was followed by washing with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate and filtered. The filtrate, inhibited with 4-methoxyphenol (0.02 g), was concentrated under reduced pressure at 30° C.–40° C. to give an oil (˜36 g). N-(2-hydroxy-3-(3-(tris(trimethylsilyloxy)silyl)propyloxy)propyl)-2-methyl acrylamide was purified by column chromatography.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:29][C:30](=O)[CH2:31][C:32]1[NH:33][N:34]=[C:35]([CH2:37][CH3:38])[N:36]=1)C>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:30](=[O:29])[CH2:31][C:32]1[NH:33][N:34]=[C:35]([CH2:37][CH3:38])[N:36]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Reactant: CCOC(=O)Cc1nc(CC)n[nH]1
Product: CCc1n[nH]c(CC(=O)N2CCN(c3ccc(OC)c(OC4CCC4)c3)C[C@@H]2Cc2ccccc2)n1
Yield: 19 %

Procedure:
Prepared using the same procedure described in Example 275 from (S)-3-benzyl-1-(3-cyclobutyloxy-4-methoxy-phenyl)-piperazine and (5-ethyl-2H-[1,2,4]triazol-3-yl)-acetic acid ethyl ester with heating for 15 days to afford the title compound as tan solid (60 mg, 19%). LC/MS (Method B) 3.22 min, [M+1]+ 490.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1.[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.CN1CCN(C)C1=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][N:13]([CH2:18][C:19]4[CH:26]=[CH:25][C:22]([CH3:23])=[CH:21][CH:20]=4)[CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Reactant: Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCN(C)C1=O
Solvent: C1CCOC1
Product: COc1ccc2c3c(c(=O)oc2c1)CN(Cc1ccc(C)cc1)CC3
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.8 %

Procedure:
A solution of 8-methoxy-1,2,3,4-tetrahydro-chromeno[3,4-c]pyridin-5-one (1.2 g, 5.2 mmol) and 4-methylbenzaldehyde (0.68 g, 5.7 mmol) in 20 mL of tetrahydrofuran and 7 mL of 1,3-dimethyl-2-imidazolidinone is treated with glacial acetic acid (0.29 mL, 5.2 mmol). The mixture is stirred for 10 minutes, and then sodium triacetoxyborohydride (1.6 g, 7.5 mmol) is added in portions over 30 minutes. The mixture is stirred for 16 hours, then added to 300 mL of ice water. The precipitated solid is filtered, washed with water, and recrystallized from ethyl acetate to yield 1.2 g (70%) of product, mp 147°-149° C.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]([CH2:11][O:12][CH2:13][CH2:14][P:15](=[O:20])([O-:19])[O:16]CC)[CH:6]=[N:7]2)=[N:3][CH:2]=1.[NH4+].CO.O>CN(C=O)C>[N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]([CH2:11][O:12][CH2:13][CH2:14][P:15](=[O:16])([OH:19])[OH:20])[CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: CCOP(=O)([O-])CCOCn1cnc2c(N)ncnc21
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2COCCP(=O)(O)O
Temperature: 40 °C
Reaction time: 6 h
Yield: 43.9 %

Procedure:
To a solution of 12 (0.32 g, 1.0 mmol) in DMF (7.0 mL) was added Me3 SiBr (1.07 g, 7.01 mmol). After the solution was stirred at 40° C. for 6 h, a mixture of MeOH and H2O(5:1, 20 mL) was added and the solvents were evaporated. The crude residue was purified by use of column chromatography (resin XAD-4, H2O) to afford 13 (0.12 g, 45%): mp 296° C. (dec.); TLC Rf 0.32 (MeOH); UV λmax (EtOH): 259 nm (ε13 700); 1H NMR(DMSO-d6 /D2O): δ1.49 (m, 2 H, CH2P), 3.80 (m, 2 H, CH2O), 5.55 (s, 2 H, OCH2 N), 7.90, 8.19 (2 s, 2 H, HC(2)+HC(8)). Anal. (C8H12N5 O4P) C, H, N.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[F:26][C:27]([F:32])([CH2:30][NH2:31])[CH2:28][NH2:29]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:29][CH2:28][C:27]([F:32])([F:26])[CH2:30][NH2:31])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCC(F)(F)CN
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(F)(F)CN)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2,2-difluoropropane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 447, 1H NMR (400 MHz, CD3OD) δ ppm 8.09-8.07 (d, 1 H), 7.95 (s, 1 H), 7.86-7.84 (d, 1 H), 7.77-7.69 (m, 2 H), 7.64-7.58 (m, 2 H), 6.26 (s, 1 H), 5.34 (s, 2 H), 4.53 (s, 2 H), 4.23 (t, 2 H), 3.74-3.66 (m, 4 H), 2.48 (s, 3 H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[N:5][N:4]=[N:3]1.S(Cl)([Cl:16])=O>C1C=CC=CC=1.CN(C=O)C>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][C:11]([Cl:16])=[O:13])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCCCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: Cn1nnnc1SCCCC(=O)Cl

Procedure:
2.2 g of 4-(1-methyltetrazol-5-ylthio)-butyric acid are stirred in 20 ml of absolute benzene with 1.03 ml of thionyl chloride and 4 drops of DMF for 20 minutes at the reflux temperature. The solvent is then concentrated by evaporation under reduced pressure. After dissolving and concentrating by evaporation twice more in toluene, the pure title compound is obtained in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][NH2:15].[Cl:16][C:17]1[O:21][C:20]([CH:22]=O)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[O:21][C:20]([CH2:22][NH:15][CH2:14][CH2:13][CH2:12][C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[Cl:1])=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(Cl)o1
Reactant: NCCCc1ccc2ccccc2c1Cl
Product: Clc1ccc(CNCCCc2ccc3ccccc3c2Cl)o1
Yield: 85 %

Procedure:
Prepared from 3-(1-chloronaphthalen-2-yl)propan-1-amine and 5-chlorofuran-2-carbaldehyde in 85% yield as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)[CH2:3][CH2:4][NH2:5].[Cl:11][C:12]1[S:16][C:15]([C:17](Cl)=[O:18])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[S:16][C:15]([C:17]([NH:5][CH2:4][CH2:3][CH:2]([N:6]2[CH:10]=[CH:9][N:8]=[CH:7]2)[CH3:1])=[O:18])=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(Cl)s1
Reactant: CC(CCN)n1ccnc1
Product: CC(CCNC(=O)c1ccc(Cl)s1)n1ccnc1

Procedure:
When gamma-methyl-1H-imidazole-1-propanamine is treated with 5-chlorothiophene-2-carbonyl chloride by the procedure of Example 36, the above compound, m.p. 141°-143° C., is obtained.
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10](=[O:45])[CH2:11][NH:12][C:13]2[N:18]=[C:17]([N:19]3[CH:24]=[C:23]([CH:25]4[C:31]5[CH:32]=[CH:33][C:34]([CH2:36][CH3:37])=[CH:35][C:30]=5[CH:29]=[CH:28][C:27]5[CH:38]=[C:39]([CH3:42])[CH:40]=[CH:41][C:26]4=5)[C:22](=[O:43])[NH:21][C:20]3=[O:44])[CH:16]=[CH:15][N:14]=2)[S:7][CH:8]=1)#[N:2].C[Sn]([N:50]=[N+:51]=[N-:52])(C)C.CO>C1(C)C=CC=CC=1>[CH2:36]([C:34]1[CH:33]=[CH:32][C:31]2[CH:25]([C:23]3[C:22](=[O:43])[NH:21][C:20](=[O:44])[N:19]([C:17]4[CH:16]=[CH:15][N:14]=[C:13]([NH:12][CH2:11][C:10]([NH:9][C:6]5[S:7][CH:8]=[C:4]([CH2:3][C:1]6[NH:52][N:51]=[N:50][N:2]=6)[N:5]=5)=[O:45])[N:18]=4)[CH:24]=3)[C:26]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][C:27]=3[CH:28]=[CH:29][C:30]=2[CH:35]=1)[CH3:37]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(NCC(=O)Nc3nc(CC#N)cs3)n2)c(=O)[nH]c1=O
Solvent: Cc1ccccc1
Solvent: CO
Product: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(NCC(=O)Nc3nc(Cc4nnn[nH]4)cs3)n2)c(=O)[nH]c1=O

Procedure:
A mixture of the product of step (iv) (0.35 g) and trimethyltin azide (0.5 g) in toluene (10 ml) was heated at reflux for 48 hours. Methanol was added and the resultant precipitate filtered off. The solution was evaporated to dryness and the residue purified by reverse phase chromatography. The fraction containing product was concentrated under reduced pressure, acidified with 2N HCl and extracted with ethyl acetate. The extract was evaporated to dryness and the residue triturated with diethyl ether. The product was collected by filtration. Yield 0.16 g.
Reaction SMILES: [Br:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]=[CH2:13].C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[Br:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:13][O:22]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc2c(c1Br)COC2=O
Solvent: ClCCl
Product: O=C1OCc2c1ccc(C1CO1)c2Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-bromo-5-ethenyl-2-benzofuran-1(3H)-one (2.00 g, 8.37 mmol) in DCM (20 mL) was slowly added mCPBA (2.6 g, 8.4 mmol) at 0° C. The flask was warmed to room temperature; the mixture was then stirred for 12 hours. The mixture was washed with aq. Na2S2O3, aq. NaHCO3, and water. The organic layers was washed with brine and then concentrated to dryness. The residue was purified over silica gel to give the title compound.
Reaction SMILES: C[Al](C)C.[CH:5]1([CH2:8][NH:9][CH2:10][CH2:11][CH3:12])[CH2:7][CH2:6]1.C(O[C:16]([C:18]1[N:22]2[C:23]3[CH:24]=[C:25]([F:39])[CH:26]=[CH:27][C:28]=3[N:29]([C:30]3[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=3[CH3:38])[C:21]2=[N:20][C:19]=1[CH3:40])=[O:17])C.[OH-].[Na+]>C1C=CC=CC=1>[CH:5]1([CH2:8][N:9]([CH2:10][CH2:11][CH3:12])[C:16]([C:18]2[N:22]3[C:23]4[CH:24]=[C:25]([F:39])[CH:26]=[CH:27][C:28]=4[N:29]([C:30]4[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=4[CH3:38])[C:21]3=[N:20][C:19]=2[CH3:40])=[O:17])[CH2:7][CH2:6]1
Reactant: CCOC(=O)c1c(C)nc2n(-c3c(C)cc(C)cc3C)c3ccc(F)cc3n12
Reactant: CCCNCC1CC1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CCCN(CC1CC1)C(=O)c1c(C)nc2n(-c3c(C)cc(C)cc3C)c3ccc(F)cc3n12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.8 %

Procedure:
A solution of trimethylaluminum (2.0 M in heptane, 1.4 mL, 2.8 mmol) was added to a solution of N-cyclopropylmethyl-N-propylamine (0.40 mL, 2.8 mmol) in benzene (3 mL) at 0° C. The mixture was warmed up to room temperature and stirred at this temperature for 1.5 hours, and then added to a stirred solution of 5-fluoro-2-methyl-8-(2,4,6-trimethyl-phenyl)-8H-1,3a,8-triaza-cyclopenta[a]indene-3-carboxylic acid ethyl ester (0.13 g, 0.35 mmol) in benzene (2.0 mL). The mixture was refluxed for 12 hours. Upon cooling at 0° C., 1 N sodium hydroxide (15 mL) was added dropwise to the above mixture. The mixture was extracted with dicholoromethane (30 mL), and the organic layer was dried over anhydrous sodium sulfate. Solvents were removed in vacuo and the residue was subjected to chromatography using ethyl acetate/hexanes (3:7) as eluent to afford the title compound as an off-white solid (0.156 g, 100% yield). 1H NMR (CDCl3, 300 MHz) δ 7.60 (dd, J=8.7, 2.5 Hz, 1H), 6.99 (s, 2H), 6.92 (td, J=9.0, 2.5 Hz, 1H), 6.75 (dd, J=8.8, 4.4 Hz, 1H), 3.66 (t, J=7.1 Hz, 2H), 3.46 (d, J=6.9 Hz, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 1.92 (s, 6H), 1.71–1.63 (m, 2H), 1.11–1.05 (m, 1H), 0.88 (t, J=7.2 Hz, 3H), 0.57–0.53 (m, 2H), 0.19–0.16 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 163.6, 159.4, 156.3, 148.9, 143.3, 139.4, 137.0, 131.6, 129.7, 128.7, 124.8 (d, J=13 Hz), 114.2, 110.6 (d, J=25 Hz), 101.2 (d, J=29 Hz), 51.3, 48.6, 21.1, 21.0, 17.8, 15.7, 11.3, 10.1, 3.8. LC/MS: tR=1.95 min, 447.22 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.[CH2:15]([C:17]1[O:21][C:20]([NH2:22])=[N:19][N:18]=1)[CH3:16].C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]([NH:22][C:20]1[O:21][C:17]([CH2:15][CH3:16])=[N:18][N:19]=1)=[O:14]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Reactant: CCc1nnc(N)o1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nnc(NC(=O)c2ccc(S(C)(=O)=O)cc2Cl)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
415 mg (1.77 mmol) of 2-chloro-4-(methylsulfonyl)benzenecarboxylic acid and 200 mg (1.77 mmol) of 5-ethyl-1,3,4-oxadiazol-2-amine are dissolved at RT in 9 ml of CH2Cl2. Then 1.68 g (2.64 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in THF) are added, the mixture is stirred at RT for one hour and then 0.246 ml (1.77 mmol) of triethylamine, 43 mg (0.35 mmol) of 4-dimethylaminopyridine are added. The reaction mixture is stirred at RT for 48 h and then washed twice with 4 ml each time of water, and purified by column chromatography (prep. HPLC; acetonitrile/water). Yield 41 mg (6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[N:10][C:9]=1[N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(C(C)C)C(C)C)C.Cl.[NH2:44][C@@H:45]1[CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]1[OH:51].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.C(OCC)(=O)C>[OH:51][C@@H:46]1[CH2:47][CH2:48][CH2:49][CH2:50][C@H:45]1[NH:44][C:14]([C:12]1[CH:11]=[N:10][C:9]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:13]=1)=[O:16]
Reactant: O=C(O)c1cnc(N2CCCC2)c(-c2ccccc2Cl)n1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(N2CCCC2)c(-c2ccccc2Cl)n1
Reaction time: 72 h
Yield: 41.7 %

Procedure:
To a solution of 0.10 g 6-(2-chloro-phenyl)-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid in 3.0 ml of DMF is added at room temperature 0.082 g 1,1′-carbonyl-diimidazole, 0.22 ml N-ethyldiisopropylamine and 0.057 g (1R,2R)-2-amino-cyclohexanol hydrochloride and stirred for 72 hours. To the mixture is added citric acid 10% solution and ethyl acetate. The organic layer is washed with sodium bicarbonate 10% solution and sodium chloride saturated solution. The organic layer is separated and dried over sodium sulfate and evaporated at the rotary evaporator. The residue is purified by chromatography on silica gel with heptane/ethyl acetate 40/60 to yield 0.055 g of the title compound as white solid, MS (ISP) 401.3 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([CH2:8][N:9]2[C:15](=[O:16])[CH2:14][C:13]3[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:12]=3[CH2:11][CH2:10]2)[CH2:2]1.[NH2:25][C:26]1[C:36]([Br:37])=[CH:35][C:29]([O:30][CH2:31][CH2:32][CH2:33][Cl:34])=[CH:28][C:27]=1[Br:38]>C(N(CC)CC)C>[ClH:34].[ClH:34].[NH2:25][C:26]1[C:27]([Br:38])=[CH:28][C:29]([O:30][CH2:31][CH2:32][CH2:33][N:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([CH2:8][N:9]3[C:15](=[O:16])[CH2:14][C:13]4[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:12]=4[CH2:11][CH2:10]3)[CH2:2]2)=[CH:35][C:36]=1[Br:37]
Reactant: Nc1c(Br)cc(OCCCCl)cc1Br
Reactant: COc1cc2c(cc1OC)CC(=O)N(CC1CCCCNC1)CC2
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CC(=O)N(CC1CCCCN(CCCOc3cc(Br)c(N)c(Br)c3)C1)CC2
Product: Cl

Procedure:
Prepared from 1.2 g (3.6 mmol) of 3-[(hexahydro-azepin-3-yl)methyl]-7,8-dimethoxy-1,3,4, 5-tetrahydro-2H-3-benzazepin-2-one and 1.36 g (3.96 mmol) of 3-(4-amino-3,5-dibromo-phenoxy)-propyl chloride in 5 ml triethylamine analogously to Example 26.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH:10]([C:16]([O:18]CC)=[O:17])[C:11]([O:13]CC)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[O:1]([CH2:8][CH2:9][CH:10]([C:16]([OH:18])=[O:17])[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CCOc1ccccc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(CCOc1ccccc1)C(=O)O
Yield: 63.8 %

Procedure:
Diethyl 2-phenoxyethylmalonate (1 g) was treated with sodium hydroxide (285 mg, 2 eq) in ethanol (10 ml) and water (5 ml). After 16 h the solution was diluted with water (10 ml), washed with diethyl ether (3×20 ml), acidified to pH 2 (5M hydrochloric acid) and extracted with ethyl acetate (2×20 ml). The combined extracts were washed with water (3×20 ml), saturated brine (20 ml), dried (MgSO4) and evaporated to yield the title compound (510 mg, 64%). νmax (KBr) 2915 (br), 1730 and 1243 cm-1. δH [(CD3)2CO] 2.36 (2H, m, CH2CH), 3.69 (1H, t, J 7.2 Hz, CH), 4.12 (2H, t, J 7.3 Hz, OCH2), 6.94, 7.28 (5H, m, Ph). EIMS M+ 224, DCIMS MNH4+ 242.