Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)O)[CH2:15][CH2:14]3)[S:10][N:9]=2)=[CH:4][CH:3]=1.CCN(S(F)(F)[F:36])CC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]([F:36])[C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH2:15][CH2:14]3)[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1ccc(C(O)CN2CCN(c3nc(-c4ccc(Cl)cc4)ns3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C(F)CN2CCN(c3nc(-c4ccc(Cl)cc4)ns3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(4-(3-(4-chlorophenyl)-1,2,4-thiadiazol-5-yl)piperazin-1-yl)-1-(4-methoxyphenyl)ethanol (30 mg, 69.6 μmol) and DAST (22.4 mg, 18.4 μl, 139 μmol) in 2 mL DCM at 0-5° C. was warmed to RT and stirred for 2 h. 10% aq. Na2CO3-solution was added and stirred for 10 min. The organic layer was separated and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with a gradient formed from heptane and EtOAc to yield, after evaporation of the product containing fraction, 24 mg (80%) of the title compound as light yellow solid. MS (m/e): 433.3 (MH+).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])=[C:4]([NH:11][S:12]([C:15]2([CH2:18][C@H:19]3[CH2:23][O:22]C(C)(C)[O:20]3)[CH2:17][CH2:16]2)(=[O:14])=[O:13])[C:5]([O:9][CH3:10])=[CH:6][C:7]=1[F:8]>C1COCC1.Cl>[F:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])=[C:4]([NH:11][S:12]([C:15]2([CH2:18][C@H:19]([OH:20])[CH2:23][OH:22])[CH2:17][CH2:16]2)(=[O:13])=[O:14])[C:5]([O:9][CH3:10])=[CH:6][C:7]=1[F:8]
Reactant: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1NS(=O)(=O)C1(C[C@H]2COC(C)(C)O2)CC1
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1NS(=O)(=O)C1(C[C@H](O)CO)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)—N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)cyclopropane-1-sulfonamide is dissolved in a mixture of THF and HCl and stirred overnight at room temperature. The solvents are removed under reduced pressure and the residue dissolved in ethyl acetate. The organic phase is washed with aqueous NaHCO3, dried (Na2SO4), and concentrated.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[CH:18]([S:20]([CH:23]=[CH2:24])(=[O:22])=[O:21])=[CH2:19].[NH2:25][C@H:26]([C:32](O)=[O:33])[CH2:27][CH2:28][C:29](=[O:31])[OH:30].N[C@H](C(O)=O)CC(=O)N>>[NH2:25][C@H:26]([C:32]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:33])[CH2:27][CH2:28][C:29](=[O:30])[OH:31].[CH:18]([S:20]([CH:23]=[CH2:24])(=[O:22])=[O:21])=[CH2:19]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)CC(N)=O)C(=O)O
Agent: C=CS(=O)(=O)C=C
Agent: NC(=O)C[C@H](N)C(=O)O
Product: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CCC(=O)O)C(=O)O

Procedure:
This compound is synthesized as described above for compound (i), except that Glu-asparagine is used in step (g).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[CH3:19][N:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:21](Cl)=[O:22]>>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:21](=[O:22])[N:20]([CH3:19])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:11][CH:12]=1
Reactant: Oc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(Oc2cccc(C(F)(F)F)c2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-(3-trifluoromethyl-phenoxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was purified by preparative HPLC (73%, white crystals). HPLC-MS m/z=388.2 (M+1), Rt: 5.37 min.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH2:19]([C@@:22]1([CH2:65][O:66][CH2:67][CH2:68][Si:69]([CH3:72])([CH3:71])[CH3:70])[CH2:27][C@H:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C@@H:25]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[N:24]([C@@H:42]([CH2:62][CH3:63])[CH2:43][O:44][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C:23]1=[O:64])[CH:20]=[CH2:21]>C1COCC1.CCOC(C)=O>[CH2:19]([C@@:22]1([CH2:65][O:66][CH2:67][CH2:68][Si:69]([CH3:72])([CH3:71])[CH3:70])[CH2:27][C@H:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C@@H:25]([C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)[N:24]([C@@H:42]([CH2:62][CH3:63])[CH2:43][OH:44])[C:23]1=[O:64])[CH:20]=[CH2:21]
Reactant: C=CC[C@@]1(COCC[Si](C)(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC[C@@]1(COCC[Si](C)(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O

Procedure:
A 1M solution of TBAF in THF (2.15 mL, 2.15 mmol) was added to a solution of (3S,5R,6S)-3-allyl-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2-one (Example 414, Step A; 860 mg, 1.074 mmol) in THF. The reaction was heated to reflux for 3 hours. After cooling, it was diluted with EtOAc and washed with HCl (1N in water). The organic extract was washed with satd NaCl and dried over Na2SO4. The solution was filtered and concentrated to give the crude material as a glass which was purified by chromatography on silica eluting with 20% EtOAc in hexane, to provide the title compound as a solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[Br-:13].[Li+]>CC(C)=O>[Br:13][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: [Br-]
Reactant: Cc1ccc(CCl)cc1[N+](=O)[O-]
Agent: [Li+]
Solvent: CC(C)=O
Product: Cc1ccc(CBr)cc1[N+](=O)[O-]
Yield: 85.5 %

Procedure:
4-Chloromethyl-1-methyl-2-nitro-benzene (5 g) was dissolved in 50 ml of acetone and 23.4 g of lithium bromide was added. The reaction mixture was heated at reflux for 18 hr. The solvent was evaporated off and the residue was tritrated with hexane to give 5.3 g of 4-bromomethyl-1-methyl-2-nitro-benzene as a tan solid. ##STR125##
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[OH:9].[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:12]=1[C:13]#[N:14]>>[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([O:9][CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]2[O:2][CH3:1])[C:12]=1[C:13]#[N:14]
Reactant: N#Cc1c(N)cccc1F
Reactant: COC1CCCCC1O
Product: COC1CCCCC1Oc1cccc(N)c1C#N

Procedure:
Prepared as in Example 22b from 2-methoxycyclohexanol and 2-amino-6-fluoro-benzonitrile as a yellow oil (34%). MS 247 (MH+).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:2]1[S:6][C:5]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: O=C(O)C=Cc1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(O)C=Cc1ccc(-c2ccccc2F)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
9.38 g (40.2 mmol) of 3-(5-Bromo-thiophen-2-yl)-acrylic acid and 6.97 g (6 mmol) of tetrakis(triphenylphosphine)palladium were dissolved in 50 ml of degassed DME and stirred for 10 min at room temperature. 8.44 g (60.4 mmol) of 2-fluorophenylboronic acid and 50 ml of a 2 M aqueous sodium carbonate solution were added together with an additional 5 ml of degassed DME. The reaction mixture was heated to 95° C. for 4 h, and then stirred at room temperature for 16 h. The product precipitated partially from the reaction solution and was collected by filtration. This solid was boiled for 1 h in ethyl acetate and filtered while hot. The solvent was removed under reduced pressure. The remaining reaction solution was evaporated to dryness. The residue was taken up in ethyl acetate/water and filtered. The organic phase was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The combined product was purified by silica gel chromatography. Yield: 7.5 g.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([C:17]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[O:18])[CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:25][C:26]1[CH:27]=[C:28]([NH:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]=[CH:30][CH:31]=1>>[C:33]([NH:32][C:28]1[CH:27]=[C:26]([NH:25][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[C:15]([C:17]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[O:18])[CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:31]=[CH:30][CH:29]=1)(=[O:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: Nc1cccc(NC(=O)c2ccccc2)c1
Reactant: CN(C)CCNC(=O)c1ccc2c(=O)[nH]c3nccc(Cl)c3c2c1
Product: CN(C)CCNC(=O)c1ccc2c(=O)[nH]c3nccc(Nc4cccc(NC(=O)c5ccccc5)c4)c3c2c1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 267 using 296 (40 mg, 0.12 mmol) and N-(3-amino-phenyl)-benzamide to provide 301. LC-MS (M+H=521, obsd.=521).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:17][CH:16]3[CH:12]([CH2:13][NH:14][CH2:15]3)[CH2:11]2)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[N:32]=[CH:31][CH:30]=[N:29]2)[C:20]=1[C:21](O)=[O:22]>>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[N:32]=[CH:31][CH:30]=[N:29]2)[C:20]=1[C:21]([N:14]1[CH2:13][CH:12]2[CH:16]([CH2:17][N:10]([C:7]3[N:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][N:6]=3)[CH2:11]2)[CH2:15]1)=[O:22]
Reactant: O=[N+]([O-])c1cnc(N2CC3CNCC3C2)nc1
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Product: O=C(c1c(F)cccc1-n1nccn1)N1CC2CN(c3ncc([N+](=O)[O-])cn3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 46 and Intermediate 12. MS (ESI): mass calculated for C19H17FN8O3, 424.14; m/z found 425.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 9.10 (ddd, J=9.9, 5.7, 3.3, 2H), 7.90-7.79 (m, 2H), 7.74 (d, J=6.6, 1H), 7.55-7.44 (m, 1H), 7.22-7.10 (m, 1H), 4.13-3.60 (m, 7H), 3.40-3.07 (m, 3H).
Reaction SMILES: [O:1]=[S:2]1(=[O:26])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:14]=[C:15]([C:19](=[N:21][OH:22])[NH2:20])[CH:16]=[CH:17][CH:18]=3)[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:23][CH2:24][CH2:25][C:4]2=[N:3]1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[S:28].C1CCN2C(=NCCC2)CC1>CC#N>[O:26]=[S:2]1(=[O:1])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:14]=[C:15]([C:19]4[NH:20][C:27](=[S:28])[O:22][N:21]=4)[CH:16]=[CH:17][CH:18]=3)[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:23][CH2:24][CH2:25][C:4]2=[N:3]1
Reactant: NC(=NO)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=S1(=O)N=C2CCCN2c2ccc(Oc3cccc(-c4noc(=S)[nH]4)c3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of the product obtained in Step A of Example 13 (300 mg, 0.81 mmol) in 6 ml of CH3CN there are added 239 mg (1.21 mmol) of thiocarbonyldiimidazole and then 481 μl (3.22 mmol) of DBU. The reaction solution is stirred at ambient temperature for 1 hour. Evaporation to dryness and chromatography on silica (CH2Cl2/MeOH 95/5) are carried out. After evaporating the fractions containing the product formed, the residue is triturated in MeOH and the title product is recovered by filtration.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]1([C:16]2[C:21](=[O:22])[N:20]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:26][CH:25]=3)[C:19]([CH2:38][CH2:39][CH3:40])=[N:18][C:17]=2[CH2:41][CH3:42])[CH2:15][CH2:14]1>O>[CH:13]1([C:16]2[C:21](=[O:22])[N:20]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]4[NH:3][C:4](=[O:7])[O:5][N:37]=4)=[CH:26][CH:25]=3)[C:19]([CH2:38][CH2:39][CH3:40])=[N:18][C:17]=2[CH2:41][CH3:42])[CH2:14][CH2:15]1
Reactant: CCCc1nc(CC)c(C2CC2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(CC)c(C2CC2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
A mixture of hydroxylammonium chloride (2.35 g), sodium hydrogen carbonate (3.34 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-[(5-cyclopropyl-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.79 g) was added, and the mixture was stirred at 90° C. for 16 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitate was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.48 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.45 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.38 g, 42%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:15]O>>[CH3:15][O:12][C:11](=[O:13])[CH2:10][NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)CNc1ccc(F)c(F)c1
Agent: Cl
Product: COC(=O)CNc1ccc(F)c(F)c1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Through a suspension of 3,4-difluorophenylglycine (2.00 g, 10.7 mmol) in methanol (100 mL) was passed gaseous hydrochloric acid for 40 min while cooling with an ice-bath to keep ambient temperature. The resulting solution was stirred for 1 h at 5° C. and for 30 min at ambient temperature. Nitrogene was passed through the reaction mixture for 120 min. Concentration afforded the title compound (2.52 g, 99%) as a white solid. MS m/e: 202.2 [M−HCl+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:9]=2)=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([O:14][CH2:22][C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Oc1cc(-c2ccccc2)nc(-c2ccc(Cl)cc2)n1
Product: O=C(O)c1ccc(COc2cc(-c3ccccc3)nc(-c3ccc(Cl)cc3)n2)cc1

Procedure:
The title compound was prepared from 2-(4-chloro-phenyl)-6-phenyl-pyrimidin-4-ol (which was obtained in Intermediate 1) and methyl 4-(bromomethyl)benzoate according to Method A and Method B; 1H NMR (DMSO-d6, 300 MHz) δ 5.61 (s, 2H), 7.26 (t, J=9.0 Hz, 2H), 7.45-7.70 (m, 8H), 8.25-8.35 (m, 2H), 8.55 (d, J=6.0 Hz, 2H); LC retention time 3.86 min; MS: m/z (ESI) 415 (M−H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@H:27]4[C@H:31]([OH:32])[CH2:30][NH:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@H:27]4[C@H:31]([OH:32])[CH2:30][N:29]([C:33](=[O:36])[CH2:34][CH3:35])[CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CNC[C@H]1O
Agent: Cl
Product: CCC(=O)N1C[C@@H](O)[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f10) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[CH2:5][S:4][CH2:3]1.[BH4-].[Na+]>CO>[OH:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[CH2:5][S:4][CH2:3]1
Reactant: N#Cc1ccc2c(c1)CSCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc2c(c1)CSCC2O
Reaction time: 1 h

Procedure:
To a solution of 4-oxo-isothiochroman-7-carbonitrile (830 mg, 4.4 mmol) in methanol (25 mL) at 0° C. is added NaBH4 (330 mg, 8.8 mmol). The reaction is permitted to stir for 1 hour and then quenched with 1N aqueous HCl. The reaction is concentrated to approximately half of its original volume and diluted with ethyl acetate. The organic layer is separated, dried with Na2SO4, filtered and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-hexanes, 0:1 to 1:1) to afford 4-hydroxy-isothiochroman-7-carbonitrile; MS: (ESI) m/z 192.1 (M+H)+.
Reaction SMILES: [Na+].[N+:2]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[S:18])=[O:12])=[CH:7][CH:6]=1)([O-:4])=[O:3].C(O[C@@H:26]1[NH:29][C:28](=[O:30])[C@H:27]1[O:31][CH3:32])(=O)C.O1CCOCC1.C(Cl)Cl>P([O-])([O-])([O-])=O>[N+:2]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][C:17]([S:18][C@H:26]2[NH:29][C:28](=[O:30])[C@@H:27]2[O:31][CH3:32])=[O:19])=[O:12])=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: CO[C@@H]1C(=O)N[C@H]1OC(C)=O
Reactant: O=C(NCCCC([O-])=S)OCc1ccc([N+](=O)[O-])cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CO[C@H]1C(=O)N[C@@H]1SC(=O)CCCNC(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
Analogously to Example 55b), an aqueous solution of 480 mg of 4-p-nitrobenzyloxycarbonylaminothiobutyric acid sodium salt is added to 159 mg of (3S,4S)-4-acetoxy-3-methoxy-2-oxoazetidine in 6 ml of a phosphate buffer of a pH of 7 and 0.4 ml of dioxan. After working up and chromatography over silica gel, the title compound with the following IR spectrum (CH2Cl2) is obtained:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)=[N:6][C:7]=1Br.[CH3:25][S-:26].[Na+].O>CN1CCN(C)C1=O>[NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)=[N:6][C:7]=1[S:26][CH3:25]
Reactant: CC(C)n1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: CSc1nc(-c2ccc(=O)n(C(C)C)n2)c(-c2ccccc2)nc1N
Temperature: 102.5 °C
Yield: 41.6 %

Procedure:
A mixture of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (11.35 g) and sodium thiomethoxide (4.12 g) in 1,3-dimethyl-2-imidazolidinone (17 ml) was heated at 100-105° C. for one hour. The mixture was poured into water (170 ml). The precipitate was collected by filtration, dissolved in CHCl3, dried over MgSO4, concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (50:50 v/v) to give 6-[5-amino-6-(methylthio)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone as a solid (4.32 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.N1C=CC=CC=1.O.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29](Cl)(=[O:31])=[O:30]>C1COCC1>[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1)(=[O:31])=[O:30]
Reactant: Nc1ccc(SCC(=O)O)c2ccccc12
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)CSc1ccc(NS(=O)(=O)c2cccs2)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.6 %

Procedure:
32.5 mg 21 was dissolved in 1 ml THF, to which at 0° C. was added 0.28 ml pyridine solution (0.5 M in THF) followed by 0.5 ml water. Upon stirring, 25.6 mg thiophene-2-sulfonyl chloride in 1 ml THF was added dropwise. Additional 0.28 ml pyridine solution was added. The resulting solution was stirred vigorously at 0° C. and slowly warmed to room temperature. After 4 hours, the organic solvent was removed. The aqueous portion was diluted with 10 ml water and acidified at 0° C. with NaHSO4 solution (0.5 M). The mixture was extracted with ethyl acetate. The organic phase was combined, washed with water and brine and dried over Na2SO4. After removal of Na2SO4, the organic phase was concentrated and the crude product was purified via flash chromatography (5 g silica gel, DCM/CH3OH=20:1) affording 31 mg (58.4%) grey solid. 1H NMR (400 MHz, CD3CN) δ 8.36 (d, J=8.4 Hz, 1H), 8.00 (d, J=8.5 Hz, 1H), 7.68 (dd, J=5.0, 1.3 Hz, 1H), 7.62 (ddd, J=8.3, 6.8, 1.2 Hz, 1H), 7.54 (m, 2H), 7.43 (dd, J=3.8, 1.3 Hz, 1H), 7.28 (d, J=7.9 Hz, 1H), 7.04 (dd, J=5.0, 3.8 Hz, 1H), 3.78 (s, 2H). LRMS (ES−) 378 (M−H)−; HRMS (ES−) m/z calculated for C16H12NO4S3 (M−H)− 377.9934, found 377.9937.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)([CH3:5])[CH2:3][NH2:4].[CH2:11]=O>>[CH2:11]=[N:4][CH2:3][C:2]([CH3:5])([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[CH3:1]
Reactant: C=O
Reactant: CC(C)(CN)c1ccsc1
Product: C=NCC(C)(C)c1ccsc1

Procedure:
5.8 g (37 mmol) 2-methyl-2-thiophene-3-yl-propylamine and 3.6 mL (44 mmol) formaldehyde were stirred overnight together with 2.0 g molecular sieve (4 Å powder) at RT. The reaction mixture was filtered and the filtrate was concentrated to dryness by rotary evaporation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[NH:13][C:12](=[O:14])[O:11][C:9](=O)[C:8]=12.[NH:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1C(O)=O>CS(C)=O>[CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:11])[N:15]3[CH2:22][CH2:21][CH2:20][C@H:16]3[C:12](=[O:14])[NH:13][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2[nH]c(=O)oc(=O)c12
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Product: COc1cccc2c1C(=O)N1CCC[C@H]1C(=O)N2

Procedure:
4.8 g (0.025 mmol) of 6-methoxyisatoic acid anhydride and 3.0 g (0.026 mol) of L-proline in 40 ml of dimethyl sulphoxide is heated to 70° for 2 hours, the solvent is removed in a high vacuum and the oil obtained is heated to 170° for 15 minutes. After treatment with active carbon, the crude product is recrystallized from methanol, there being obtained (S)-1,2,3,11a-tetrahydro-6-methoxy-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione of melting point 247°-251°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2.[C:12](OC(=O)C)(=[O:14])[CH3:13].C(Cl)(=O)C.C(N(CC)CC)C>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12](=[O:14])[CH3:13])[CH2:6][CH2:5]2
Reactant: Oc1ccc2c(c1)CCNC2
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Product: CC(=O)N1CCc2cc(O)ccc2C1

Procedure:
5.0 g of 6-hydroxy-1,2,3,4-tetrahydroisoquinoline are converted into the bisacetyl compound using acetic anhydride or acetyl chloride/triethylamine, and, without purification, this compound is heated under reflux for 6 hours with 10 ml of diethylamine in 50 ml of ethanol. The mixture is evaporated in vacuo in a rotary evaporator, and the residue is chromatographed on silica gel using ethyl acetate/methanol in the ratio 9:1. A yellow oil which crystallizes on trituration with diethyl ether is obtained. Yield: 5.2 g (78% of theory), melting point: 129°-130°.