Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:37]([CH3:40])([CH3:39])[CH3:38])/[CH:30]=[CH:31]/[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:9]=2)=[N:6][CH:7]=1.CCOC(C)=O.[H][H]>CO.[Pd]>[F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:37]([CH3:38])([CH3:40])[CH3:39])[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=3)(=[O:20])=[O:19])[CH:9]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)/C=C/[C@@H](Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)CC[C@@H](Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C(C)(C)C

Procedure:
To a nitrogen purged flask charged with 10% Pd/C (0.033 g, 0.310 mmol) was added enough methanol to cover the catalyst. To this mixture was added a solution of (R,E)-ethyl 4-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhex-2-enoate, 38a, (0.330 g, 0.579 mmol) in MeOH. Note, a small amount of EtOAc was added to fully solubilize the starting material. The reaction mixture was then stirred under 1 atmosphere of hydrogen for 3 hours. LCMS shows presence of significant amounts of starting material. The contents of the reaction mixture were transferred to a pressure vessel containing a fresh source of palladium (0.033 g, 0.310 mmol). The reaction mixture was stirred in a Parr hydrogenation flask under 46 psi of hydrogen overnight. The mixture was diluted with methanol and filtered through celite. The filtrate was concentrated in vacuo to afford 331 mg of the desired product that was used without further purification: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=3.75 minutes (M+H) 572.35.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH2:15]([OH:18])[C:16]#[CH:17].[H-].[Na+].O>CN(C)C=O>[F:14][C:10]1[CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([O:18][CH2:15][C:16]#[CH:17])[N:3]=[CH:4][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1
Reactant: C#CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1cc(-c2cccc(F)c2)ncn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 75.1 %

Procedure:
In 7 ml of N,N-dimethylformamide were dissolved 207 mg of 4-chloro-6-(3-fluorophenyl)pyrimidine and 67 mg of 2-propyn-1-ol, to which 48 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 6 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 170 mg of 4-(3-fluorophenyl)-6-(2-propynyloxy)pyrimidine (the present compound (56)).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:16])=[C:4]([CH:13]([CH3:15])[CH3:14])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.[CH3:17]OC1C=CC(N)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(OCC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[C:3]([CH3:16])=[C:4]([C:13]([CH3:17])([CH3:14])[CH3:15])[C:5]2[O:9][CH2:8][C:7]([CH3:10])([CH3:11])[C:6]=2[CH:12]=1
Reactant: Cc1c(Br)cc2c(c1C(C)C)OCC2(C)C
Reactant: COc1ccc(N)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1c(Br)cc2c(c1C(C)(C)C)OCC2(C)C
Temperature: 80 °C
Yield: 102 %

Procedure:
A mixture of 5-bromo-7-isopropyl-3,3,6-trimethyl-2,3-dihydro-benzofuran (Compound 50, 0.56 g, 1.98 mmol), p-anisidine (0.48 g, 3.96 mmol), sodium tert-butoxide (0.27 g, 2.77 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.020 g, 0.02 1 mmol) and (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.040 g, 0.064 mmol) in 6 mL of anhydrous toluene was heated at 80° C. under argon overnight. The reaction mixture was cooled to ambient temperature, diluted with diethylether and filtered. The filtrate was evaporated in vacuo to a residue which on flash column chromatography using 10% ethyl acetate in hexane as the eluent afforded the title compound (0.6 g, 93%) as a pink solid. 1H NMR (300 MHz, CDCl3): δ 6.76 (d, 2H, J=8.9 Hz), 6.75 (s, 1H), 6.61 (d, 2H, J=8.9 Hz), 5.0 (s, 1H), 4.15 (s, 2H), 3.71 (s, 3H), 3.24 (heptet, 1H, J=7.0 Hz), 2.17 (s, 3H), 1.33 (d, 6H, J=7.0 Hz), 1.25 (s, 6H).
Reaction SMILES: N([O-])=O.[Na+].[C:5]([C:8]1[CH:12]=[C:11]([C:13]([NH:15][C@@H:16]([CH3:34])[CH2:17][N:18]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[C:25]([N+]([O-])=O)[CH:24]=3)=[N:19]2)=[O:14])[NH:10][N:9]=1)(=[O:7])[CH3:6].S(=O)(=O)(O)O.[I-:40].[K+]>O.CC#N>[C:5]([C:8]1[NH:9][N:10]=[C:11]([C:13]([NH:15][C@@H:16]([CH3:34])[CH2:17][N:18]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[C:25]([I:40])[CH:24]=3)=[N:19]2)=[O:14])[CH:12]=1)(=[O:7])[CH3:6]
Reactant: [I-]
Reactant: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c([N+](=O)[O-])c3)n2)[nH]n1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(I)c3)n2)n[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.3 %

Procedure:
Sodium nitrite (50 mg, 0.73 mmol) in 1 ml of water was added slowly to a solution of (S)-3-acetyl-N-(1-(3-(4-cyano-3-nitrophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide (250 mg, 0.66 mmol) in water (2 ml), sulfuric acid (71 μl, 1.33 mmol) and MeCN (3 ml) at 0° C. After 15 min potassium iodide (0.22 g, 1.32 mmol) in 1 ml of water was added. Reaction mixture was stirred at RT for 2 h and then poured into 10 ml of water. Thus resulting precipitate was filtered and washed with 10% sodium bisulfite solution and water. Crude product was purified by CombiFlash (column: silica, eluent: 3-10% MeOH in DCM) to yield 75 mg (23%) of the title compound. 1H-NMR (400 MHz; MeOD): δ 1.27 (d, 3H), 2.55 (s, 3H), 4.35 (m, 1H), 4.39 (m, 1H), 4.57 (m, 1H), 6.63 (d, 1H), 7.28 (br s, 1H), 7.42 (s, 1H), 7.57 (d, 1H), 7.66 (d, 1H), 7.93 (br s, 1H), 8.35 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)=[O:4].C1N2CN3CN(C2)C[N:17]1C3.C(O)C.Cl>CN(C)C=O>[ClH:1].[NH2:17][CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)=[O:4]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=C1CCc2cc(C(=O)CCl)ccc2N1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: NCC(=O)c1ccc2c(c1)CCC(=O)N2
Reaction time: 2 h
Yield: 37.2 %

Procedure:
In to a suspension of 3.0 g of 6-chloroacetyl-3,4-dihydrocarbostyril being suspended in 20 ml of dimethylformamide was added dropwise gradually a solution consisting of 1.9 g of hexamine and 20 ml of dimethylformamide. After the addition was completed the reaction mixture was stirred at 50° to 60° C. for 2 hours. Then the crystals precipitated in the reaction mixture were collected by filtration, and were washed with methanol, dried to obtain 3.5 g of crude crystals of 6-hexaminiumacetyl-3,4-dihydrocarbostyril chloride. Then, 15 ml of ethanol and 6 ml of concentrated hydrochloric acid were added to the 3.5 g of the crude crystals of 6-hexaminiumacetyl-3,4-dihydrocarbostyril chloride and the mixture was stirred at a room temperature for 12 hours. The crystals thus formed were collected by filtration, and recrystallized from methanol-water to obtain 1.2 g of 6-aminoacetyl-3,4-dihydrocarbostyril monohydrochloride in the form of colorless powdery crystals. Melting point: Higher than 300° C.
Reaction SMILES: [Br:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:11].Cl.[NH2:13][OH:14].C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([C:6]([NH:13][OH:14])=[NH:7])=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1cc(C#N)cc(C)c1Br
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(C(=N)NO)cc(C)c1Br
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-3,5-dimethyl-benzonitrile (1.50 g), hydroxylamine hydrochloride (0.90 g), triethylamine (1.8 mL) and ethanol (30 mL) is stirred at reflux temperature for 4 h. After cooling to room temperature, the mixture is concentrated, the residue is taken up in water, and the resulting mixture is extracted with ethyl acetate. The combined extract is washed with brine, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 7:3→3:7) to give the title compound. LC (method 11): tR=0.73 min; Mass spectrum (ESI+): m/z=243/245 (Br) [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[C:18](=O)[CH:17]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CO.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[CH:18]=[C:17]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)CC1Cc2cccc(-c3ccc(C(C)(C)C)cc3)c2C1=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)CC1=Cc2c(cccc2-c2ccc(C(C)(C)C)cc2)C1
Temperature: 50 °C
Reaction time: 4 h
Yield: 73.9 %

Procedure:
50 g (150 mmole) 7-(4′-tert-Butyl-phenyl)-2-(2,2-dimethyl-propyl)-indan-1-one were dissolved in 180 ml toluene in a 500 ml-roundbottom flask equipped with a reflux condenser. 6.22 g (1.1 eq.) sodium borohydride were added. Then 26.1 ml (4.3 eq.) methanol were added at 50° C. and the mixture was stirred for 4 h at 50° C. Another 3.11 g sodium borohydride and 10.3 g methanol were added and the mixture was stirred at 50° C. overnight. 2M sulphuric acid was added until the gas evolution ceased. After addition of 100 ml water the layers were separated and the organic layer was washed two times with 2M sulphuric acid and once with a saturated sodium chloride solution. The solvent was evaporated and the crude indanol was dissolved in approx. 300 ml of toluene. After addition of 1 g p-toluene sulfonic acid the mixture was heated to reflux using a Dean-Stark-trap until TLC showed complete conversion (90 min). The solution was washed twice with a saturated NaHCO3-solution, once with water and once with a saturated sodium chloride solution. Drying over magnesium sulphate, evaporation of the solvent and recrystallization from 500 ml ethanol afforded 35.3 g (74%) of the desired indene as white crystals. 1H-NMR (400 MHz, CDCl3): δ=7.47 (s, 4H, aromatic), 7.34 (d, 1H, aromatic), 7.25 (d, 1H, aromatic), 7.16 (t, 1H, aromatic), 6.72 (s, 1H, C═CH), 3.44 (s, 2H, benzylic), 2.36 (s, 2H, CH2-t-Bu), 1.37 (s, 9H, Ph-t-Bu), 0.96 (s, 9H, CH2-t-Bu) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:17]#[N:18])[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10]([OH:12])=O.Cl.[NH:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([C:17]#[N:18])[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([C:10]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:27]=[CH:28][C:29]([C:30]#[N:31])=[CH:32][CH:33]=3)[CH2:22][CH2:21]2)=[O:12])[CH:13]=[CH:14][C:15]=1[CH3:16]
Reactant: Cc1ccc(C(=O)O)cc1-c1[nH]c(C#N)nc1Cl
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1-c1[nH]c(C#N)nc1Cl
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 25.4 %

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of 3-(4-chloro-2-cyano-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 234.5, 60 mg, 0.23 mmol) in N,N-dimethylformamide (2 mL). 4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.2, 61 mg, 0.27 mmol), HBTU (131 mg, 0.35 mmol), DIEA (123 μL, 0.69 mmol) were added to the reaction. The reaction mixture was stirred for 30 min at 15° C. The reaction mixture was diluted with 40 mL of EtOAc, then was washed with 2×30 mL of brine and 2×30 mL of NH4Cl (sat.), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (160 mg) was purified by Prep-HPLC with the following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, SunFire Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, WATER WITH 0.05% TFA and MeCN (49.0% MeCN up to 62.0% in 7 min, up to 100.0% in 3 min, down to 49.0% in 1 min); Detector, Waters 2489, 254 and 220 nm. This resulted in 25.1 mg (25%) of the title compound as a white solid. m/z (ES+) 430 (M+H)+.
Reaction SMILES: [SH3+].[I-].C(O[C@:11]([N:35]=[C:36]=[O:37])([C:17](=[O:34])[NH:18][C@H:19]1[CH2:28][CH2:27][C:22]2([O:26][CH2:25][CH2:24][O:23]2)[CH2:21][C@H:20]1[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:12][CH2:13][S+](C)C)C1C=CC=CC=1.[C:38](=[O:41])([O-])[O-].[Cs+].[Cs+].CS(C)=O>[Cl-].[Na+].O.C(OCC)(=O)C>[CH2:38]([O:41][C:36]([NH:35][C@H:11]1[CH2:12][CH2:13][N:18]([C@H:19]2[CH2:28][CH2:27][C:22]3([O:23][CH2:24][CH2:25][O:26]3)[CH2:21][C@H:20]2[C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:17]1=[O:34])=[O:37])[C:19]1[CH:28]=[CH:27][CH:22]=[CH:21][CH:20]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)[C@@H]1CC2(CC[C@@H]1NC(=O)[C@@](CC[S+](C)C)(N=C=O)OCc1ccccc1)OCCO2
Agent: [Cl-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1CC2(CC[C@@H]1N1CC[C@H](NC(=O)OCc3ccccc3)C1=O)OCCO2

Procedure:
Example 1, 2nd Alternative Preparation, Step 2: Sulfonium salt 3 (619.4 g), and cesium carbonate (416.8 g) and anhydrous dimethyl sulfoxide (6.2 L) were combined in a reactor equipped with a scrubber to neutralize volatile sulfides. Vigorous agitation was maintained until complete conversion was obtained (HPLC). Ethyl acetate (12.4 L) was added, followed by 20% brine (3 L). The organic phase was separated, washed twice with brine (2×3 L) and evaporated to obtain a solution of ethyl (7R,8S)-8-((S)-3-benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl)-1,4-dioxa-spiro[4.5]decane-7-carboxylate 4 in ethyl acetate (˜0.8 L). Acetone (2.55 L) was added, followed by aqueous 0.5 M hydrochloric acid solution (2.3 L). With good mixing, the solution was heated to 50 to 60° C. until conversion of 4 to ethyl (1R,2S)-2-((S)-3-benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl)-5-oxo-cyclohexanecarboxylate 5 was complete (HPLC). The mixture was concentrated under reduced pressure while below 40° C., cooled to ˜30° C., and water (4.1 L) was added. The resulting slurry was cooled to 5 to 10° C. and agitated for ˜1 hour. The product was filtered and the cake was washed with water (2×2.5 L). Upon deliquoring, the cake was dried to a constant weight below 40° C. in a vacuum oven. Cyclohexanone 5 (272 g, 70% yield) was obtained (HPLC purity 98.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[S:63]1[C:71]2[CH2:70][CH2:69][NH:68][CH2:67][C:66]=2[CH:65]=[CH:64]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:68]1[CH2:69][CH2:70][C:71]3[S:63][CH:64]=[CH:65][C:66]=3[CH2:67]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: c1cc2c(s1)CCNC2
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCc4sccc4C3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine in DMSO at ambient temperature.
Reaction SMILES: CN([CH:4]=[CH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)=O)C.[NH:15]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[C:16]([NH2:18])=[NH:17].CN1C(=O)CCC1>O>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:18]=[C:16]([NH:15][C:19]3[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:26])=[O:27])=[CH:21][CH:20]=3)[N:17]=2)=[CH:9][CH:10]=1
Reactant: N=C(N)Nc1ccc(S(N)(=O)=O)cc1
Reactant: CN(C)C=CC(=O)c1ccc(Br)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: NS(=O)(=O)c1ccc(Nc2nccc(-c3ccc(Br)cc3)n2)cc1
Temperature: 120 °C
Reaction time: 20 h
Yield: 99.9 %

Procedure:
A flask is charged with the 1-(4-bromo-phenyl)-3-dimethylamino-propenone (1.05 g, 4.10 mmol), 4-guanidino-benzenesulfonamide (1.33 g, 6.20 mmol), and NMP (30 ml). The reaction mixture is stirred at 120° C. for 20 h. The reaction mixture is cooled to room temperature, diluted with water, and filtered. The solid residue is washed with water and dried to yield 1.66 g of a white solid. MS (ESI) m/z 405.1; HRMS: calcd for C16H13BrN4O2S+H+, 405.00153; found (ESI-FTMS, [M+H]1+), 405.00158.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.NCCS(O)(=O)=O.C1COCC1.[OH-].[Na+:42]>C1C=CC=CC=1.CN(C=O)C>[Na+:42].[C:11]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([O-:10])=[O:9])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NCCS(=O)(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C([O-])C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 3 h

Procedure:
Triphenylacetic acid (2 g, 6.94 mmol) was dissolved in 5 mL of benzene in a round bottom flask. One drop of DMF was added as a catalyst and the solution was cooled with an ice bath. Once the solution had cooled oxalyl chloride (3 mL, 34.7 mmol) was added dropwise resulting in a vigorously bubbling solution. The reaction was allowed to stir 3 hours and the volatiles were removed under vacuum. The resulting oil was dissolved in 25 mL of THF and the round bottom flask was fitted with an addition funnel. The solution was cooled and a solution of taurine (1.3 g, 11.6 mmol) in 13 mL of 1 N NaOH was mixed with 12 mL of THF and the solution was placed into the addition funnel and added dropwise. The reaction was stirred overnight and the THF was removed by rotary evaporation. The resulting solid was collected and washed with water. The material was then recrystallized from water providing 2.5 g (90%) of light yellow plates. IR (KBr): 3439 (N—H), 2763 (br), 1655 (C═O), 1218. 1H NMR (CDCl3/DMSO-d6, 300 MHz): δ 2.58 (t, J=22, 1H); 2.75 (t, J=22 Hz, 6H); 2.92 (dt, J=18, 22, 1H); 3.48 (s, 6H); 3.562 (dt, J=22,18 Hz, 1H); 7.17-7.30 (m, 16H); 7.42 (t, J=18 Hz, 0.5H)); 13C NMR (CDCl3/DMSO-d6, 75.4 MHz): δ 172.0 (C), 143.5 (C),130.2 (CH), 127.5 (CH), 126.4 (CH), 67.3 (C), 52 (CH2), 49.8 (CH2), 37.67 (CH2), 36.3 (CH2).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:28])[C@@H:10]([CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:11]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.FC(F)(F)C(O)=O.[OH-].[Na+]>O>[CH2:1]([NH:8][C:9](=[O:28])[C@@H:10]([CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: N[C@H](COCc1ccccc1)C(=O)NCc1ccccc1
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of N-benzyl-O-benzyl-N2-Boc-D-serinamide (16 g) and dichloromethane (80 mL), trifluoroacetic acid (80 mL) was added. The solution was stirred for 2 hours and the reaction was monitored for completion of reaction. The solution was concentrated under vacuum to obtain solid which was dissolved in water. The aqueous solution was basified to pH 8-10 with 5% sodium hydroxide and was extracted with ethyl acetate. The organic layer was separated and washed with a brine solution. The organic layer was concentrated under vacuum to obtain an oily residue 11 g of N-benzyl-O-benzyl-D-serinamide.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.C([Si](C)(C)C)#C.[CH2:12]([N:19]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:20]([C@@H:22]1[CH2:24][O:23]1)[CH3:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.B(F)(F)F.CCOCC.[Cl-].[NH4+].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH2:12]([N:19]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:20]([C@@H:22]([OH:23])[CH2:24][C:1]#[CH:2])[CH3:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [Li]CCCC
Reactant: C[C@@H]([C@@H]1CO1)N(Cc1ccccc1)Cc1ccccc1
Agent: C#C[Si](C)(C)C
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#CC[C@H](O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5 M solution in hexanes, 131 mL, 328 mmol) was added drop-wise over approximately 9 minutes to a −70° C. solution of ethynyl(trimethyl)silane (46.3 mL, 328 mmol) in tetrahydrofuran (1 L), and the reaction mixture was stirred at −70° C. for 30 minutes. A solution of (1S)—N,N-dibenzyl-1-[(2R)-oxiran-2-yl]ethanamine (C37, see J. Barluenga et al., J. Org. Chem. 1995, 60, 6696-6699) (79.6 g, 298 mmol) in tetrahydrofuran (250 mL) was added; the reaction mixture, which had warmed as a result of the addition, was recooled to approximately −65° C., and boron trifluoride diethyl etherate (37.6 mL, 298 mmol) was added. The reaction mixture was then stirred for 1.5 hours at −70° C. Saturated aqueous ammonium chloride solution (200 mL) was added, and the mixture was allowed to warm to room temperature. The organic layer was washed with saturated aqueous sodium chloride solution, and the aqueous layer from the quenched reaction was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in methanol (500 mL), treated with potassium carbonate (206 g, 1.49 mol) and stirred at room temperature for 18 hours. After filtration through Celite and rinsing with ethyl acetate, the crude product solution was concentrated in vacuo, dissolved in diethyl ether (1 L), washed with water (250 mL) and with saturated aqueous sodium chloride solution (75 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. After seeding with a small sample of solid product, heptane (60 mL) was added, and the mixture was vigorously stirred for 5 minutes, then filtered; the isolated solid was rinsed with heptane (50 mL) to afford the product as a pale orange solid. Yield: 37.3 g, 127 mmol, 43%. 1H NMR (400 MHz, CDCl3) δ 7.22-7.36 (m, 10H), 4.53 (s, 1H), 3.84 (d, J=13.1 Hz, 2H), 3.63 (ddd, J=9.5, 5.8, 4.0 Hz, 1H), 3.34 (d, J=13.3 Hz, 2H), 2.80 (dq, J=9.4, 6.6 Hz, 1H), 2.46 (ddd, half of ABXY pattern, J=17.0, 4.0, 2.6 Hz, 1H), 2.21 (ddd, half of ABXY pattern, J=17.0, 6.0, 2.6 Hz, 1H), 1.86 (dd, J=2.7, 2.5 Hz, 1H), 1.07 (d, J=6.8 Hz, 3H).