Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)[C:2]#[CH:3].[Li]CCCC.B(F)(F)F.[CH3:20][Si:21]([CH3:30])([CH3:29])[CH2:22]/[CH:23]=[CH:24]\[CH2:25][C@@H:26]1[CH2:28][O:27]1>C1COCC1>[O:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]1[O:4][CH2:1][C:2]#[C:3][CH2:28][C@H:26]([OH:27])[CH2:25]/[CH:24]=[CH:23]\[CH2:22][Si:21]([CH3:30])([CH3:20])[CH3:29]
Reactant: C#CCOC1CCCCO1
Reactant: C[Si](C)(C)C/C=C\C[C@@H]1CO1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C/C=C\C[C@@H](O)CC#CCOC1CCCCO1
Reaction time: 0.83 h
Yield: 93.1 %

Procedure:
24.5 ml (174 mmol) of Tetrahydro-2-(2-propynyloxy)2H-pyran was dissolved in 285 ml of abs. THF and deprotonated at -13°--6° by adding slowly 112 ml of nBuLi (1.55 M, hexane). 20 Minutes later, the solution was cooled to -75° and 21.85 ml of BF3 oEtOEt was added. Afterwards, 10.51 g of (Z)-(R)-trimethyl-(4-oxiranyl-but-2-enyl)-silane, dissolved in 96 ml of abs. THF, was added within 75 minutes while maintaining the temperature below -70°. The reaction mixture was kept for another 50 minutes at this temperature and then poured onto crushed ice/NaHCO3, extracted with ether, washed with brine, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=8/2) produced 17.83 g of (Z)-(5R)-9-(tetrahydro-pyran-2-yloxy)-1-trimethylsilanyl-non-2-en-7-yn-5-ol as colorless oil (1:1 epimeric mixture).
Reaction SMILES: CO[N:3](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:4]1[NH:5][C:6](=[O:30])[C:7]2[N:8]=[CH:9][N:10]([C@@H:13]3[O:24][C@H:23]([CH2:25][OH:26])[C@@H:15]([O:16]C4CCCCO4)[C@@:14]3([C:28]#[CH:29])[F:27])[C:11]=2[N:12]=1>CC(O)=O.C1COCC1.O>[C:28]([C@@:14]1([F:27])[C@H:15]([OH:16])[C@@H:23]([CH2:25][OH:26])[O:24][C@H:13]1[N:10]1[CH:9]=[N:8][C:7]2[C:6](=[O:30])[NH:5][C:4]([NH2:3])=[N:12][C:11]1=2)#[CH:29]
Reactant: C#C[C@@]1(F)[C@H](OC2CCCCO2)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N(OC)C(c3ccccc3)(c3ccccc3)c3ccccc3)nc21
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: C#C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21

Procedure:
20 was synthesized from 19 (0.09 mmol), as described for 9k. The crude material was then stirred at room temperature in AcOH/THF/H2O (4/2/1) solution overnight. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (DCM/MeOH) to yield the title compound. White lyophilized powder. Molecular Formula C26H37FN5O9PS2 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 1.16 (s, 20H), 3.06-3.09 (m, 4H), 3.90-3.91 (d, J=5.40 Hz, 1H), 3.99-4.10 (q, J=6.70 Hz and J=7.00 Hz, 4H), 4.32-4.38 (m, 2H), 4.63 (m, 1H), 6.10-6.14 (d, J=16.93 Hz, 1H), 6.69 (s, 2H), 7.79 (s, 1H), 10.96 (s, 1H) 31P NMR (DMSO-d6, 162 MHz) δ (ppm) −1.91 (s, 1P) 19F NMR (DMSO-d6, 376 MHz) δ (ppm) −156.82 (s, 1F) Scan ES+ 678 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:18][O:19][C:20](=[O:23])[CH2:21]Br>CN(C=O)C>[CH3:18][O:19][C:20](=[O:23])[CH2:21][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:15])[C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][N:9]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)ccn1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN(C(=O)OC(C)(C)C)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 289.1 %

Procedure:
To a DMF suspension (1 ml) of (4-chloro-pyridin-2-yl)-carbamic acid tert-butyl ester (100 mg, 0.437 mmol), NaH (60% mineral oil dispersion, 68 mg) was added with ice cooling, followed by stirring at room temperature for 30 minutes. To the reaction mixture, bromoacetic acid methyl ester (0.19 ml, 2.06 mmol) was added, followed by stirring at room temperature for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate (20 ml×2). The organic layers were combined, and washed with saturated aqueous sodium chloride solution. After the organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10:1), to obtain [tert-butoxycarbonyl-(4-chloro-pyridin-2-yl)-amino]-acetic acid methyl ester as a colorless liquid (380 mg, 97%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([C:14]([O:16][CH3:17])=[O:15])[CH:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[I-].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O.CCOCC>[C:7]1([C@H:6]2[C@@H:5]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][CH2:3][CH2:2][NH:13]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)C(CCCCl)C(N)c1ccccc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CCCN[C@H]1c1ccccc1
Yield: 78 %

Procedure:
3-(3'-Chloropropyl)-4-phenyl-1-(tert.-butyldimethylsilyl)azetidin-2-one (3.07 gm, 9.0 mmole) was dissolved in 10% methanolic sulfuric acid and refluxed for 16 hours. At the end of this period, the reaction mixture was cooled, the sulfuric acid was neutralized with sodium bicarbonate and the mixture was taken up in ether (2×200 ml). The ethereal solution was washed with water (2×50 ml) and dried (anhyd. magnesium sulfate). Evaporation afforded essentially pure 5-chloro-2-carbomethoxy-1-phenylpent-1-ylamine as an oil (2.11 gms). The 5-chloro-2-carbomethoxy-1-phenylpent-1-ylamine thus obtained was dissolved in the dimethylformamide ("DMF") (20 ml) and sodium iodide (2.11 gm) and sodium bicarbonate (2.11 gm) were added. The resulting mixture was refluxed for 15 min. At the end of this period, the reaction mixture was cooled and taken up in ether (200 ml). The ethereal solution as washed with water (2×50 ml) and dried (anhyd. magnesium sulfate). Evaporation of the ether afforded chromatographically pure cis-methyl 2-phenylpiperidine-3-carboxylate as an oil (1.54 gm, 78%).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH:11]([C:13]1[N:14]=[C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[S:16][CH:17]=1)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.O>[CH:11]([C:13]1[N:14]=[C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[S:16][CH:17]=1)=[CH2:1]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=O)cs2)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a cold (−50° C.) suspension of methyltriphenylphosphonium bromide (1.2 g, 3.3 mmol) in tetrahydrofuran (5 mL) was added a solution of sodium bis(trimethylsilyl)-amide (3.4 mL, 3.4 mmol), and the resulting mixture was stirred for 1 h at room temperature. The resulting cloudy yellow solution was re-cooled to −30° C., and 1,1-dimethylethyl 4-(4-formyl-2-thiazolyl)-1-piperidinecarboxylate (0.5 g, 1.68 mmol) was added. The resulting slightly yellow solution was stirred at room temperature for 3 h, then diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and purified by column chromatography on silica gel using 15-30% ethyl acetate in hexanes as eluant to give 471 mg of the title compound as a colorless oil.
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:20][C:21](S(C)(=O)=O)=[N:22][N:23]=4)[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1.[CH3:29][NH2:30].O1CCCC1>CN1CCCC1=O>[F:1][CH:2]([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:20][C:21]([NH:30][CH3:29])=[N:22][N:23]=4)[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)c1nnc(-c2ccc3ncn(-c4ccc(OC(F)F)cc4)c3c2)o1
Reactant: CN
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CNc1nnc(-c2ccc3ncn(-c4ccc(OC(F)F)cc4)c3c2)o1
Yield: 67 %

Procedure:
In the same manner as in Example 433 and using 1-[4-(difluoromethoxy)phenyl]-6-[5-(methylsulfonyl)-1,3,4-oxadiazol-2-yl]-1H-benzimidazole instead of 6-[5-(methylsulfonyl)-1,3,4-oxadiazol-2-yl]-1-[4-(trifluoromethoxy)phenyl]-1H-benzimidazole, using 2M methylamine-tetrahydrofuran solution instead of sodium methoxide, and using 1-methyl-2-pyrrolidone instead of N,N-dimethylformamide, the title compound (yield 67%) was obtained as colorless crystals.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:16]([OH:18])=O)=[N:8][C:9]=2[O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH2:3][CH2:2]1.[CH3:19][C:20]([CH3:27])([C:22]1[S:23][CH:24]=[CH:25][N:26]=1)[NH2:21]>>[CH3:19][C:20]([NH:21][C:16]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])[N:8]=1)=[O:18])([C:22]1[S:23][CH:24]=[CH:25][N:26]=1)[CH3:27]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC(F)(F)F)n1
Reactant: CC(C)(N)c1nccs1
Product: CC(C)(NC(=O)c1ccc(C2CC2)c(OCC(F)(F)F)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 280c, using 5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 301a) and α,α-dimethyl-2-thiazolemethanamine (Example 12c) as starting materials, MS (EI): m/e=386.3 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([CH:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)=[N:19]3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])([CH3:5])[CH3:4].FC(F)(F)C(O)=O>ClCCl>[OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([CH:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)=[N:19]3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])([CH3:5])[CH3:4]
Reactant: CN1CCC(c2nn(-c3cnc4c(n3)c(C(=O)NC(C)(C)CO)cn4COCC[Si](C)(C)C)c3ccccc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(c2nn(-c3cnc4[nH]cc(C(=O)NC(C)(C)CO)c4n3)c3ccccc23)CC1
Yield: 22.6 %

Procedure:
To a stirred solution of N-(1-hydroxy-2-methylpropan-2-yl)-2-(3-(1-methylpiperidin-4-yl)-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (57 m g, 98.7 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). After 15 h the mixture was concentrated in vacuo then 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane added. After 1 h the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-6% methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-[3-(1-methyl-piperidin-4-yl)indazol-1-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)amide (10 mg, 23%). MS (M+H)+=447; 1H NMR (DMSO-d6) δ: 9.00 (s, 1H), 8.64 (d, J=8.5 Hz, 1H), 8.37 (s, 1H), 7.99 (d, J=7.9 Hz, 1H), 7.65 (s, 1H), 7.57 (t, J=7.3 Hz, 1H), 7.35 (t, J=7.5 Hz, 1H), 5.06 (t, J=5.7 Hz, 2H), 3.62 (d, J=5.7 Hz, 2H), 2.98 (d, J=11.5 Hz, 2H), 2.30 (s, 3H), 1.94-2.24 (m, 5H), 1.44 (s, 6H)
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][S:8](Cl)(=[O:10])=[O:9])(=[O:3])[CH3:2].[CH3:12][NH2:13]>ClCCl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][S:8]([NH:13][CH3:12])(=[O:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCS(=O)(=O)Cl
Reactant: CN
Solvent: ClCCl
Product: CNS(=O)(=O)CCCOC(C)=O

Procedure:
15 g of 3-acetoxy-1-propanesulfonylchloride was dissolved in 150 ml dichloromethane. To the mixture was added dropwise 11.6 g of methylamine (40% methanol solution) with stirring under ice coioling. The reaction mixture was stirred for 1.5 hours under ice cooling.
Reaction SMILES: C=CC1C=CC=CC=1.CCCCCCCCCCC.C(=O)=O.C1(CCC=O)C=CC=CC=1.[C:33]1([C@@H:39]([CH3:42])[CH:40]=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:33]1([CH:39]([CH3:42])[CH:40]=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: C[C@@H](C=O)c1ccccc1
Agent: O=C=O
Agent: O=CCCc1ccccc1
Solvent: CCCCCCCCCCC
Solvent: C=Cc1ccccc1
Product: CC(C=O)c1ccccc1
Temperature: -60 °C

Procedure:
To a 300 mL stainless steel autoclave equipped with two sapphire windows containing Rh(acac)(CO)2 (10.4 mg, 4×10-2 mmol) and (R,S)-BINAPHOS (60 mg, 8×10-2 mmol) were added styrene (2.08 g, 2.0 mmol) and n-undecane (156 mg, 1.0 mmol) (the internal standard for GC analysis). The air was replaced by CO through pressurization (2-3 atm) and release for 2-3 times, and CO (7 atm) was introduced followed by H2 (14 atm). The reaction vessel was cooled to -60° C. and CO2 (78 atm) was introduced. The mixture was allowed to stir at 65° C. and 100 atm overnight. The autoclave was cooled to 0° C. and all the gasses were carefully released. The GC analysis showed that the conversion of the reaction was 91% and the ratio of 3-phenylpropanal to (R)-2-phenylpropanal was 1:12.5. The enantiomeric purity of 2-phenylpropanal thus formed was determined to be 85% enantiomeric excess by converting it to (R)-2-phenylpropanol followed by esterification with (S)-methoxy(trifluoromethyl)phenylacetyl chloride in the presence of triethylamine in CH2Cl2, and subjecting the resulting chiral ester to the 1H NMR analysis.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:33][O:34][C:35]([C:37]1([NH2:40])[CH2:39][CH2:38]1)=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:33][O:34][C:35]([C:37]1([NH:40][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])[CH2:39][CH2:38]1)=[O:36]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)C1(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.43 mmol), 1-amino-cyclopropanecarboxylic acid methyl ester hydrochloride (100 mg, 0.86 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 243.3 mg, 0.64 mmol) and iPr2NEt (0.22 mL, 1.2 mmol) in CH2Cl2 (20 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified flash column chromatography (1-100% ethyl acetate/heptane) to afford rac-1-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-cyclopropanecarboxylic acid methyl ester as a white powder (120 mg, 49.6%). HRMS (ES+) m/z Calcd for C28H29Cl2F2N3O3+H [(M+H)+]: 564.1627. found: 564.1627.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([O:15]C(OC(C)(C)C)=O)=O)([CH3:11])([CH3:10])[CH3:9].[CH3:23][S:24]([NH2:27])(=[O:26])=[O:25]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:23][S:24]([NH:27][C:13](=[O:15])[O:12][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
Triethylamine (2.2 mL, 16 mmol), di-tert-butyldicarbonate (2.65 g, 12.1 mmol) and 4-dimethylaminopyridine (0.096 g, 0.79 mmol) were added sequentially to a solution of methanesulfonamide (0.75 g, 7.9 mmol) in methylene chloride (20 mL) at room temperature. The reaction was stirred at room temperature for 2 h and then concentrated. EtOAc was added, and the resultant mixture was washed with 1N aq. HCl solution, dried over MgSO4 and concentrated to give the desired product (1 g) to be used in the next step directly.
Reaction SMILES: Cl.[CH2:2]([O:6][C:7]1[CH:12]=[C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:10]=[CH:9][N:8]=1)[CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.[Cl:26][CH2:27][C:28](Cl)=[O:29]>>[Cl:26][CH2:27][C:28]([N:16]1[CH2:17][CH2:18][N:13]([C:11]2[CH:12]=[C:7]([O:6][CH2:2][CH:3]([CH3:5])[CH3:4])[N:8]=[CH:9][N:10]=2)[CH2:14][CH2:15]1)=[O:29]
Reactant: CC(C)COc1cc(N2CCNCC2)ncn1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)COc1cc(N2CCN(C(=O)CCl)CC2)ncn1
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
To a mixture of 4-isobutoxy-6-(piperazin-1-yl)pyrimidine hydrochloride (300 mg, 0.97 mmol) and triethylamine (0.68 mL, 4.9 mmol) was added chloroacetyl chloride (121 mg, 1.07 mmol) at 0° C. After being stirred at the same temperature for 30 min, the mixture was poured onto water, and the aqueous layer was extracted with dichloromethane (twice). The combined organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/EtOAc (1.5:1-1:1) to give the title compound (262 mg, 86%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([OH:13])[CH:7]=1)[CH3:2].[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][C:22](F)=[C:21]([Cl:26])[CH:20]=1)(=[O:18])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+].CN1C(=O)CCC1>O>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:22]2[CH:23]=[CH:24][C:19]([S:16]([CH3:15])(=[O:18])=[O:17])=[CH:20][C:21]=2[Cl:26])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(Cl)c(O)c1
Reactant: CS(=O)(=O)c1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc(S(C)(=O)=O)cc2Cl)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
The product from step (iv) (4.4 g), 3-chloro-4-fluorophenyl methyl sulfone (4.27 g), cesium carbonate (6.5 g) and NMP (40 ml) were charged to a flask and stirred at 90° C. for 2 h. The reaction was diluted with water, extracted with EtOAc, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography (eluent 2:1 isohexane/ether) to give the subtitle compound (3.6 g).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:32](O)=[O:33])[CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([NH2:30])=[C:22]([CH3:31])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[O:68]1[CH2:73][CH2:72][CH:71]([N:74]2[CH2:79][CH2:78][NH:77][CH2:76][CH2:75]2)[CH2:70][CH2:69]1>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:27])[F:29])[C:23]([NH2:30])=[C:22]([CH3:31])[CH:21]=3)[C:32](=[O:33])[N:77]3[CH2:76][CH2:75][N:74]([CH:71]4[CH2:72][CH2:73][O:68][CH2:69][CH2:70]4)[CH2:79][CH2:78]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C(F)(F)F)c1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(C(F)(F)F)c1N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 100 mg (0.19 mmol) (R)-2-(4-amino-3-methyl-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 67 mg (0.21 mmol) TBTU and 50 μL (0.36 mmol) triethylamine in 1 mL DMF was stirred for 10 min at RT. Then 40 mg (0.24 mmol) 1-(tetrahydropyran-4-yl)-piperazine were added and the reaction mixture was stirred for a further 20 h at RT. The reaction solution was purified by HPLC without any further working up. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4](O)[C@H:2]1O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[CH:4]=[CH:2]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC[C@@H]1C=C[C@H](n2cnc3c(O)ncnc32)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
To a solution of 21 (3.0 g, 8.6 mmol) in dry tetrahydrofuran (THF) (65 ml), cooled in an ice-bath, was added a 1M solution of tetra-n-butylammonium fluoride in THF (34 ml, 34.0 mmol). The mixture was stirred at 0° C. for 30 minutes, and the solvent was evaporated under vacuum. The residue was purified by chromatography on a silica gel column using CHCl3 methanol (7:1) as the eluent. Concentration of the TLC purified fractions yielded 1.36 g (67%) of 8: mp >310° C. (methanol); 1H NMR (DMSO-d6) δ 3.56 (2H, d, J =2.6 Hz, 5'-H), 4.84 (2H, m, 4'-H and OH, collapses to a multiplet integrating to one proton after D20 exchange), 6.12 (1H, br d, J=5.7 Hz, 2'-H), 6.47 (1 H, br d, J=5.7 Hz, 3'-H), 6.90 (1H, m, 1'-H), 8.06 (1H, s, 8-H), 8.10 (1H, s, 2-H), 12.40 (1H, br s, NH).
Reaction SMILES: [C:1]([CH2:4][O:5][CH2:6][CH2:7]N1CCN(C(OC(C)(C)C)=O)CC1)(=[O:3])N.[ClH:21].[OH2:22]>>[ClH:21].[ClH:21].[CH2:6]([O:5][CH2:4][C:1]([OH:3])=[O:22])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCN(CCOCC(N)=O)CC1
Reactant: O
Agent: Cl
Product: CCOCC(=O)O
Temperature: 60 °C

Procedure:
1 g (0.00348 mol) of tert-butyl 4-(2-carbamoylmethoxyethyl)piperazine-1-carboxylate prepared in Example I.4.3. and 2 ml of water are placed in a 10 ml conical flask. 2 ml of 37% hydrochloric acid solution are added and the mixture is heated on an oil bath at 60° C. for 1 hour. The water is eliminated on a rotary evaporator under reduced pressure. The residue is taken up in toluene. After evaporation, 1.1 g of a pale yellow solid are obtained. This finely ground solid is placed in a Büchi sublimator. The apparatus is placed under vacuum (0.3 mmHg) and heated at 150° C. for 8 hours. 800 mg (88%) of 2-1-piperazinyl)ethoxy acetic acid dihydrochloride are obtained in the form of white crystals. The analyses correspond to those obtained with the compound prepared in Example I.1.4.