Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][O:34][CH2:33]4)[CH:30]=3)[C:25]([OH:27])=O)=[CH:17][CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[NH2:37][C:38]1[CH:43]=[N:42][CH:41]=[CH:40][N:39]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][O:34][CH2:33]4)[CH:30]=3)[C:25]([NH:37][C:38]3[CH:43]=[N:42][CH:41]=[CH:40][N:39]=3)=[O:27])=[CH:17][CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1
Reactant: Nc1cnccn1
Reactant: O=C(O)c1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(O[C@H]2CCOC2)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cnccn1)c1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(O[C@H]2CCOC2)c1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 23.7 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (0.095 mL, 0.75 mmol) was added to a solution of 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoic acid (250 mg, 0.65 mmol) in DCM (6 mL) and stirred at RT for 30-40 minutes. 2-Aminopyrazine (125 mg, 1.31 mmol) and pyridine (0.106 mL, 1.31 mmol) were added and the reaction stirred at RT for 2 hours. The solvent was removed in vacuo, water (20 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL). The organic extracts were combined and washed with 2N hydrochloric acid (20 mL), a saturated solution of sodium bicarbonate (20 mL), water (20 mL), brine (20 mL), dried (MgSO4) and evaporated in vacuo. The crude product was chromatographed on silica, eluting with a gradient of 0-10% methanol in DCM, to give the desired compound (71 mg).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5](C(=O)C(F)(F)F)[C:4]2[CH:19]=[CH:20][CH:21]=[CH:22][C:3]1=2.[OH-].[Na+]>C(O)C>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][NH:5][C:4]2[CH:19]=[CH:20][CH:21]=[CH:22][C:3]1=2
Reactant: CN1c2ccccc2CN(C(=O)C(F)(F)F)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1c2ccccc2CNc2ccccc21
Yield: 94.7 %

Procedure:
1-(10,11-Dihydro-5-methyl-dibenzo[b,e][1,4]diazepin-10-yl)-2,2,2-trifluoroethanone of Step B (1.0 g) in ethanol (25 mL) was treated with 1 N sodium hydroxide (10 mL). The reaction mixture was refluxed for five hours, cooled, all volatiles removed in vacuo and the residue triturated with water. The resulting solid was filtered off, redissolved in dichloromethane and dried over anhydrous sodium sulfate. The solution was filtered through a short column of Magnesol® which was eluted with several additional volumes of dichloromethane. The total effluent was evaporated to dryness to provide the title compound as an off-white crystalline solid (0.65 g), m.p. 115–117° C.
Reaction SMILES: C(N)(C)C.[Li]CCCC.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.[C:38]([O:42][C:43](=[O:45])[CH3:44])([CH3:41])([CH3:40])[CH3:39].Br[C:47]1[CH:56]=[CH:55][C:54]([F:57])=[C:53]2[C:48]=1[CH:49]=[CH:50][N:51]=[CH:52]2>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:57][C:54]1[CH:55]=[CH:56][C:47]([CH2:44][C:43]([O:42][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:45])=[C:48]2[C:53]=1[CH:52]=[N:51][CH:50]=[CH:49]2
Reactant: Fc1ccc(Br)c2ccncc12
Reactant: CC(=O)OC(C)(C)C
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CC(C)N
Product: CC(C)(C)OC(=O)Cc1ccc(F)c2cnccc12
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 59.5 %

Procedure:
A 30 mL reaction vial was flame dried and charged with isopropylamine (0.67 mL, 4.8 mmol) in toluene (3 mL). The solution was chilled to 0° C. before a 1.5M solution of nBuLi (4.8 mmol, 3.2 mL) was added. Pd2(dba)3 catalyst (184 mg, 0.2 mmol) was added, followed by ligand 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (160 mg, 0.4 mmol), and t-butylacetate (464 mg, 4 mmol). After 15 min, a toluene (3 mL) solution of 5-bromo-8-fluoroisoquinoline (200 mg, 0.9 mmol) was added. The reaction was stirred for 16 h while warming to 23° C. The crude mixture was purified by column chromatography (3% MeOH/DCM) to give tert-butyl 2-(8-fluoroisoquinolin-5-yl)acetate (140 mg). LCMS showed an m/z of 262.1 with a retention time of 1.469 min, method [1].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2OC2C=CC=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].[CH:58]([Si:61]([CH:66]([CH3:68])[CH3:67])([CH:63]([CH3:65])[CH3:64])[SH:62])([CH3:60])[CH3:59]>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].C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[S:62][Si:61]([CH:63]([CH3:65])[CH3:64])([CH:66]([CH3:68])[CH3:67])[CH:58]([CH3:59])[CH3:60]
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Reactant: COC(=O)c1cc(C)ccc1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C)ccc1S[Si](C(C)C)(C(C)C)C(C)C
Temperature: 150 °C

Procedure:
2-Bromo-5-methyl-benzoic acid methyl ester (2.06 g, 9.00 mmol), tris(dibenzylideneacetone)dipalladium (0) (83 mg, 0.09 mmol), bis(2-diphenylphosphinophenyl)ether (97 mg, 0.18 mmol), sodium tert-butoxide (1.00 g, 10.4 mmol), triisopropylsilanethiol (1.37g, 7.2 mmol) and dry toluene (10 mL) are all placed in an Emrys Optimizer EXP 20 mL microwave reactor tube. The reaction vessel is sealed and subjected to microwave heating at 150° C. for 30 minutes. Upon cooling the mixture is poured onto a plug of silica and the product is eluted with ethyl acetate-heptane (2:8). This furnishes the title compound as an oil, which is used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]1([C:16]2[O:17][CH:18]=[C:19]([CH2:21][CH2:22]O)[N:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:10]1([C:16]2[O:17][CH:18]=[C:19]([CH2:21][CH2:22][O:1][C:2]3[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=3)[CH:5]=[O:6])[N:20]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OCCc1coc(-c2ccccc2)n1
Reactant: O=Cc1cccc(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1cccc(OCCc2coc(-c3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10.00 g (81.89 mmoles) of 3-hydroxybenzaldehyde, 15.49 g (81.89 mmoles) of 2-(2-phenyl-4-oxazolyl)ethanol, and 21.48 g (81.89 mmoles) of triphenylphosphine were dried under vacuum and combined with 200 mL THF under N2. The mixture was treated with 16.12 mL (81.89 mmoles) of diisopropylazodicarboxylate added dropwise over 0.25 hr resulting in a mild exotherm. After stirring for 24 hr at ambient temperature, the crude reaction mixture was concentrated under reduced pressure to a viscous amber oil. The oil was diluted in 300 mL EtOAc, washed with 2.5 N NaOH (3×200 mL), H2O (2×300), and brine 300 mL. The combined organics were dried over MgSO4 and concentrated under reduced pressure again to a viscous amber oil. The reaction mixture was separated using silica gel column chromatography (6:1 Hex:EtOAc) from which the product was recovered and then recrystallized from iprOH to afford 15.10 g (63.10%.) of white crystalline solid, m.p. 51-53° C.
Reaction SMILES: [NH2:1][C:2]([CH3:15])([CH2:13]C)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[CH2:16]=O>CCOCC>[CH2:16]=[N:1][C:2]([CH3:15])([CH3:13])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: CCC(C)(N)C(=O)OCc1ccccc1
Reactant: C=O
Solvent: CCOCC
Product: C=NC(C)(C)C(=O)OCc1ccccc1
Reaction time: 4 h
Yield: 106.7 %

Procedure:
To benzyl 2-amino-2-methylbutyrate (12.96 g) was dropped at room temperature 37% formalin (7.62 g), and the mixture was stirred for 4 h. The reaction mixture was dissolved in ether and washed with water. The organic phase was dried over magnesium sulfate, filtered and evaporated to get the captioned compound (13.7 g).
Reaction SMILES: [NH2-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].Cl[CH2:10][C:11]([NH:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])=[O:12].O>C1(C)C=CC=CC=1>[CH3:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=1[NH:13][C:11](=[O:12])[CH2:10][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8]
Reactant: O=C1CCCN1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(C)c1NC(=O)CN1CCCC1=O
Reaction time: 2 h
Yield: 91.2 %

Procedure:
In 300 ml of toluene was suspended 9.0 g of sodium amide in a nitrogen stream, and 21.3 g of 2-pyrrolidinone was slowly added thereto dropwise. After stirring the mixture at 60° to 70° C. for 2 hours, 19.7 g of 2-chloro-N-(2,6-dimethylphenyl)acetamide was added thereto, followed by allowing to react at 60° to 70° C. for 2 hours. To the reaction mixture was added 50 ml of hot water of about 70° to 85° C., and the mixture was allowed to cool with stirring. The precipitated crystals in the aqueous layer were recovered by filtration and dried under reduced pressure to obtain 22.4 g (91%) of the titled compound.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH3:16][O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>ClCCl>[CH3:16][O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](=[O:21])[CH2:8][CH2:7][CH2:6][C:5]1[CH:4]=[CH:3][CH:2]=[CH:1][N:9]=1
Reactant: COc1ccccc1C(=O)Cl
Reactant: NCCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccccc1C(=O)CCCc1ccccn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 0.5 gm of phenethylamine (4.12 mmol) in 5 mL of dichloromethane and 0.978 mL of pyridine (8.2 mmol) at 0° C. was added 1.39 gm of 2-methoxybenzoyl chloride (1.14 mL, 8.2 mmol). The reaction was allowed to warm to room temperature and was stirred for 4 hr. The reaction mixture was concentrated, 5mL of heptane were added and the mixture was evaporated to dryness this being repeated one more time. The residue was purified by HPLC (RCM SepPak, silica 25×100, 3.6% CH3CN, 14.4% tBuOCH3, 82% hexane) to give the title compound.
Reaction SMILES: C1(S(O)(=O)=O)C2C=CC=C(S(O)(=O)=O)C=2C=CC=1.[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([O:24][CH:25]([N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)[C:26](=[O:32])[C:27]([CH3:31])([CH3:30])[CH2:28][Cl:29])=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+].[BH4-].[Na+]>C(Cl)Cl.C(O)(C)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH:25]([N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)[CH:26]([OH:32])[C:27]([CH3:30])([CH3:31])[CH2:28][Cl:29])=[CH:38][CH:39]=1
Reactant: CC(C)(CCl)C(=O)C(Oc1ccc(Cl)cc1)n1ccnc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)c1cccc2c(S(=O)(=O)O)cccc12
Agent: [BH4-]
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)(CCl)C(O)C(Oc1ccc(Cl)cc1)n1ccnc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 74.4 %

Procedure:
18.8 g (0.04 mol) of 1-(4-chlorophenoxy)-1-(imidazol-1-yl)-3,3-dimethyl-4-chloro-butan-2-one naphthalene-1,5-disulphonate were suspended in 100 ml of methylene chloride, and 100 ml of sodium bicarbonate solution were added. The organic phase was separated off, dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. The base thus obtained was taken up in 100 ml of isopropanol, and 2 g (0.05 mol) of sodium borohydride were added in portions at 5° to 10° C. The mixture was stirred at room temperature for 15 hours and the isopropanol was then distilled off. The residue was taken up in 100 ml of methylene chloride and, after adding 100 ml of water, the mixture was stirred at room temperature for a further 15 hours. The organic phase was then separated off, washed twice with 50 ml of water each time, dried over sodium sulphate and concentrated. The oil which remained was boiled up in 100 ml of petroleum ether, whereupon crystallization occurred. 9.8 g (75% of theory) of 1-(4-chlorophenoxy)-1-(imidazol-1-yl)-3,3-dimethyl-4-chloro-butan-2-ol of melting point 120°-125° C. were obtained. ##STR15##
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[N:14]=[N:15][NH:16][CH:17]=2)=[CH:5][CH:4]=1.Br.[OH-].[Na+]>>[NH:16]1[CH:17]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)[N:14]=[N:15]1
Reactant: COc1ccc(CCCCc2c[nH]nn2)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: Oc1ccc(CCCCc2c[nH]nn2)cc1
Temperature: 80 °C
Reaction time: 9 h

Procedure:
A mixture of 500 mg 4-(4-(4-methoxy-phenyl)-butyl)-1H-[1,2,3]triazole and 1.5 ml 48% hydrobromic acid was stirred at 80° C. for 9 h. After adjustment to pH=6 by addition of conc. sodium hydroxide solution, the aqueous layer was discarded and the remaining sticky residue purified by HPLC-MS(RP18, methanol/water 7:3, pH=2.3). Yield 170 mg (36%).
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:9][C:10]1[C:15]([C:16]2(O)[C:24]3[C:19](=[CH:20][C:21]([F:27])=[C:22]([C:25]#[N:26])[CH:23]=3)[NH:18][C:17]2=[O:28])=[CH:14][CH:13]=[CH:12][N:11]=1)[CH3:8].S(Cl)([Cl:32])=O>ClCCl>[Cl:32][C:16]1([C:15]2[C:10]([O:9][CH2:7][CH3:8])=[N:11][CH:12]=[CH:13][CH:14]=2)[C:24]2[C:19](=[CH:20][C:21]([F:27])=[C:22]([C:25]#[N:26])[CH:23]=2)[NH:18][C:17]1=[O:28]
Reactant: O=S(Cl)Cl
Reactant: CCOc1ncccc1C1(O)C(=O)Nc2cc(F)c(C#N)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1ncccc1C1(Cl)C(=O)Nc2cc(F)c(C#N)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
0.47 ml (5.81 mmol) of pyridine was added to 1.3 g (4.15 mmol) of 3-(2-ethoxypyridin-3-yl)-6-fluoro-3-hydroxy-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile in 30 ml of dichloromethane. After the reaction mixture had been cooled to 0° C., 0.42 ml (5.81 mmol) of thionyl chloride was added dropwise. The mixture was stirred at room temperature for one hour and then poured into ice-water. After stirring for 15 minutes, the organic phase was separated off. The aqueous phase was extracted several times with dichloromethane. The combined organic phase was dried over magnesium sulfate and filtered, and the solvent was removed in vacuo. 1.13 g of 3-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile were obtained as a solid which was employed without further purification in the next stage.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:50]([C:52]([C:71]1[CH:76]=[CH:75][C:74](/[CH:77]=[CH:78]/[C:79]2([OH:84])[CH2:83][CH2:82][CH2:81][CH2:80]2)=[C:73]([CH3:85])[CH:72]=1)([C:55]1[CH:60]=[CH:59][C:58](B2OC(C)(C)C(C)(C)O2)=[C:57]([CH3:70])[CH:56]=1)[CH2:53][CH3:54])[CH3:51].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:58]2[CH:59]=[CH:60][C:55]([C:52]([CH2:53][CH3:54])([C:71]3[CH:76]=[CH:75][C:74](/[CH:77]=[CH:78]/[C:79]4([OH:84])[CH2:80][CH2:81][CH2:82][CH2:83]4)=[C:73]([CH3:85])[CH:72]=3)[CH2:50][CH3:51])=[CH:56][C:57]=2[CH3:70])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: CCC(CC)(c1ccc(/C=C/C2(O)CCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(/C=C/C2(O)CCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 29.4 %

Procedure:
(4-Bromo-phenyl)acetic acid methyl ester (Tetrahedron Letters 44 (2003) 331-334; 35 mg, 0.153 mmol), palladium acetate (2.2 mg, 0.010 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (8.2 mg, 0.020 mmol), potassium phosphate (65 mg, 0.306 mmol) and water (0.2 mL) were added to a solution of (E)-1-[2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-vinyl]-cyclopentanol (Example 33-(3); 50 mg, 0.102 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for 2.5 hours. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the target compound as a colorless oil (15.3 mg, 29%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:30]1[CH2:29][CH2:28][CH:27]([NH:26][C:24]([C:20]2[C:16]3=[N:17][CH:18]=[CH:19][C:14]([C:8]4[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)=[C:15]3[NH:22][C:21]=2[CH3:23])=[O:25])[CH2:32][CH2:31]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f4) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH2:12])[CH3:11])=[CH:5][CH:4]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([NH:12][C@H:10]([CH3:11])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CC(C)N)cc1
Solvent: c1ccncc1
Product: COc1ccc(C[C@@H](C)NC(C)=O)cc1
Reaction time: 1 h

Procedure:
In 6 ml of pyridine was dissolved 1.5 g of (-)-2-(p-methoxyphenyl)-1-methylethylamine ([α]D23 : -30.1° (c=1.2, methanol)), and after adding thereto 3 ml of acetic anhydride, the mixture was allowed to stand at room temperature for 1 hour. After distilling off the solvent, the residue was extracted with ethyl acetate. The ethyl acetate extract was washed with water, and dried over anhydrous sodium sulfate, and the solvent was distilled off and the crude crystals formed were recrystallized from a mixture of n-hexane and benzene to provide 1.8 g of (R)(+)-N-acetyl-2-(p-methoxyphenyl)-1-methylethylamine.
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10].Cl.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([CH:25]([NH:27][C:28](=[O:34])[CH:29]([NH2:33])[CH:30]([CH3:32])[CH3:31])[CH3:26])=[CH:22][C:21]=2[CH:35]=1.O>ClCCl>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([CH:25]([NH:27][C:28](=[O:34])[C@H:29]([CH:30]([CH3:31])[CH3:32])[NH:33][C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH3:26])=[CH:22][C:21]=2[CH:35]=1
Reactant: CC(NC(=O)C(N)C(C)C)c1cc2cc(Cl)ccc2o1
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)OC(=O)N[C@H](C(=O)NC(C)c1cc2cc(Cl)ccc2o1)C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 47.1 %

Procedure:
0.54 g of N-methylmorpholine, and subsequently 0.7 g of isopropyl chloroformate were added to a solution containing 1.57 g of N-[1-(5-chloro-2-benzofuranyl)ethyl]-2-amino-3-methylbutanamide hydrochloride dissolved in 40 ml of dichloromethane at -15° C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the dichloromethane layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue, which was a crude crystal, was purified by column chromatography on silica gel, thus obtaining 0.85 g of the desired product in the form of a white powder.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)(O)[O-].[Na+]>>[CH3:1][N:2]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNc1ccccc1
Reactant: CCOC(=O)CCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)CCCCN(C)c1ccccc1
Temperature: 110 °C
Reaction time: 22 h
Yield: 84.1 %

Procedure:
A mixture of N-methylaniline (16 g) and ethyl 5-bromovalerate (30.2 g) was stirred at 110° C. for 22 hours. Then the mixture was made alkaline with an aqueous sodium bicarbonate. The resulting mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated. The residue was distilled under reduced pressure to obtain ethyl 5-(N-methylanilino)valerate (28.6 g).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:29][C:30]([O:32][C:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[CH:35][C:34]=1[S:40][S:41][CH2:42][CH3:43])=[O:31])[C:17]([O:19][C:20](C1C=CC=CC=1)(C)[CH3:21])=[O:18])=[O:14])([CH3:11])([CH3:10])[CH3:9].CC[N:46](C(C)C)C(C)C>ClCCl.BrCC#N>[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:29][C:30]([O:32][C:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[CH:35][C:34]=1[S:40][S:41][CH2:42][CH3:43])=[O:31])[C:17]([O:19][CH2:20][C:21]#[N:46])=[O:18])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCSSc1cccc(C)c1OC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)c1ccccc1
Agent: N#CCBr
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCSSc1cccc(C)c1OC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.8 %

Procedure:
Trifluoroacetic acid (0.040 ml, 0.519 mmol) was added to a solution of 4-(2-(ethyldisulfanyl)-6-methylphenyl) 1-(2-phenylpropan-2-yl) (S)-2-((tert-butoxycarbonyl)amino)succinate (Compound 110) (240 mg, 0.450 mmol) in dichloromethane (4 ml), and the mixture was stirred at room temperature for 1.5 hours. Trifluoroacetic acid (0.040 ml, 0.519 mmol) was further added and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was then concentrated under reduced pressure. DIPEA (0.259 ml, 1.49 mmol) was added to a solution of the resulting residue in bromoacetonitrile (4.70 ml), and the mixture was stirred at room temperature for 10 minutes. The reaction solution was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→50/50) to afford 1-(cyanomethyl) 4-(2-(ethyldisulfanyl)-6-methylphenyl) (S)-2-((tert-butoxycarbonyl)amino)succinate (Compound 112) (151 mg, 74%).
Reaction SMILES: [OH:1][C:2]1[C:7]([C@@H:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C@H:9]2[CH2:14][OH:15])=[C:6]([O:16][CH3:17])[CH:5]=[C:4]([O:18][CH3:19])[C:3]=1[C:20](=[O:22])[CH3:21].CO[C:25](=O)[C:26]1[CH:31]=[C:30]([N:32]([CH3:34])[CH3:33])[CH:29]=[CH:28][C:27]=1[Cl:35].[H-].[Na+]>CN(C=O)C>[Cl:35][C:27]1[CH:28]=[CH:29][C:30]([N:32]([CH3:34])[CH3:33])=[CH:31][C:26]=1[C:25]1[O:1][C:2]2[C:3]([C:20](=[O:22])[CH:21]=1)=[C:4]([O:18][CH3:19])[CH:5]=[C:6]([O:16][CH3:17])[C:7]=2[C@@H:8]1[CH2:12][CH2:11][N:10]([CH3:13])[C@H:9]1[CH2:14][OH:15]
Reactant: COC(=O)c1cc(N(C)C)ccc1Cl
Reactant: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2CO)c(O)c1C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)cc(-c3cc(N(C)C)ccc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO

Procedure:
Compound of example 6 (0.8 g, 2.58 mmol) in dry DMF (15 mL) was reacted with methyl-2 chloro-5-dimethylaminobenzoate (1.65 g, 7.7 mmol) in the presence of NaH (50%, 0.62 g, 12.9 mmol) as described in example 16 to obtain the title compound.