Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.O[C:29]1[CH:39]=[CH:38][C:32]([O:33][CH2:34][C:35]([OH:37])=[O:36])=[C:31]([CH3:40])[CH:30]=1.[CH2:41](P(CCCC)CCCC)[CH2:42]CC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:41]([O:37][C:35](=[O:36])[CH2:34][O:33][C:32]1[CH:38]=[CH:39][C:29]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:30][C:31]=1[CH3:40])[CH3:42]
Reactant: CCCCP(CCCC)CCCC
Reactant: Cc1cc(O)ccc1OCC(=O)O
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)COc1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1C
Yield: 16 %

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c), (4-hydroxy-2-methyl-phenoxy)-acetic acid (CAS RN 317319-10-1), tri-n-butylphosphin and N,N,N′,N′-tetramethylazodicarboxamide. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30) to give the title compound as a light yellow foam (16%). MS (Turbo Spray): m/z=583.3 [M+H].
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13]CC2C=CC(OC)=CC=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([NH:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][CH:8]=1)(=[O:5])=[O:6])[CH3:2]
Reactant: CCNS(=O)(=O)c1ccc(SCc2ccc(OC)cc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCNS(=O)(=O)c1ccc(S)cc1
Temperature: 80 °C

Procedure:
To N-ethyl-4-(4-methoxy-benzylsulfanyl)-benzenesulfonamide 5.95 g was added trifluoroacetic acid 60 ml containing triethyl silane 3 ml and the mixture heated at 80° C. for 2 h. The reaction mixture was cooled and evaporated in vacuo. The residue was taken up in ethyl acetate and evaporated in vacuo ×2. The residue was then taken up in ethyl acetate and extracted with 2M sodium hydroxide 3×30 ml and the combined aqueous solution washed with ethyl acetate (×1). The aqueous solution was then acidified with conc. hydrochloric acid and extracted with dichloromethane X3 and the organic solution washed with water, dried MgSO4 and evaporated in vacuo to give N-ethyl-4-mercapto-benzenesulfonamide, as a pale yellow oil, 3.05 g 79%. 1HNMR 7.72 (2H, d), 7.34 (2H, d), 4.65 (1H, bs), 3.70 (1H, s), 2.99 (2H, q), 1.11 (3H, t).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[NH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15].CN[CH2:18][CH2:19]N>[Cu]I>[I:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.[NH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15].[CH3:11][CH2:12][CH2:13][CH2:18][CH2:19][CH2:7][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:8].[CH3:8][C:6]1[CH:7]=[C:2]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:3]=[C:4]([CH3:9])[CH:5]=1
Reactant: CNCCN
Agent: [Cu]I
Agent: Cc1cc(C)cc(I)c1
Agent: O=C1CCCN1
Product: CCCCCCCCCCCC
Product: Cc1cc(C)cc(N2CCCC2=O)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
A test tube with a screw thread was equipped with a 10×3 mm Teflon-coated stirring bar and charged with CuI (9.6 mg, 0.050 mmol, 5.0 mol %) and K5P3O10 (Strem, finely ground, 430 mg, 0.96 mmol). The test tube was closed with an open-top screw cap fitted with a Teflon-lined silicon rubber septum, evacuated through a 21-gauge needle, and then backfilled with argon. Meanwhile, a stock solution of 5-iodo-m-xylene (2.16 mL), 2-pyrrolidinone (1.40 mL), and dodecane (internal GC standard, 0.68 mL) in toluene (15 mL) was prepared in a 25 mL pear-shaped flask under argon. A portion of the stock solution (1.28 mL) containing 1.0 mmol of 5-iodo-m-xylene and 1.2 mmol of 2-pyrrolidinone was added using a syringe, followed by N-methylethylenediamine (8.9 μL, 1.0 mmol, 10 mol %). The reaction mixture in the test tube was stirred in a 60±15° C. oil bath for 5 h. The test tube was then allowed to reach room temperature, the screw cap was removed, and ethyl acetate (2 mL) was added. A 50-100 μL sample of the supernatant solution from the test tube was diluted with ethyl acetate (1 mL). GC analysis of the resulting solution indicated a 95% yield of N-(3,5-dimethylphenyl)-2-pyrrolidinone.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]([CH3:14])[CH3:13])[C:7](=[O:15])[CH:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1.IC.[CH3:22]C([O-])(C)C>CS(C)=O.O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]([CH3:13])[CH3:14])[C:7](=[O:15])[C:6]3([CH3:22])[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1
Reactant: CC(C)N1C(=O)C2COCCN2c2nc(Cl)ncc21
Reactant: CC(C)(C)[O-]
Solvent: CS(C)=O
Solvent: O
Solvent: CI
Product: CC(C)N1C(=O)C2(C)COCCN2c2nc(Cl)ncc21
Reaction time: 8 h
Yield: 7.8 %

Procedure:
2-Chloro-5-isopropyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (1.20 g, 4.24 mmol) and iodomethane (1.324 mL, 21.22 mmol) were mixed in DMSO. The mixture was frozen, 2-methylpropan-2-olate (1.224 g, 12.73 mmol) was added, covered by a layer of DMSO and refrozen. The mixture was allowed to room temperature and stirred overnight. Another 1 eq of 2-methylpropan-2-olate and iodomethane was added and the mixture stirred overnight at 30° C. The solution was diluted with water and extracted with EtOAc twice. The organic layers were combined, dried over magnesium sulfate, filtered, and evaporated in vacuo. The residue was absorbed onto silica and purified by column chromatography using 10-60% EtOAc in hexanes then 5% methanol in dichloromethane as eluent. Relevant fractions were evaporated in vacuo to give 98 mg (8%) 2-chloro-5-isopropyl-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one. MS [M+H] Found 297.
Reaction SMILES: N1CCOCC1.Cl.Cl.[N:9]1([CH2:15][C:16]2[N:17]=[C:18]([NH2:21])[S:19][CH:20]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[Cl:22][C:23]1[C:24]([CH3:33])=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1>>[ClH:22].[Cl:22][C:23]1[C:24]([CH3:33])=[C:25]([S:29]([NH:21][C:18]2[S:19][CH:20]=[C:16]([CH2:15][N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[N:17]=2)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1nc(CN2CCOCC2)cs1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Agent: Cl
Solvent: C1COCCN1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CN2CCOCC2)cs1
Temperature: 25 °C
Yield: 6 %

Procedure:
A mixture of INTERMEDIATE 19 (0.50 g, 2.70 mmol) and morpholine (1.65 g, 18.92 mmol) was stirred at room temperature over night. The solvent was evaporated and the solid residue was purified by reversed phase flash chromatography on LiChroprep RP-18. The product was eluting with (1% CH3CN in H2O/0.5% conc. HCl) giving approximately a 1:1 mixture of 4-(4-morpholinylmethyl)-1,3-thiazol-2-amine dihydrochloride and morpholine (1.33 g). This material was sulphonylated with 3-chloro-2-methylbenzenesulphonyl chloride according to the preparation as described for EXAMPLE 205A giving 17 mg (6%) of a solid: 1H NMR (DMSO) δ 2.65 (s, 3H), 3.08 (br m, 4H), 3.78 (br m, 4H), 4.13 (br s, 2H), 7.07 (s, 1H), 7.40 (t, 1H), 7.68 (d, 1H), 7.91 (d, 1H); MS (Ionspray, [M+H]+) m/z 387.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:18])[CH3:17].CO>C(Cl)Cl>[C:16]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: NCc1ccccc1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
10 g of benzylamine was dissolved in 200 ml of methylene chloride followed by the addition of 26 ml of triethylamine and dropwise addition of 7.3 ml of acetyl chloride at 0° C. After stirring for 1 hour at room temperature, 2 ml of methanol was added to the reaction system at 0° C. followed by 120 ml of water and separation of the phases. The aqueous layer was extracted with 100 ml of chloroform, and the resulting organic layer was concentrated after drying with anhydrous sodium sulfate to obtain 8.55 g of the target compound (yield: 61%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:32])[C@H:4]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:5][C:6](=[O:24])[C@@H:7]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1Br)[NH:8][C:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12].CN(C)C=O.[C:38](O)(=[S:40])[CH3:39].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O.ClCCl>[CH3:1][NH:2][C:3](=[O:32])[C@H:4]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:5][C:6](=[O:24])[C@H:7]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:38](=[S:40])[CH3:39])[NH:8][C:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](CCc1ccccc1Br)NC(=O)CC(C)C
Reactant: CC(O)=S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCc1ccccc1C(C)=S)NC(=O)CC(C)C
Reaction time: 18 h

Procedure:
Combine (R)-2-bromo-3-methylbutyroyl-(L)-homophenylalanyl-(L)-phenylalanine N-methyl amide (0.466 g, 0.93 mmol) and dimethylformamide (3 mL). Add thioacetic acid (0.066 mL, 0.93 mmol) and cesium carbonate (0.151 g, 0.46 mmol). After 18 hours, partition the reaction mixture between ethyl acetate and an aqueous 2 M hydrochloric acid solution. separate the layers, extract the organic layer with water and a saturated aqueous sodium bicarbonate solution, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 10% acetone/dichloromethane, 15% acetone/dichloromethane, and then 20% acetone/dichloromethane to give the title compound.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:46])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:46])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(-c2cccc(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1nc(C)n(-c2cccc(F)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
A mixture of hydroxylammonium chloride (1.79 g), sodium hydrogen carbonate (2.60 g) and dimethyl sulfoxide (13 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(3-fluorophenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.16 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (13 mL), N,N′-carbonyldiimidazole (0.54 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.51 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.87 g, 66%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][Cl:17])=[C:7]([OH:19])[CH:6]=1)(=[O:3])[CH3:2].[C:20](=O)([O-])[O-].[K+].[K+].IC>C(C(C)=O)C>[C:1]([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][Cl:17])=[C:7]([O:19][CH3:20])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Nc1cc(O)c(C(=O)CCCCCl)cc1Cl
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CI
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)CCCCCl
Yield: 67.7 %

Procedure:
1-(4-Acetylamino-5-chloro-2-hydroxyphenyl)-5-chloropentan-1-one (1.07 g, 3.5 mmol), potassium carbonate (1.38 g, 10.0 mmol) and iodomethane (0.62 mL, 10.0 mmol) were combined in methyl ethyl ketone (20 mL) and stirred at reflux temperature for 4 hours, 15 minutes. The mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, washed in brine, dried over sodium sulfate, and then evaporated to leave a solid residue. Crystallization of the residue from ethyl acetate-hexanes gave 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloro-pentan-1-one (0.720 g, 2.37 mmol), m.p. 98°-100° C.
Reaction SMILES: Cl[C:2]1C=C(SC2C3C(=CC(C)=CC=3)NC=2CCC(N)=O)C=C(Cl)[CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([CH3:42])[CH:40]=3)[NH:35][C:34]=2[C:43]([OH:45])=[O:44])=[CH:28][CH:27]=1.C(Cl)(=O)C(Cl)=O.CCO>C1COCC1>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([CH3:42])[CH:40]=3)[NH:35][C:34]=2[C:43]([O:45][CH2:2][CH3:7])=[O:44])=[CH:30][CH:31]=1
Reactant: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CCC(N)=O)[nH]c2c1
Reactant: Cc1ccc2[nH]c(C(=O)O)c(Sc3ccc(Cl)cc3)c2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1[nH]c2ccc(C)cc2c1Sc1ccc(Cl)cc1
Yield: 76 %

Procedure:
Following the method used to prepare 24a, the use of 1b (0.23 mmol) and oxalyl chloride in THF followed by allowing the intermediate acid chloride to react with EtOH (5 mL) provided 61 mg (76%) of product 10 as a white solid, mp 158-160° C. 1H NMR (300 MHz, DMSO-d6) δ 1.24 (t, J=7 Hz, 3H), 2.34 (s, 3H), 4.30 (q, J=7 Hz, 2H), 7.05 (d, J=8 Hz, 2H), 7.16 (d, J=8 Hz, 1H), 7.26-7.29 (m, 3H), 7.46 (d, J=9 Hz, 1H), 12.38 (s, 1H). LC-MS (CI): m/z 346.1 [(M+H)+ C18H16ClNO2S requires 345.06]. Purity (100%). Calcd for C18H16ClNO2S: C, 62.51; H, 4.66; N, 4.05; S, 9.27; Cl, 10.25. Found: C, 62.37; H, 4.60; N, 3.95; S, 9.21; Cl, 10.30.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH:11]=[CH:10][N:9]=[C:8]2[CH3:12])=[CH:4][CH:3]=1.[Li]CCCC.[CH2:18]([Sn:22](Cl)([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21].[NH4+].[Cl-]>C1COCC1>[CH3:12][C:8]1[N:7]([C:5]2[S:6][C:2]([Sn:22]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:3][CH:4]=2)[CH:11]=[CH:10][N:9]=1
Reactant: Cc1nccn1-c1ccc(Br)s1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(-n2ccnc2C)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 275.8 %

Procedure:
To the solution of 1-(5-bromothiophen-2-yl)-2-methyl-1H-imidazole (2 g, 8.3 mmol) in dried THF was added dropwise n-BuLi (2.5 M in hexane, 4 mL, 10 mmol) at −78° C., the mixture was stirred at −78° C. for 30 min. A solution of tributyltin chloride (4.6 g, 0.96 mmol) in THF was added dropwise, the solution was stirred at −78° C. for 1 hour, and the reaction solution was allowed to warm to room temperature and stirred for 1 hour. The reaction solution was poured into NH4Cl aqueous solution, the mixture was extracted with EtOAc (100 mL×3). The organic layer was washed with brine, dried over Na2SO4, then concentrated under reduced pressure, and the residue was purified by column chromatography to give 2-methyl-1-(5-(tributylstannyl)thiophen-2-yl)-1H-imidazole as a yellow oil (1.2 g, yield 31.8%).
Reaction SMILES: CN(C(ON1N=[N:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[CH3:33][N:34]1[CH2:39][CH2:38][CH:37]([CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:36][CH2:35]1.[CH2:46]([C:48]1[CH:49]=[C:50]([CH2:56][CH:57]([NH:61][C:62]([N:64]2[CH2:69][CH2:68][CH:67]([N:70]3[CH2:76][CH2:75]C4C=CC=CC=4N[C:71]3=[O:81])[CH2:66][CH2:65]2)=[O:63])[C:58](O)=[O:59])[CH:51]=[CH:52][C:53]=1[CH2:54][CH3:55])[CH3:47]>C1COCC1.C(N(CC)CC)C>[CH2:46]([C:48]1[CH:49]=[C:50]([CH:51]=[CH:52][C:53]=1[CH2:54][CH3:55])[CH2:56][CH:57]([NH:61][C:62]([N:64]1[CH2:69][CH2:68][CH:67]([N:70]2[CH2:76][CH2:75][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH:16][C:71]2=[O:81])[CH2:66][CH2:65]1)=[O:63])[C:58]([N:43]1[CH2:44][CH2:45][CH:40]([CH:37]2[CH2:36][CH2:35][N:34]([CH3:33])[CH2:39][CH2:38]2)[CH2:41][CH2:42]1)=[O:59])[CH3:47]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CN1CCC(C2CCNCC2)CC1
Reactant: CCc1ccc(CC(NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1ccc(CC(NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(C)CC3)CC2)cc1CC
Temperature: 40 °C
Reaction time: 2 h

Procedure:
0.3 mL of triethylamine, 323 mg (1.01 mmol) of TBTU, 155 mg (1.01 mmol) of HOBt and 184 mg (1.01 mmol) of methyl-[4,4′]bipiperidinyl were added to a solution of 500 mg (1.02 mmol) of 3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid in 50 mL of THF and stirred for 4 h at RT and 2 h at 40° C. The reaction mixture was evaporated down, the residue was stirred with 40 mL of saturated NaHCO3 solution, the precipitated product was suction filtered, washed twice with water and triturated with EtOH. The white substance precipitated was suction filtered and washed twice with diethyl ether.
Reaction SMILES: [CH:1]1([C:4]([OH:28])([CH3:27])[CH2:5][NH:6][C:7]([C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[N:13][C:12](Br)=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1.[CH:29]1([CH2:32][O-:33])[CH2:31][CH2:30]1>CS(C)=O>[CH:1]1([C:4]([OH:28])([CH3:27])[CH2:5][NH:6][C:7]([C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[N:13][C:12]([O:33][CH2:32][CH:29]3[CH2:31][CH2:30]3)=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: [O-]CC1CC1
Reactant: CC(O)(CNC(=O)c1nc(-c2ccc(Cl)cc2)c(Br)nc1C(F)(F)F)C1CC1
Solvent: CS(C)=O
Product: CC(O)(CNC(=O)c1nc(-c2ccc(Cl)cc2)c(OCC2CC2)nc1C(F)(F)F)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.048 g 5-bromo-6-(4-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid (2-cyclopropyl-2-hydroxy-propyl)-amide in 0.3 ml dimethylsulfoxide was added 0.2 ml of a 1M solution of cyclopropylmethoxide in dimethylsulfoxide and the mixture was stirred at room temperature for 30 min. The orange reaction mixture was partitioned between 10% citric acid and ethyl acetate. The phases were separated and the organic phase was purified by chromatography on silica gel with heptane: ethyl acetate=9:1 to 1:1 to yield 0.015 g of the title compound as white solid. MS (M+H) at 468.3.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:9][C:10]=2[C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][N:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[N+:28]([C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]Br)([O-:30])=[O:29]>CN(C=O)C>[CH:18]1([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:33][C:32]4[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=4[N+:28]([O-:30])=[O:29])[CH:12]=3)[N:9]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: Nc1nccn2c(C3CCC3)nc(-c3cccc(O)c3)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1nccn2c(C3CCC3)nc(-c3cccc(OCc4ccccc4[N+](=O)[O-])c3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-(8-Amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenol (2.00 g, 7.13 mmol) in DMF (36.7 mL) was charged with Cs2CO3 (3.48 g, 10.7 mmol) and stirred at rt for 30 min. A DMF solution of 2-nitrobenzyl bromide (1.54 g, 7.13 mmol), was then added to the reaction mixture. The reaction was allowed to progress at rt under nitrogen for 3.5 h. TLC analysis showed that the reaction was complete. The product was purified using silica gel column chromatography (1-3% NH3 in MeOH:CH2Cl2). The final product was concentrated to a yellow solid; 1H NMR (CDCl3, 400 MHz) δ 2.00-2.08 (m, 1H), 2.11-2.23 (m, 1H), 2.45-2.53 (m, 2H), 2.59-2.69 (m, 2H), 3.77-3.86 (m, 1H), 5.57 (s, 2H), 7.01-7.05 (m, 2H), 7.11 (d, J=5.6 HZ, 1H), 7.27-7.30 (m, 1H), 7.32-7.33 (m, 1H), 7.42 (t, J=16.4 Hz, 1H), 7.48-7.52 (m, 1H), 7.67-7.71 (m, 1H), 7.92 (dd, J=8.0 Hz, 1H), 8.17 (d, J=9.5 Hz, 1H); MS (ES+): m/z 416.01 (100) [MH+].
Reaction SMILES: [OH-].[Na+].C(N(CC)CC)C.CN1[C:15](=[O:16])/[C:14](=[CH:17]/[CH:18]2[C:22](=[O:23])[CH2:21][CH2:20][C:19]2=O)/[S:13]C1=S.[OH:26]P([O-])(O)=O.[K+]>O>[O:23]=[C:22]1[C:18]2[CH:17]=[C:14]([C:15]([OH:16])=[O:26])[S:13][C:19]=2[CH2:20][CH2:21]1
Reactant: O=P([O-])(O)O
Reactant: CN1C(=O)/C(=C/C2C(=O)CCC2=O)SC1=S
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)c1cc2c(s1)CCC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
In a 500-mL round-bottomed flask equipped with a magnetic stirrer and reflux condenser, was charged with sodium hydroxide (3.34 g, 83.6 mmol) and water (65 mL). The solution was degassed with nitrogen for 15 min. 4 (7.19 g, 20.2 mmol) was added and the mixture was stirred at room temperature for 3 h. After this time, 1 M aqueous potassium phosphate monobasic was added to adjust the pH of the reaction mixture to 8.0, followed by water (200 mL). After heating at 50° C. for 16 h, the water was evaporated to 50 mL under reduced pressure, and 12 N hydrochloric acid was added to adjust the pH to 2.8 (pH meter). The resulting precipitate was collected by vacuum filtration, washed with water (5 mL) and dried for 16 h under vacuum at 50° C. to afford 5 in 37% yield (1.37 g) as a green solid: mp 195-196° C.; 1H NMR (500 MHz, DMSO-d6) δ 13.30 (br s, 1H), 7.64 (s, 1H), 3.23 (t, 2H, J=5.5 Hz), 2.76 (t, 2H, J=5.5 Hz); MS (APCI+) m/z 183.2 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][C:11]1[CH:12]=[CH:13][C:14]2[O:19][CH2:18][C:17](=[O:20])[NH:16][C:15]=2[CH:21]=1)[C:2]1C=CC=CC=1.[C:23]([O:27][Li])([CH3:26])([CH3:25])[CH3:24].C1COCC1.Cl.[CH3:35][N:36]([CH:38]=[O:39])C>>[C:23]([O:27][C:38](=[O:39])[NH:36][CH2:35][C@H:1]1[O:8][C:9](=[O:22])[N:10]([C:11]2[CH:12]=[CH:13][C:14]3[O:19][CH2:18][C:17](=[O:20])[NH:16][C:15]=3[CH:21]=2)[CH2:2]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C1COc2ccc(NC(=O)OCc3ccccc3)cc2N1
Reactant: CN(C)C=O
Reactant: [Li]OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@@H]1CN(c2ccc3c(c2)NC(=O)CO3)C(=O)O1
Temperature: 0 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
A solution of (3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-carbamic acid benzyl ester (prepared according to method C, 1.4 g, 4.7 mmol) and intermediate 4.i (0.984 g, 4.7 mmol) in DMF (15 mL) at 0° C. was treated dropwise with a 2.2M solution of t-BuOLi in THF (6.4 mL, 3 eq.). The mixture was stirred at 0° C. for 1 h and at rt overnight. 1M HCl (9.4 mL) was added and the mixture partitioned between EA and water. The aq. phase was extracted once more with EA and the combined org. phases were washed several times with water and brine, dried over MgSO4 and concentrated. The residue was purified by FC (Hept/EA 1:2, EA) to give the title intermediate as a colourless solid (0.5 g, 29% yield).