Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:22]([NH:24][CH2:25][CH3:26])=[O:23].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[Cl:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1[N:30]1[CH2:31][CH2:32][N:33]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][C@H:8]4[C:7](=[O:16])[NH:6][C:5]=3[CH:4]=2)[CH2:34][CH2:35]1)[C:22]([NH:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(Cl)c1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)c(Cl)c1
Temperature: 105 °C
Yield: 35.3 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), 3-chloro-N-ethyl-4-(piperazin-1-yl)benzamide hydrochloride (139 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 10-95% ACN in water). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-methanol (5:1, 6 mL) and dried in vacuum to afford (S)-3-chloro-N-ethyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (75.6 mg, 0.161 mmol, 35.3% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (t, J=7.20 Hz, 3H) 1.76-1.93 (m, 3H) 2.06-2.17 (m, 1H) 2.44-2.51 (m, 4H) 2.96 (br. s., 4H) 3.14-3.23 (m, 2H) 3.28-3.38 (m, 3H) 3.46-3.58 (m, 1H) 3.88-3.97 (m, 1H) 6.92 (d, J=2.02 Hz, 1H) 7.10 (d, J=8.34 Hz, 1H) 7.56 (d, J=1.77 Hz, 1H) 7.70 (dd, J=8.34, 2.02 Hz, 1H) 7.81 (d, J=2.27 Hz, 1H) 8.37 (t, J=5.43 Hz, 1H) 10.38 (s, 1H). [M+H] calc'd for C24H29ClN6O2, 469. found, 469.
Reaction SMILES: [C:1]([N:4]1[C@:8]([CH2:15][CH2:16][CH:17]=O)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][C:6]([C:19]2[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:20]=2[F:26])=[N:5]1)(=[O:3])[CH3:2].[C:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])[CH3:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:27]([N:30]1[CH2:35][CH2:34][N:33]([CH2:17][CH2:16][CH2:15][C@:8]2([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:4]([C:1](=[O:3])[CH3:2])[N:5]=[C:6]([C:19]3[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:20]=3[F:26])[CH2:7]2)[CH2:32][CH2:31]1)(=[O:29])[CH3:28]
Reactant: CC(=O)N1CCNCC1
Reactant: CC(=O)N1N=C(c2cc(Br)ccc2F)C[C@@]1(CCC=O)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(=O)N1CCN(CCC[C@@]2(c3ccccc3)CC(c3cc(Br)ccc3F)=NN2C(C)=O)CC1
Reaction time: 8 h

Procedure:
To a solution of 57 mg (0.137 mmol) 3-6 in 1.0 mL of anhydrous DCE under Ar was added 26.3 mg (0.206 mmol) 1-acetylpiperazine followed by 58.1 mg (0.274 mmol) sodium triacetoxyborohydride. The mixture stirred overnight before quenching with saturated aqueous NaHCO3 solution and adding a small amount of DCM. The aqueous phase was re-extracted with DCM and the organic phases were loaded directly onto silica gel for flash chromatography using a mixture of hexanes, EtOAc, and 20:1:1 EtOH—NH4OH—H2O to give 3-7 as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@:8]([NH:18][S@](C(C)(C)C)=O)([CH2:14][CH2:15][O:16][CH3:17])[C:9]([F:13])([F:12])[CH2:10][OH:11])[C:5]([F:25])=[CH:4][CH:3]=1.Cl.C(OCC)C.N>CO>[NH2:18][C@@:8]([C:6]1[C:5]([F:25])=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)([CH2:14][CH2:15][O:16][CH3:17])[C:9]([F:12])([F:13])[CH2:10][OH:11]
Reactant: COCC[C@@](N[S@@](=O)C(C)(C)C)(c1nc(Br)ccc1F)C(F)(F)CO
Agent: Cl
Agent: N
Solvent: CO
Solvent: CCOCC
Product: COCC[C@@](N)(c1nc(Br)ccc1F)C(F)(F)CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a solution of (S)-2-methyl-propane-2-sulfinic acid [(R)-1-(6-bromo-3-fluoro-pyridin-2-yl)-2,2-difluoro-3-hydroxy-1-(2-methoxy-ethyl)-propyl]amide (1.50 g, 3.33 mmol) in methanol (8.4 ml) was added 2M HCl in diethyl ether (6.56 ml, 13.11 mmol). The reaction mixture was stirred for 1.5 h at room temperature. 7 M ammonia in methanol (2.7 ml) was added to the reaction mixture and the resulting colourless suspension was evaporated in vacuo. The remaining solid was triturated with warm dichloromethane, cooled to rt, filtered and rinsed with dichloromethane. The filtrate was evaporated affording the title compound which was used without purification in the next step. 1.42 g colourless, viscous oil. 100% yield.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[N:11]([CH3:27])[CH:12]=[C:13]([NH:15][C:16]([C:18]3[N:19]([CH3:26])[CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=3)=[O:17])[CH:14]=2)=[O:9])[CH:4]=[C:3]1[C:28](O)=[O:29].[ClH:31].Cl.[NH2:33][CH2:34][CH2:35][NH:36][C:37]([NH2:39])=[NH:38].O.ON1C2C=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[ClH:31].[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[N:11]([CH3:27])[CH:12]=[C:13]([NH:15][C:16]([C:18]3[N:19]([CH3:26])[CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=3)=[O:17])[CH:14]=2)=[O:9])[CH:4]=[C:3]1[C:28]([NH:33][CH2:34][CH2:35][NH:36][C:37]([NH2:39])=[NH:38])=[O:29]
Reactant: Cn1cc(NC(=O)c2cc(NC(=O)c3cc([N+](=O)[O-])cn3C)cn2C)cc1C(=O)O
Reactant: N=C(N)NCCN
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(NC(=O)c2cc(NC(=O)c3cc([N+](=O)[O-])cn3C)cn2C)cc1C(=O)NCCNC(=N)N
Yield: 105 %

Procedure:
A solution of 1-methyl-4-[1-methyl-4-[1-methyl-4-nitropyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxylic acid (590 mg) (prepared as reported in Tetrahedron 34,2389-2391,1978) in 20 ml of DMF, 2-aminoethylguanidine dihydrochloride (500 mg), 1-hydroxybenzotriazole hydrate(350 mg), dicycloexylcarbodiimide (880 mg), and sodium bicarbonate (385 mg) was stirred at 70° C. for 4 hours. The solution obtained after filtration was evaporated in vacuo and the residue purified by flash chromatography (methylene chloride/methanol: 8/2) to yield 800 mg of 2-[1-methyl-4-[1-methyl-4-[1-methyl-4-nitropyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]ethylguanidine hydrochloride, which was dissolved in methanol (100 ml), added with 1N hydrochloric acid solution (2 ml) and reduced over Pd catalyst (10% on charcoal) in hydrogen atmosphere (50 psi) in a Parr apparatus. The solution obtained after filtration of the catalyst was evaporated in vacuo and the solid residue washed with dry ethanol to yield 750 mg of the intermediate as a brown powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([O:33][CH3:34])=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[CH:19]=[C:18]2[NH:24][C:25]1[C:30]([Cl:31])=[CH:29][N:28]=[CH:27][C:26]=1[Cl:32]>>[Cl:32][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([Cl:31])[C:25]=1[NH:24][C:18]1[C:17]2[C:22](=[C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[C:14]([O:33][CH3:34])=[CH:15][CH:16]=2)[O:21][C:20](=[O:23])[CH:19]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCBr
Reactant: C1COCCN1
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCN1CCOCC1

Procedure:
The title compound was prepared from morpholine and 8-(4-bromobutoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 25) following the procedure outlined in Example 52. 1H NMR (400 MHz, DMSO-d6; HCl salt): δ 10.67 (br, 1H), 9.65 (br s, 1H), 8.82 (s, 2H), 8.01 (d, 1H), 7.22 (d, 1H), 4.64 (s, 1H), 4.01 (t, 2H), 3.93 (s, 3H), 3.92 (m, 2H), 3.76 (t, 2H), 3.42 (d, 2H), 3.20 (m, 2H), 3.05 (m, 2H), 1.97 (m, 2H), 1.74 (m, 2H); MS (ESI): 494.0.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:15]([Si:19]([CH3:22])([CH3:21])Cl)([CH3:18])([CH3:17])[CH3:16].N1C=CN=C1.O>CN(C=O)C>[Si:19]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:9][CH:10]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:22])[CH3:21]
Reactant: Nc1ncccc1-c1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cccnc2N)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 4-(2-aminopyridin-3-yl)phenol (19.8 g), tert-butyldimethylchlorosilane (21.8 mL) and 1H-imidazol (8.69 g) in DMF (200 mL) was stirred at room temperature for 20 hr. To the mixture was added water, and the resulting precipitate was collected by filtration, and then washed with water to give the title compound (30.5 g) as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH:13]=[CH:12]2)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[F:24][C:21]1[CH:22]=[CH:23][C:18]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=3)[CH2:12][CH2:13]2)=[CH:19][CH:20]=1
Reactant: Fc1ccc(-n2ccc3cc(OCc4ccccc4)ccc32)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Oc1ccc2c(c1)CCN2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.6 %

Procedure:
3.17 g (10 mmol) 5-Benzyloxy-1-(4-fluoro-phenyl)-1H-indole in 25 ml acetic acid was hydrogenated in the presence of 300 mg 10%Pd/C, filtered and hydrogenated with 60 mg PtO2 for 3 h. The catalyst was removed by filtration and the solution concentrated. The residue was dissolved in 15 ml trifluoroacetic acid and treated with 1.9 g (30 mml) sodium cyanoborhydride at 0° C. The solution was stirred at RT for 30 min, concentrated and dissolved in ether, 0.5M NaOH. The inorganic phase was extracted with ether, the combined organic phases were washed with brine and dried over Na2SO4. Column chromatography on silica gel with CH2Cl2/MeOH 19:1 yielded 1.0 g (44%) 1-(4-Fluoro-phenyl)-2,3-dihydro-1H-indol-5-ol as colorless solid; MS: 229 (M).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH2:7]([O:14][C:15]1[C:20](=[O:21])[CH:19]=[CH:18]O[C:16]=1[CH3:22])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].Cl>O.C(O)C>[CH2:7]([O:14][C:15]1[C:20](=[O:21])[CH:19]=[CH:18][N:1]([CH2:2][CH2:3][C:4]([OH:6])=[O:5])[C:16]=1[CH3:22])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCCC(=O)O
Reactant: Cc1occc(=O)c1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCC(=O)O

Procedure:
β-Alanine (5 g) in water (50 ml) is added to 3-benzyloxy-2-methyl-4-pyrone (10 g) in 95% ethanol (100 ml) and sodium hydroxide (4 g) in water (50 ml) is then slowly added to the reaction mixture until a pH of 13 is obtained. The solution is refluxed for 15 minutes during which time the colour changes from yellow to amber. After cooling, the solution is acidified to pH 2.5 with concentrated HCl (about 2 ml) and is then rotary evaporated at 50° C. The resulting oil is subjected to a methylene chloride/water extraction. The solid which remains is triturated with acetone and recrystallised from water to give 3-benzyloxy-1-(2'-carboxyethyl)-2-methylpyrid-4-one, m.p. 81°-83° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:11][CH:12]1[CH2:17][CH2:16][Si:15]([CH2:24][CH2:25][CH2:26][CH2:27][F:28])(C2C=CC=CC=2)[CH2:14][CH2:13]1>>[F:1][C:2]1[CH:3]=[C:4]([O:9][CH2:11][C@H:12]2[CH2:13][CH2:14][Si@H:15]([CH2:24][CH2:25][CH2:26][CH2:27][F:28])[CH2:16][CH2:17]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: FCCCC[Si]1(c2ccccc2)CCC(CBr)CC1
Reactant: Oc1ccc(F)c(F)c1
Product: FCCCC[Si@H]1CC[C@H](COc2ccc(F)c(F)c2)CC1

Procedure:
The general procedure of Example 9 was repeated using 3,4-difluorophenol and 4-bromomethyl-1-(4-fluorobutyl)-1-phenyl-1-silacyclohexane, thereby obtaining the intended compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[S:18](=[O:20])(=[O:19])[N:17](C(OC)=O)[CH2:16][CH:15]([CH3:25])[CH2:14]1.[OH-].[Na+]>CO>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[CH2:14][CH:15]([CH3:25])[CH2:16][NH:17][S:18]1(=[O:19])=[O:20]
Reactant: COC(=O)N1CC(C)CN(c2c(Cl)cc(C(F)(F)F)cc2Cl)S1(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CNS(=O)(=O)N(c2c(Cl)cc(C(F)(F)F)cc2Cl)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To methyl 6-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-methyl-1,2,6-thia-diazinan-2-carboxylate 1,1-dioxide (3.58 g, 8.50 mmol) in MeOH (60 mL), was dropwisely added 1 N NaOH (85 mL, 85 mmol) and agitated for 12 hr at room temperature. Following concentration under reduced pressure, ethyl acetate (30 mL) and water (30 mL) were added to the resultant to obtain the organic layer. The organic layer was dried over MgSO4 and crystallized using ethyl acetate (10 mL) and hexane (70 mL), giving the compound of interest (2.96 g, 96%, white solid). 1H NMR (300 MHz, CDCl3): δ 7.65 (s, 2H), 4.48-4.43 (m, 1H), 4.04-3.96 (m, 1H), 3.61-3.55 (m, 2H), 3.42-3.36 (m, 1H), 2.32 (m, 1H), 0.97 (d, 3H, J=6.8 Hz).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([NH:20][C@@H:21]([C:23]([OH:25])=O)[CH3:22])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[NH2:26][CH2:27][CH:28]([OH:30])[CH3:29]>C(Cl)Cl>[C:16]([O:15][C:13]([NH:20][C@@H:21]([C:23]([NH:26][CH2:27][CH:28]([OH:30])[CH3:29])=[O:25])[CH3:22])=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(O)CN
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(O)CNC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
A mixture of CDI (19 g, 0.12 mol), Boc-D-alanine (20 g, 0.11 mol) and DCM (300 ml), was stirred at r.t. for 1 h, before 1-amino-2-propanol (14 ml, 0.18 mol) was added. The reaction mixture was stirred at r.t. overnight. After concentration, the residue was purified by column, and 13 g (46.3%) of N2-(tert-butoxycarbonyl)-N-(2-hydroxypropyl)-D-alaninamide as solid was obtained. ES-MS [M+1]+: 247.01.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:6]2[C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([NH:18][C:19](=[O:25])[C@@H:20]([CH:22]([CH3:24])[CH3:23])[NH2:21])=[CH:14][N:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:26][C:2]1([CH3:1])[C:6]2[C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([N:18]4[C:19](=[O:25])[C@@H:20]([CH:22]([CH3:23])[CH3:24])[NH:21][C:28]4=[O:30])=[CH:14][N:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)[C@@H](N)C(=O)Nc1cnc(Oc2cccc3c2C(C)(C)CO3)nc1
Solvent: ClCCl
Product: CC(C)[C@H]1NC(=O)N(c2cnc(Oc3cccc4c3C(C)(C)CO4)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
To a solution of N1-{2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}-D-valinamide (Intermediate 145, 38 mg, 0.107 mmol) in dry Dichloromethane (DCM) (5 mL) TEA (0.074 mL, 0.533 mmol) was added and the reaction mixture was cooled to 0° C. A solution of triphosgene (14.24 mg, 0.048 mmol) in dry Dichloromethane (DCM) (1 mL) was slowly added and the reaction mixture was stirred for 30 minutes at the same temperature. The reaction was quenched with water (3 ml) and two phases were separated. The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a column SNAP 25 g and cyclohexane/ethyl acetate from 8:2 to 1:1 as eluent affording the title compound (15 mg) as a white solid.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]([CH3:11])([OH:10])[CH3:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12](OC(=O)C)(=[O:14])[CH3:13].OP(O)(O)=O>O>[C:12]([O:10][C:8]([CH3:11])([CH3:9])[CH2:7][CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:14])[CH3:13]
Reactant: CC(C)(O)CCC1CCCC1
Reactant: CC(=O)OC(C)=O
Agent: O=P(O)(O)O
Solvent: O
Product: CC(=O)OC(C)(C)CCC1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
10 g (64 mmol) of 4-cyclopentyl-2-methyl-2-butanol, 32.6 g (320 mmol) of acetic anhydride and a drop of H3PO4 (85% in water) were introduced in a 200 ml flask, and the mixture was stirred over night, at room temperature. Afterwards, 100 ml of water where added and the stirring was prolonged for an additional period of 2 hours. The crude product was extracted by washing the water solution with pentane. The organic phases thus obtained were washed twice with a saturated NaHCO3 water solution, then twice with brine and finally dried over MgSO4 and concentrated. It was thus obtained 12.7 g of crude product (quantitative yield) having a GC purity of 99%.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=C[CH:11]=2)[C:6](=O)[C:5]1=O)CC.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26].BrCCN1CCCCC1>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:11][CH2:12][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:20](=[O:25])[C:19]2=[O:26]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Agent: BrCCN1CCCCC1
Product: O=C1C(=O)N(CCN2CCCCC2)c2ccc(Cl)cc21

Procedure:
Was prepared in an analogous manner to 1-propylindoline-2,3-dione using commercially available 5-chloroisatin (purchased from Fisher Scientific) and 1-(2-bromoethyl)piperidine (purchased from Fisher Scientific). 1H-NMR δ 7.55 (m, 2H), 6.95 (d, 1H), 3.84 (t, 2H), 2.58 (t, 2H), 2.46 (bs, 4H), 1.54 (m, 4H), 1.43 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14][C:5]2=1.[H-].[Na+].[CH3:24]I>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:24])[C:6]1[CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14][C:5]2=1
Reactant: CC(C)(C)OC(=O)N1CCc2c([nH]c3ccc(Br)cc23)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1c2c(c3cc(Br)ccc31)CCN(C(=O)OC(C)(C)C)C2
Reaction time: 1 h
Yield: 62.1 %

Procedure:
tert-Butyl 6-bromo-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (1.15 g, 3.26 mmol) was dissolved in DMF (20 mL) and sodium hydride (60% weight dispersion in mineral oil, 196 mg, 4.89 mmol) was added. After 1 h, methyl iodide (0.30 mL, 4.9 mmol) was added and the reaction mixture was stirred for a further 30 min. The mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5×), dried over Na2SO4 and concentrated. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, 97:3 to 75:25) gave the title compound (740 mg, 36%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 7.58 (s, 1H), 7.24 (d overlapped by solvent, J=8.5, 1H), 7.14 (d, J=8.5, 1H), 4.67-4.53 (br m, 2H), 3.79-3.67 (br m, 2H), 3.60 (s, 3H), 2.78-2.66 (br m, 2H), 1.51 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:21][CH2:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH3:23])[CH:17]=4)[N:12](C(OC(C)(C)C)=O)[C:11]=3[C:10]2=[O:31])=[C:4]([F:32])[C:3]=1[O:33][C:34]1[CH:39]=[C:38]([C:40]#[N:41])[CH:37]=[C:36]([Cl:42])[CH:35]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:42][C:36]1[CH:37]=[C:38]([CH:39]=[C:34]([O:33][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[C:5]([CH2:8][N:9]3[CH2:21][CH2:20][C:19]4[C:18]5[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH3:23])[CH:17]=5)[NH:12][C:11]=4[C:10]3=[O:31])[C:4]=2[F:32])[CH:35]=1)[C:40]#[N:41]
Reactant: COc1ccc2c(c1)c1c(n2C(=O)OC(C)(C)C)C(=O)N(Cc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2[nH]c3c(c2c1)CCN(Cc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F)C3=O
Reaction time: 1 h
Yield: 78.4 %

Procedure:
1,1-Dimethylethyl 2-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-6-(methyloxy)-1-oxo-1,2,3,4-tetrahydro-9H-β-carboline-9-carboxylate (0.03 g, 0.05 mmol), was dissolved in CH2Cl2 (1.0 mL) and TFA (1.0 mL) was added dropwise. The reaction mixture was stirred 1 h and the solvent was evaporated. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA). The desired fractions were neutralized with saturated NaHCO3 and extracted with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered and evaporated to afford the title compound (0.02 g, 80%) as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.50 (br. s., 1H), 7.80 (s, 1H), 7.47-7.55 (m, 3H), 7.39 (t, 1H), 7.27 (d, 1H), 7.04 (d, 1H), 6.86 (dd, 1H), 4.76 (s, 2H), 3.75 (s, 3H), 3.66 (t, 2H), 2.97 (t, 2H). MS: m/z 510.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[F:17][C:18]([F:36])([F:35])[C:19]1[CH:20]=[C:21]([C:29]([CH3:34])([CH3:33])[C:30](O)=[O:31])[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCCl>[C:4]([C:3]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:2]=1[NH:1][C:30](=[O:31])[C:29]([C:21]1[CH:20]=[C:19]([C:18]([F:17])([F:35])[F:36])[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=1)([CH3:34])[CH3:33])(=[O:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CC(C)(C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCCl
Product: CC(C)(C(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of 233 mg (1 mmol) of 2-amino-5-chlorobenzophenone in 2 ml of 1,2-dichloroethane were added 360 mg (1.2 mmol) of 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionic acid and the reaction mixture was shaken at 80° C. for 1 h. Dicyclohexyl carbodiimide (194 mg, 1.2 mmol) was added and shaking was continued overnight at the same temperature. The solvent was evaporated and the residue obtained was purified by column chromatography on silica gel to yield 298 mg (58%) of the title compound as yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[C:11]([CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24](=[O:27])[CH2:25]Br)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:19]([O:23][C:24](=[O:27])[CH2:25][N:15]1[C:16]2[C:12](=[C:11]([CH3:18])[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:17]=2)[CH:13]=[CH:14]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cc(OCc2ccccc2)cc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)cc2c1ccn2CC(=O)OC(C)(C)C

Procedure:
In analogy to the procedure described in example 1 c], 6-benzyloxy-4-methyl-1H-indole was reacted with bromo-acetic acid tert-butyl ester in the presence of cesium carbonate in DMF to obtain (6-benzyloxy-4-methyl-indol-1-yl)-acetic acid tert-butyl ester as yellow oil.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][NH:32][CH2:31][C@H:30]4[OH:35])=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][N:32]([C:36](=[O:39])[CH2:37][CH3:38])[CH2:31][C@H:30]4[OH:35])=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ccnc23)[C@H](O)C1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f25) and commercially available propionyl chloride the title compound is obtained as colorless solid.