Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:23][C:24](=[O:26])[NH2:25])[C:3]([NH:5][C@@H:6]([C@H:10]([NH:12][C@H:13]([C:20]([OH:22])=[O:21])[CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1)[CH3:11])[C:7]([OH:9])=[O:8])=[O:4].C(N(CC)CC)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>CO.O>[C:34]([NH:1][C@@H:2]([CH2:23][C:24](=[O:26])[NH2:25])[C:3]([NH:5][C@@H:6]([C@H:10]([NH:12][C@H:13]([C:20]([OH:22])=[O:21])[CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1)[CH3:11])[C:7]([OH:9])=[O:8])=[O:4])(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H](N[C@@H](Cc1c[nH]cn1)C(=O)O)[C@H](NC(=O)[C@@H](N)CC(N)=O)C(=O)O
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)O)[C@@H](C)N[C@@H](Cc1c[nH]cn1)C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of (2S, 3R)-2-[[(2S)-2-amino-3-carbamoylpropionyl] amino]-3-[[(1S)-1-carboxy-2-(4imidazolyl)ethyl]amino]butyric acid (500 mg) and triethylamine (0.38 ml) in a mixture of methanol(30 ml) and water (6 ml) was added acetic anhydride (0.13 ml) and the mixture was stirred for 20 hours at room temperature After removal of the solvent in vacuo, the residue was dissolved in water and adjusted to pH 3 with 1N hydrochloric acid. The solution was subjected to a column of Dowex 50W X 8 (H+ form, 10 ml) and the column was washed with water. The elution was carried out with 2% aqueous ammonia. The object fractions were collected and evaporated in vacuo and the residue was dissolved in a mixture of acetic acid (28.6 ml) and water (500 ml). The solution was lyophilized and the residue was solidified with methanol to give (2S, 3R)-2-[[(2S)-2-acetylamino-3-carbamoylpropionyl]amino]-3-[[(1S)-1 -carboxy-2-(4-imidazolyl)ethyl]amino]butyric acid (500 mg).
Reaction SMILES: Br[CH2:2][CH:3]([CH3:7])[CH2:4][O:5][CH3:6].[Mg].[N:9]1[CH2:10][CH2:11][CH2:12][N:13]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15](=[O:22])[C:14]=12.[Cl-].[NH4+]>CCOCC.ClCCCl>[OH:22][C:15]1([CH2:2][CH:3]([CH3:7])[CH2:4][O:5][CH3:6])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[N:13]2[CH2:12][CH2:11][CH2:10][N:9]=[C:14]12
Reactant: COCC(C)CBr
Reactant: O=C1C2=NCCCN2c2ccccc21
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CCOCC
Product: COCC(C)CC1(O)C2=NCCCN2c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-Bromo-3-methoxy-2-methylpropane (10.02 g) in ether (50 ml) was added dropwise over 20 minutes to magnesium turnings (1.46 g) in ether (10 ml). The mixture was stirred under argon at room temperature for 30 minutes, cooled to 0° and 3,4-dihydropyrimido[1,2-a]indol-10(2H)-one (3.72 g) in dry 1,2-dichloroethane (20 ml) added dropwise over 20 minutes. The solution was stirred under argon at 0° for 1 hour, poured onto a swirling mixture of ice (100 ml) and saturated aqueous ammonium chloride (60 ml). The mixture was stirred for 20 minutes and concentrated in vacuo. The aqueous residue was extracted with chloroform (3×100 ml). The extracts were dried (Na2SO4) and concentrated in vacuo. Ether (20 ml) was added and the product was filtered and recrystallised from ethyl acetate to give the title compound as the free base (2.85 g), m.p. 162°-167° C. The free base was acidified with ethereal HCl to give the title compound as the hydrochloride, m.p. 244° (dec.).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=4[F:50])[CH:34]=3)[O:32][C@@:10]1([CH:51]=[O:52])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:53][Mg]Br>O1CCCC1>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=4[F:50])[CH:34]=3)[O:32][C@@:10]1([CH:51]([OH:52])[CH3:53])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: COc1ccc(Cc2cc([C@]34OC[C@](C=O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.3 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6,8-dioxa bicyclo[3.2.1]octane-1-carbaldehyde 21p (0.50 g, 0.69 mmol) in dry tetrahydrofuran (10 mL) was added dropwise methylmagnesium bromide (0.46 mL, 1.38 mmol, 3M in ethyl ether) under N2 at 0° C. The mixture was stirred at room temperature for 2 hours and quenched with water (10 mL). The resulting mixture was extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with saturated aqueous sodium chloride (15 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=15/1 to give the title compound 21q as a white solid (0.14 g, 19%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.41 (s, 3H), 7.31 (m, 9H), 7.21 (m, 4H), 6.98-6.86 (m, 2H), 6.68 (m, 1H), 6.53 (m, 1H), 4.96 (m, 2H), 4.80 (m, 2H), 4.34-4.24 (m, 2H), 4.16-4.05 (m, 4H), 3.98 (m, 2H), 3.85 (s, 3H), 3.82 (dd, 1H), 3.70 (m, 1H), 1.27 (d, 3H).
Reaction SMILES: C[N:2]1[CH2:7][CH:6]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[CH2:26]([O:25][C:23]([N:2]1[CH2:3][CH:4]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C1=CCN(C)CC1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccccc1
Product: CCOC(=O)C1=CCN(C(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 71.4 %

Procedure:
In 640 ml of benzene, 108.9 g of ethyl 1-methyl-1,2,3,6-tetrahydropyridine-4-carboxylate and 41.6 g of diisopropylethylamine were dissolved, and subsequently, 279.1 g of ethyl chloroformate was added dropwise thereto over 70 minutes. The reaction mixture was heated under reflux for 30 minutes, followed by cooling the reaction mixture to room temperature. A saturated aqueous solution of sodium hydrogencarbonate was poured thereinto. After the reaction mixture was extracted with ethyl acetate, the extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=7:1) to yield 104.4 g of ethyl 1-ethoxycarbonyl-1,2,3,6-tetrahydropyridine-4-carboxylate as an oil.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[CH:8]([CH3:40])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[N:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:14]([C:28]#[C:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[N:13]=1)=[O:10])(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[CH3:6][NH:7][CH:8]([CH3:40])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[N:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:14]([C:28]#[C:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[N:13]=1)=[O:10]
Reactant: CC(C(=O)Nc1ccc(-c2cnc3ccccc3c2)c(C#Cc2ccc3ccccc3c2)n1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CNC(C)C(=O)Nc1ccc(-c2cnc3ccccc3c2)c(C#Cc2ccc3ccccc3c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl-N-methyl-N-[1-[[6-(2-naphthalen-2-ylethynyl)-5-quinolin-3-yl-pyridin-2-yl]amino]-1-oxopropan-2-yl]carbamate E2b (91 mg, 0.16 mmol) and DCM:TFA (9:1, 5 ml) is stirred at RT for 1 h. The mixture is diluted with toluene (10 ml) and concentrated in vacuo. The product is purified by RP HPLC. Yield: 74 mg (99%). HPLC-MS: M+H=457; tR=1.58 min (*Method—1).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C(C)=CC=CN=1.N[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C1C=CC=CC=1.C=CCCCC.C1(C)C=CC=CC=1>>[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[CH2:22][CH2:23][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Nc1ccccc1
Reactant: O=Cc1ccccc1
Agent: Cc1cccnc1N
Agent: O=C(O)c1ccccc1
Solvent: C=CCCCC
Solvent: Cc1ccccc1
Product: CCCCCCC(=O)c1ccccc1
Temperature: 130 °C
Reaction time: 0.04 h

Procedure:
Under the same reaction procedure and conditions as in Example 1 (benzaldehyde 0.5 mmol, 2-amino-3-picoline 0.1 mmol, aniline 0.3 mmol, bezoic acid 0.03 mmol, 1-hexene 2.5 mmol, toluene 0.87 mmol), the mixture in a 500 ml pressure reactor was stirred at normal temperature for 2-3 minutes and then various transition metal catalysts as shown in the following table 6 were added to each reactor. While the reactor was stopped with a stopper, the reactants were heated at 130° C. for 1 hour with stirring. After completion of the reaction, gas chromatography was conducted to determine the yields of heptanophenone, products according to various transition metal catalysts. The results are shown in Table 6, below.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][CH2:16][C:17]([OH:19])=O)([CH3:14])[CH2:6][CH2:5]2.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl.C1COCC1>[CH3:14][C:7]1([CH2:15][CH2:16][CH2:17][OH:19])[CH2:6][CH2:5][C:4]2[C:9](=[C:10]([CH3:13])[C:11]([CH3:12])=[C:2]([O:1][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][O:20]3)[CH:3]=2)[O:8]1
Reactant: Cc1c(O)cc2c(c1C)OC(C)(CCC(=O)O)CC2
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1c(OC2CCCCO2)cc2c(c1C)OC(C)(CCCO)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(6-hydroxy-2,7,8-trimethyl-chroman-2-yl)-propionic acid (500 mg), 3,4-dihydro-2-H-pyran (2 mL) and pyridinium p-toluenesulfonate (PPTS) (50 mg) in dichloromethane (20 mL) was stirred at RT for overnight. The mixture was washed with water, dried over MgSO4, and concentrated to give an oily residue. The oil was dissolved in THF, then LiAIH4 (85 mg) was added and the mixture was stirred at RT for 2 h. The excess LiAIH4 was destroyed by adding ethyl acetate, and the mixture was poured into water and extracted with EtOAc. The organic layer was washed with water, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography eluting with 30% EtOAc in hexane to give 732 mg of 3-[2,7,8-trimethyl-6-(tetrahydro-pyran-2-yloxy)-chroman-2-yl]-propan-1-ol as an oily product. 1H-NMR (300 MHz, CDCl3) δ (ppm): 6.67 (s, 1H), 5.32 (t, J=3.2 MHz, 1H), 4.0-3.9 (m, 1H), 3.70-3.55 (m, 3H), 2.75-2.70 (m, 2H), 2.15, 2.09 (2s, 6H), 2.10-1.60 (m, 12H), 1.25 (s, 3H). 13C-NMR (75 MHz, CDCl3) δ (ppm): 148.08, 146.23, 125.51, 125.25, 117.66, 112.99, 112.96, 97.36, 75.17, 63.25, 62.09, 60.41, 36.26, 36.03, 31.51, 31.47, 30.78, 26.97, 25.41, 24.01, 23.81, 22.48, 21.05, 19.11, 14.19, 12.18, 11.94.
Reaction SMILES: [N+](=[CH2:3])=[N-].[C:4]([NH:12][C@H:13]1[C:20](=[O:21])[N:19]2[C@@H:14]1[O:15][CH2:16][C:17]([OH:29])=[C:18]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CCOCC.C(Cl)Cl>[C:4]([NH:12][C@H:13]1[C:20](=[O:21])[N:19]2[C@@H:14]1[O:15][CH2:16][C:17]([O:29][CH3:3])=[C:18]2[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])(=[O:11])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)C1=C(O)CO[C@@H]2[C@@H](NC(=O)c3ccccc3)C(=O)N12
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: ClCCl
Product: COC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](NC(=O)c3ccccc3)[C@H]2OC1
Yield: 62 %

Procedure:
A solutin of diazomethane in ether was added to a solution of 260 mg (0.72 mmol) of tert.-butyl (6R, 7R)-7-benzoylamino-3-hydroxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate in 3 ml of anhydrous methylene chloride at room temperature until a yellow coloration remained. The solvent and excess diazomethane were then evaporated off in vacuo and the residue was chromatographed on 18 g of silica gel (toluene:ethyl acetate 2:3). 169 mg (62%) of the title compound were obtained as a colorless rigid foam.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[O:17]=[C:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][CH2:24][CH2:25][NH:26][C:27]([C:29]1[C:33]([CH3:34])=[C:32]([CH:35]=O)[NH:31][CH:30]=1)=[O:28]>N1CCCCC1.C(O)C>[O:17]=[C:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][CH2:24][CH2:25][NH:26][C:27]([C:29]1[C:33]([CH3:34])=[C:32]([CH:35]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[NH:11][C:10]2=[O:16])[NH:31][CH:30]=1)=[O:28]
Reactant: Cc1c(C(=O)NCCCN2CCCC2=O)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)NCCCN2CCCC2=O)c[nH]c1C=C1C(=O)Nc2cccc(C3CCNCC3)c21
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A mixture of 4-piperidin-4-yl-1,3-dihydroindol-2-one (35.6 mg, 0.165 mmol), 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid [3-(2-oxo-pyrrolidin-1-yl)propyl]-amide (48 mg, 0.173 mmol) and piperidine (2 drops) in ethanol (0.5 mL) was stirred at room temperature for 7 days. The reaction was concentrated and ether was added to the residue. The precipitate which formed was collected by vacuum filtration, washed with ethanol and ether and dried to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[N:6]([CH3:8])[CH3:7].[O:12]1[CH2:14][C@@H:13]1[C@@H:15]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[CH3:7][N:6]([CH3:8])[C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][CH:9]=1)[CH2:2][NH:1][CH2:14][C@@H:13]([OH:12])[C@@H:15]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Reactant: CN(C)c1cccc(CN)c1
Solvent: ClCCl
Product: CN(C)c1cccc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)c1
Temperature: 50 °C

Procedure:
3-(aminomethyl)-N,N-dimethylaniline (1.2 eq) was dissolved in the minimum amount of anhydrous CH2Cl2 under Ar, followed by the addition of tert-butyl (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (1 eq) with stirring. Anhydrous CH2Cl2 was added dropwise until all of the epoxide had dissolved. The reaction was heated to 50° C. After heating overnight all of the solvent was gone leaving a solid in the flask. Purification via flash chromatography yielded tert-butyl (2S,3R)-4-(3-(dimethylamino)benzylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]4[C:18]([CH:19]([C:21]5[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]([F:28])[C:22]=5[Cl:29])[CH3:20])=[CH:17][NH:16][C:13]4=[N:14][CH:15]=3)[CH:7]=[N:6]2)[CH2:2]1.[CH:30](OCC)=[O:31]>>[Cl:29][C:22]1[C:23]([F:28])=[CH:24][CH:25]=[C:26]([Cl:27])[C:21]=1[CH:19]([C:18]1[C:12]2[C:13](=[N:14][CH:15]=[C:10]([C:8]3[CH:7]=[N:6][N:5]([CH:3]4[CH2:2][N:1]([CH:30]=[O:31])[CH2:4]4)[CH:9]=3)[CH:11]=2)[NH:16][CH:17]=1)[CH3:20]
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CNC4)c3)cc12
Reactant: CCOC=O
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CN(C=O)C4)c3)cc12
Temperature: 50 °C

Procedure:
A mixture of 5-(1-azetidin-3-yl-1H-pyrazol-4-yl)-3-[1-(2,6-dichloro-3-fluorophenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (6.0 mg, 0.014 mmol) and ethyl formate (2 mL) was heated to 50° C. overnight in a sealed tube. The solution was concentrated in vacuo, redissolved in MeOH and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.89 (d, J=7.3 Hz, 3 H), 4.37 (ddd, J=6.2, 5.1, 4.9 Hz, 1 H), 4.46-4.54 (m, 1 H), 4.60 (dd, J=9.2, 5.4 Hz, 1 H), 4.71 (t, J=8.6 Hz, 1 H), 5.30 (q, J=7.3 Hz, 1 H), 5.38 (tt, J=8.2, 5.5 Hz, 1 H), 7.16-7.23 (m, 1 H), 7.38 (d, J=1.3 Hz, 1 H), 7.39-7.57 (m, 2 H), 7.72 (s, 1 H), 7.95 (s, 1 H), 8.07 (s, 1 H), 8.33 (d, J=1.8 Hz, 1 H). MS (ES+): m/z 458.06 (100) [MH+]. HPLC: tR=3.22 min (ZQ3, polar—5 min).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[F:10][C:11]([F:31])([F:30])[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[CH:22]([CH2:27][CH2:28][CH3:29])[C:23](OC)=[O:24].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1>[F:10][C:11]([F:30])([F:31])[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][C:13]=1[CH:22]([CH2:27][CH2:28][CH3:29])[CH2:23][OH:24]
Reactant: CCCC(C(=O)OC)c1cc(C(F)(F)F)ccc1C(F)(F)F
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC(CO)c1cc(C(F)(F)F)ccc1C(F)(F)F
Reaction time: 0.75 h

Procedure:
DiBAL (7.62 ml, 1M in DCM, 7.62 mmol) was added to a solution of methyl 2-[2,5-bis(trifluoromethyl)phenyl]pentanoate (1 g, 3.05 mmol) in THF at −30° C. The mixture was stirred for 45 min. Sodium potassium tartrate (100 ml, satd. aq. solution) was added and the mixture was stirred at room temperature for 30 min then extracted into EtOAc. The combined organic phases were washed with brine, then dried (MgSO4) and concentrated in vacuo to give the product as a colourless oil. This was purified by chromatography on silica using hexane/EtOAc (9:1) as eluant to afford the product as an oil (710 mg). 1H NMR (500 MHz, CDCl3): δ 0.89 (3H, t, J 7.3), 1.10-1.20 (1H, m), 1.28-1.36 (1H, m), 1.60-1.68 (1H, m), 1.80-1.87 (1H, m), 3.33-3.39 (1H, m), 3.79 (2H, t, J 5.5), 7.59 (1H, d, J 8.3), 7.74 (1H, s), 7.79 (1H, d, J 8.2).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].Cl[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:14]=2)[CH:8]=1>CC(O)(CC)C.[Cl-].[Zn+2].[Cl-]>[CH3:1][N:2]([C:17]1[CH:16]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:14]=[C:13]([C:9]2[CH:8]=[CH:7][CH:12]=[CH:11][N:10]=2)[CH:18]=1)[CH2:3][CH2:4][OH:5]
Reactant: Clc1ccnc(-c2cccc(-c3ccccn3)n2)c1
Reactant: CNCCO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCC(C)(C)O
Product: CN(CCO)c1cc(-c2ccccn2)nc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.5 %

Procedure:
129 g (1.72 mol) 2-methylamino-ethanol and 390 mg (2.86 mmol) zinc(II)-chloride are successively added to a suspension of 15.3 g (57.2 mmol) 4′-chloro-2,2′;6,2″-terpyridine in 100 ml 2-methyl-2-butanol. The reaction mixture is refluxed for 2.5 days. A brown suspension is obtained, which is evaporated under vacuum to a yellow-brown solid product. 100 ml water is added to this product and stirred at room temperature for 20 minutes. Then, the obtained mixture is filtrated and the filter residue dried for 12 hours at (45° C., 10 mbar). 14.8 g (84%) of 2-(methyl-[2,2′;6′2″]terpyridine-4′yl-amino)-ethanol as colourless solid product is obtained.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[Cl:11].[CH2:13]([Sn](CCCC)(CCCC)C=C)[CH2:14]CC>C1COCC1>[Cl:11][C:5]1[CH:6]=[C:7]([CH:13]=[CH2:14])[CH:8]=[CH:9][C:4]=1[C:3]([OH:2])=[O:12]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(Br)cc1Cl
Solvent: C1CCOC1
Product: C=Cc1ccc(C(=O)O)c(Cl)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 4-bromo-2-chlorobenzoic acid methyl ester (500 mg, 2 mmol) in THF (15 mL) was added tributyl(vinyl)tin (620 μl, 2.1 mmol) and PdCl2(dppf)-2-DCM (165 mg, 0.2 mmol). The solution was heated to 60° C. for 12 hours. The crude reaction mixture was then concentrated down and taken up in 20 mL EtOAc and 100 mL concentrated KF solution. The reaction stirred at room temperature for 3 hours, filtered through a pad of celite and concentrated down. The residual oil was subjected to flash chromatography (Isco Companion, 40 g SiO2 cartridge, solid loaded SiO2, neat heptanes to EtOAc gradient) to give 2-chloro-4-vinylbenzoic acid as a yellow oil. Amount obtained: 235 mg (60%). LCMS (M/Z): 197 (M+H). 1H NMR (Chloroform-d) δ: 3.93 (s, 3 H) 5.42 (d, J=10.9 Hz, 1 H) 5.86 (d, J=17.6 Hz, 1 H) 6.66 (dd, J=17.6, 10.7 Hz, 1 H) 7.28-7.35 (m, 1 H) 7.43-7.50 (m, 1 H) 7.82 (d, J=8.0 Hz, 1 H).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH:6]1([N:9]2[C:17]3[C:12](=[C:13]([O:23][CH3:24])[CH:14]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=3)[CH:11]=[CH:10]2)[CH2:8][CH2:7]1.CN([CH:28]=[O:29])C>CCOC(C)=O.[OH-].[Na+]>[CH:6]1([N:9]2[C:17]3[C:12](=[C:13]([O:23][CH3:24])[CH:14]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=3)[C:11]([CH:28]=[O:29])=[CH:10]2)[CH2:7][CH2:8]1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc(OC)c2ccn(C3CC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(OC)c2c(C=O)cn(C3CC3)c2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.28 ml of POCl3 was added dropwise to a solution of 3.24 g of ethyl 1-cyclopropyl-4-methoxy-1H-indole-6-carboxylate in 30 ml of DMF and the mixture was stirred at 0° C. for 2 hrs. The mixture was diluted with EtOAc and 25 ml of 1N NaOH was added. Then the mixture was made basic using saturated NaHCO3aq. The mixture was extracted with EtOAc and the extract was washed with water and saturated brine, dried over Na2SO4, then concentrated. The residue was purified on SiO2 column chromatography (EtOAc-n-Hexane system) to give 2.4 g of ethyl 1-cyclopropyl-3-formyl-4-methoxy-1H-indole-6-carboxylate.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:8][NH:7][C:6](=[O:17])[NH:5]1.Cl[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O>[CH3:3][CH:4]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:15]=2)=[N:8][NH:7][C:6](=[O:17])[NH:5]1
Reactant: CCOC(=O)CCl
Reactant: CC1NC(=O)NN=C1c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C2=NNC(=O)NC2C)cc1
Yield: 55.1 %

Procedure:
0.12 g of sodium hydride (as a 55% w/w dispersion in mineral oil) was added to a solution of 0.55 g of 4,5-dihydro-5-methyl-6-(p-hydroxyphenyl)-1,2,4-triazin-3(2H)-one [prepared as described in step (a) above] dissolved in 6 ml of dimethylformamide, whilst ice-cooling and stirring, and the mixture was stirred at room temperature for 30 minutes. At the end of this time, 0.33 g of ethyl chloroacetate was added. The mixture was then heated at 105° to 110° C. for 3 hours, whilst stirring. The dimethylformamide was then distilled off under reduced pressure, and the residue was diluted with water, after which the mixture was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate, and then subjected to column chromatography through silica gel eluted with a 1:50 by volume mixture of ethanol and methylene chloride to give a brown oil. This oil was triturated with ethyl acetate to give crystals, which were recrystallized from ethyl acetate, to give 0.43 g of the title compound as pale yellow needles melting at 152°-153° C.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:30]1[CH2:31][CH2:32][C@@H:28]([NH:27][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:8]4[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:26])[CH2:29]1)(=[O:35])[CH3:34]
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c(C)[nH]c23)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(C)=O)C4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f26) and commercially available acetyl chloride the title compound is obtained as colorless solid.