Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[OH:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35]([O:42][C:43]1[CH:47]=[C:46]([CH2:48]OS(C)(=O)=O)[O:45][N:44]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CC#N.CC#N.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:48][C:46]1[O:45][N:44]=[C:43]([O:42][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:47]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCc1cc(OCc2ccccc2)no1
Reactant: O=C(OCc1ccccc1)N1CCc2ccccc2C1c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(OCc1ccccc1)N1CCc2ccccc2C1c1cc(Cl)ccc1OCc1cc(OCc2ccccc2)no1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of (±)-1-(5-chloro-2-hydroxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (159 mg, 0.4 mmol, 1 eq.) in MeCN (0.8 mL), potassium carbonate (166 mg, 1.2 mmol, 3 eq.) and methanesulfonic acid 3-benzyloxy-isoxazol-5-ylmethyl ester (113 mg, 0.4 mmol, 1 eq.) were added. The reaction mixture was stirred at 80° C. for 18 hours. The mixture was diluted with MeCN/H2O 1:1 (1 mL) and purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give (±)-1-[2-(3-benzyloxy-isoxazol-5-ylmethoxy)-5-chloro-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester.
Reaction SMILES: CO[CH:3](O)[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([F:15])[CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:16].CC([N:22]([C@@H:26]1[CH2:31][CH2:30][NH:29][CH2:28][C@@H:27]1[OH:32])[C:23](=[O:25])[O-:24])(C)C.OCC[CH2:36][C:37]1[C:42](=O)N(CC2C=CC(OC)=CC=2)NC(=O)[CH:38]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[F:15][C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[CH:7][C:6](=[O:16])[N:5]2[CH2:4][CH2:3][N:29]2[CH2:30][CH2:31][C@@H:26]([NH:22][C:23](=[O:25])[O:24][C:37]([CH3:42])([CH3:38])[CH3:36])[C@@H:27]([OH:32])[CH2:28]2)=[N:10][CH:11]=1
Reactant: COc1ccc(Cn2[nH]c(=O)cc(CCCO)c2=O)cc1
Reactant: COC(O)Cn1c(=O)ccc2ncc(F)cc21
Reactant: CC(C)(C)N(C(=O)[O-])[C@@H]1CCNC[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(CCn2c(=O)ccc3ncc(F)cc32)C[C@@H]1O
Temperature: 25 °C

Procedure:
(7-Fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde methyl hemiacetal (200 mg, 0.8396 mmol) and 1,1-dimethylethyl[(3S,4R)-3-hydroxy-4-piperidinyl]carbamate (for a synthesis see WO2004058144, Example 5(c), cis-(3-hydroxy-piperidin-4-yl)-carbamic acid tert-butyl ester Enantiomer 2) (192 mg, 1 eq.) were stirred in chloroform (10 ml) plus MeOH (0.5 ml) under argon for 2 h. Sodium triacetoxyborohydride (534 mg, 3 eq.) was added in one portion and the mixture was stirred at rt over the weekend, then quenched by addition of saturated aqueous sodium hydrogen cabonate (2 mL). The organic phase was separated using a hydrophobic frit and the aqueous phase was extracted with DCM (2×20 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give the crude product, which was purified by column chromatography on silica, eluted with 0-20% (2M ammonia in MeOH) in DCM. Appropriate fractions were combined and evaporated under reduced pressure to give 1,1-dimethylethyl {(3S,4R)-1-[2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl]-3-hydroxy-4-piperidinyl}carbamate (310 mg) as a tan foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH:16]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)([CH3:18])[CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O.C(N(CC)CC)C>[CH:16]([C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:21][CH:20]=1)([CH3:18])[CH3:17]
Reactant: CC(C)c1ccc(N)cc1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C(C(=O)Nc1ccc(C(C)C)cc1)CCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 72 %

Procedure:
7-Methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.62 g), 4-isopropylaniline (0.41 g) and triethylamine (0.84 mL) were dissolved in DMF (20 mL), and HOBt.H2O (0.48 g) and WSCI.HCl (0.61 g) were added under ice-cooling. The mixture was stirred at room temperature for one day and the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and ether was added to the residue. The precipitated solid was collected by filtration to give N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.70 g). melting point: 168-169° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][CH:25]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:33].C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30][Br:33])=[CH:26][CH:25]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(NC1CC1)c1cn(-c2cccc(-c3ccc(CO)cc3)c2)c2ncccc2c1=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(NC1CC1)c1cn(-c2cccc(-c3ccc(CBr)cc3)c2)c2ncccc2c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of N-cyclopropyl-1-[3-(4-hydroxymethylphenyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Example 16, carbon tetrabromide (2 eq), and diphos (0.6 molareq) in methylene chloride (15 ml/mmol) was stirred at room temperature for 3 hours. The mixture was concentrated at room temperature and chromatographed on silica gel eluting with a 1:1 mixture of ethyl acetate and methylene chloride to afford the N-Cyclopropyl-1-[3-(4-bromomethylphenyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([F:11])[C:5]([NH:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:40][C:41]1[CH:42]=[C:43]2[C:49]([O:50][CH2:51][CH3:52])=[N:48][N:47]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[C:44]2=[N:45][CH:46]=1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]([NH:40][C:41]2[CH:42]=[C:43]3[C:49]([O:50][CH2:51][CH3:52])=[N:48][N:47]([C:53]([O:55][C:56]([CH3:57])([CH3:59])[CH3:58])=[O:54])[C:44]3=[N:45][CH:46]=2)=[O:10])=[C:6]([F:11])[C:5]([NH:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)O)c1F
Reactant: CCOc1nn(C(=O)OC(C)(C)C)c2ncc(N)cc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)Nc2cnc3c(c2)c(OCC)nn3C(=O)OC(C)(C)C)c1F
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 21.4 %

Procedure:
A mixture of 6-chloro-2-fluoro-3-(propylsulfonamido)benzoic acid (0.446 g, 1.51 mmol), EDCI (0.723 g, 3.77 mmol), and HOBt (0.578 g, 3.77 mmol) in DMF (6 mL) was stirred at room temperature for 25 minutes. tert-Butyl 5-amino-3-ethoxy-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (0.21 g, 0.755 mmol) was added to the reaction mixture, followed by the addition of Et3N (0.53 mL, 3.77 mmol). After stirring for 4 hours, the reaction mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl, saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give the crude material. The crude material was purified by silica gel flash column chromatography (10% MeOH in CH2Cl2) to afford tert-butyl 5-(6-chloro-2-fluoro-3-(propylsulfonamido)benzamido)-3-ethoxy-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (90 mg, 22% yield).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([C:23](=O)[CH2:24][CH3:25])=[CH:4][CH:3]=1.Cl.[CH3:28][O:29][NH2:30].N1C=CC=CC=1>C(O)C>[CH3:28][O:29]/[N:30]=[C:23](\[C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)/[CH2:24][CH3:25]
Reactant: CCC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC/C(=N/OC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 26 h

Procedure:
A mixture of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-one (630 mg, 1.54 mmol), O-methylhydroxylamine hydrochloride (386 mg, 4.62 mmol) and pyridine (3.9 mL) in ethanol (16 mL) was stirred at 80° C. for 26 hr. The mixture was concentrated in vacuo, diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-40% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethanol/ethyl acetate to give the title compounds as a colorless crystal respectively (E (Example 121): 266 mg, 0.608 mmol, 39%, Z (Example 122): 159 mg, 0.363 mmol, 24%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1([CH3:27])[O:11][C@H:10]([C@H:12]([OH:14])[CH3:13])[C@H:9]([CH2:15][O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[O:8]1.C(N(CC)CC)C.O>C(OCC)(=O)C>[CH3:1][S:2]([O:14][C@@H:12]([C@H:10]1[C@H:9]([CH2:15][O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:18]([CH3:19])[CH3:20])[CH:21]([CH3:23])[CH3:22])[O:8][C:7]([CH3:6])([CH3:27])[O:11]1)[CH3:13])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)[Si](OC[C@@H]1OC(C)(C)O[C@@H]1[C@@H](C)O)(C(C)C)C(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)[Si](OC[C@@H]1OC(C)(C)O[C@H]1[C@@H](C)OS(C)(=O)=O)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.75 mL of methanesulfonyl chloride was added dropwise to a solution of 1.6 g of (1R)-1-((4R,5S)-2,2-dimethyl-5-(((tris(propan-2-yl)silyl)oxy)methyl)-1,3-dioxolane-4-yl)ethan-1-ol and 2.7 mL of triethylamine in 16 mL of ethyl acetate at a temperature of 5° C. to 10° C., and the obtained mixture was then stirred at room temperature for 10 minutes. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and it was washed with a saturated sodium chloride aqueous solution and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 1.98 g of (1R)-1-((4R,5S)-2,2-dimethyl-5-(((tris(propan-2-yl)silyl)oxy)methyl)-1,3-dioxolane-4-yl)ethyl methanesulfonate in the form of a colorless oily product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:26])[NH2:25])[CH:5]=[C:6]([CH3:8])[CH:7]=1.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:26])[NH2:25])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(Cn2c3cccc(O)c3c3c(C(N)=O)cccc32)c1
Reactant: COC(=O)CBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cc(C)cc(C)c1
Reaction time: 0.05 h
Yield: 72.4 %

Procedure:
40% Methanolic Triton B (0.13 mL, 0.28 mM) was added to a solution of the 9-[(3,5-dimethylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (80 mg, 0.23 mM) in 8 mL DMF at room temperature. After 3 minutes, methyl bromoacetate (43 mg, 0.28 mM) was added and the resultant mixture stirred at room temperature for 17 hours. The mixture was diluted with ethyl acetate, washed with H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 70 mg (72%) of the {9-[(3,5-dimethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (DMSO-d6) δ7.6 (d, 1H, J=8 Hz), 7.55 (br s, 1H), 7.45-7.3 (m, 2H), 7.25 (d, 1H, J=8 Hz), 7.2 (br s, 1H), 7.1 (d, 1H, J=8 Hz), 6.9 (s, 1H), 6.8 (s, 2H), 6.6 (d, 1H, J=8 Hz), 5.65 (s, 2H), 4.9 (s, 2H), 3.75 (s, 3H), and 2.2 (s, 6H). IR (KBr, cm−1) 3362, 3173, 1758, 1638, 1583, 1500, 1454, 1434, 1330, 1215, 1151, 1106, 772, 715, and 706. MS (FD) m/e 417.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])(=O)[CH3:2].C[CH:12]([C:20]1C=C(O)C=C([CH:26]=1)O)[CH:13](C)[CH2:14]CCCC.Cl>C(O)(=O)C>[CH2:9]1[C:4]2[CH2:1][C:2]3[C:14](=[CH:13][CH:12]=[CH:20][CH:26]=3)[O:10][C:5]=2[CH2:6][CH2:7][CH2:8]1
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Reactant: CC(=O)C1CCCCC1=O
Agent: Cl
Solvent: CC(=O)O
Product: c1ccc2c(c1)CC1=C(CCCC1)O2
Reaction time: 23 h

Procedure:
A solution of 2.48 g. of 2-acetylcyclohexanone and 4.17 g. of 5-(1,2-dimethylheptyl)resorcinol in 100 ml. of acetic acid is cooled to 15° and saturated with hydrogen chloride gas. The reaction mixture is allowed to warm to 25° and stirred for 23 hours. The solvent is removed in vacuo, the residue is distilled twice and the fraction boiling at 170°-190° (0.02 mm.) is collected and chromatographed on silica gel with benzene as eluant. The nonpolar fractions are rechromatographed on a silver nitrate impregnated silica gel "dry-column" with 18:1:1 cyclohexaneacetic acid-ether to give a mixture which is separated by distillation to give the title compounds, b.p. 180° (0.005 mm.), tetrahydro xanthene; b.p. 190° (0.003 mm.), aromatic xanthene.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:12]([OH:14])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:49][C:50]1[S:51][CH:52]=[CH:53][N:54]=1.C(N(CC)CC)C>C(Cl)Cl.O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:12]([NH:49][C:50]2[S:51][CH:52]=[CH:53][N:54]=2)=[O:14])=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCCO2)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCCCO2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
A solution of 2-(4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid (60 mg, 0.19 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluoro-phosphate (127 mg, 0.29 mmol), and 2-aminothiazole (28 mg, 0.29 mmol) in methylene chloride (5 mL) at 25° C. was treated with triethylamine (0.08 mL, 0.58 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then diluted with water (10 mL) and extracted with methylene chloride (3×15 mL). The combined organic layers were sequentially washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), a 1N aqueous hydrochloric acid solution (1×10 mL), and a saturated sodium chloride solution (1×10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 20/80 hexanes/ethyl acetate) afforded 2-(4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-2-yl)-N-thiazol-2-yl-propionamide (54 mg, 71%) as a colorless oil: EI-HRMS m/e calcd for C18H22N2O4S2 (M+) 394.1021, found 394.1021.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=1.[C:25]1([CH2:31][CH2:32][CH2:33]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:33][CH2:32][CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:6]=2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=1
Reactant: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c1[nH]c1ccccc12
Reactant: BrCCCc1ccccc1
Product: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c3ccccc3n(CCCc3ccccc3)c12
Yield: 74 %

Procedure:
Following a procedure and using relative proportions of starting materials similar to those described in Example 4, but using tert-butyl (4-methyl-1-methylthiocarbazol-2-yl)acetate and 3-phenylpropyl bromide as starting materials, the title compound was obtained in a yield of 74% as an oil.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10]O)[CH2:5][CH2:4]1)=[O:2].[F:12][C:13]1[C:22]([F:23])=[CH:21][C:16]2[N:17]=[C:18]([SH:20])[NH:19][C:15]=2[CH:14]=1.C(N(C(C)C)CC)(C)C.[I-].C(C[P+](C)(C)C)#N>C(#N)CC.O>[F:23][C:22]1[C:13]([F:12])=[CH:14][C:15]2[N:19]=[C:18]([S:20][CH2:10][CH2:9][N:6]3[CH2:7][CH2:8][N:3]([CH:1]=[O:2])[CH2:4][CH2:5]3)[NH:17][C:16]=2[CH:21]=1
Reactant: O=CN1CCN(CCO)CC1
Reactant: Fc1cc2nc(S)[nH]c2cc1F
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=CN1CCN(CCSc2nc3cc(F)c(F)cc3[nH]2)CC1
Temperature: 92 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
1-Formyl-4-(2-hydroxyethyl)piperazine (1.11 g, 7.0 mmol), 5,6-difluoro-2-mercaptobenzimidazole (1.30 g, 7.0 mmol), and diisopropylethylamine (3.62 g, 28.0 mmol) were dissolved in propionitrile (50 mL), and cyanomethyltrimethylphosphonium iodide (6.80 g, 28.0 mmol) was added thereto, followed by stirring for one hour at 92° C. under argon. The reaction mixture was allowed to cool and then poured in water (100 mL), followed by extraction with chloroform (100 mL×3). The organic layer was washed with saturated brine and then dried over sodium sulfate anhydrate, and the product was concentrated under reduced pressure. The crude product was crystallized from acetone-ether, to thereby yield 1-[2-(5,6-difluorobenzimidazol-2-ylthio)ethyl]-4-formylpiperazine (1.78 g, yield 78%) as a yellow crystalline powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:31]CN(C(OC(C)(C)C)=O)C[CH2:27]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.FC1C=C2C(=CC=1F)NC=C2C1C=NN(CC2CCNCC2)C=1.CS(OCC1C[CH2:72][O:71][CH2:70]C1)(=O)=O>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:27][CH2:72][O:71][CH2:70][CH2:31]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCC1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Agent: Fc1cc2[nH]cc(-c3cnn(CC4CCNCC4)c3)c2cc1F
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CCOCC3)c2)c2ccc(F)cc21

Procedure:
Following the general method as outlined in Intermediate 20, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 305 mg; 0.89 mmol) and (tetrahydro-2H-pyran-4-yl)methyl methanesulfonate (226 mg; 1.16 mmol), 398 mg of the title compound was obtained as a white solid, which was used directly without further purification.
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][C:5]1([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].O>CN(C)C=O>[C:12]1([NH:11][C:5]2([CH2:4][NH:3][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)CBr
Reactant: NCC1(Nc2ccccc2)CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CNCC1(Nc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
150 mg (3.75 mmol) of sodium hydride are added to a solution of 700 mg (3.42 mmol) of (1-aminomethylcyclohexyl)phenylamine (obtained in Example 2/b) in 20 ml of dimethylformamide. The solution is stirred for 1 h at room temperature and then 310 μl (3.4 mmol) of ethyl bromoacetate are added. The reaction medium is stirred at room temperature for 2 h and then poured into water and extracted with ethyl acetate. The organic phases are collected and washed with water. They are dried over sodium sulfate. The solvents are evaporated. The residue is chromatographed on silica gel (heptane then heptane/ethyl acetate 80/20, v/v). 652 mg of ethyl [(1-phenylaminocyclohexylmethyl)amino]acetate are obtained in the form of a colorless oil. Yield=65%.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([CH3:32])[C:24]([N:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>ClCCl.CN(C=O)C>[CH2:28]([N:26]([CH3:27])[C:24]1[C:23]([CH3:32])=[CH:22][C:17]2[NH:18][C:19](=[O:21])[CH2:20][C:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([N:7]4[C:3]([CH2:2][N:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)=[CH:4][N:5]=[N:6]4)[CH:9]=3)=[N:15][C:16]=2[CH:25]=1)[CH:29]([CH3:31])[CH3:30]
Reactant: Cc1cc2c(cc1N(C)CC(C)C)N=C(c1cccc(-n3nncc3CO)c1)CC(=O)N2
Reactant: C1CCNC1
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc2c(cc1N(C)CC(C)C)N=C(c1cccc(-n3nncc3CN3CCCC3)c1)CC(=O)N2

Procedure:
The title compound was prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isobutyl-methyl-amino)-8-methyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 132) (200 mg, 0.46 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with pyrrolidine in DMF according to the method described in Example 45. Obtained as a light yellow solid (50 mg, 22%).
Reaction SMILES: [F:1][C:2]1([F:25])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18](=O)/[CH:19]=[CH:20]/[N:21](C)C)=[N:12]3)=[CH:10][C:4]=2[O:3]1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[NH:34]N>>[F:1][C:2]1([F:25])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18]4[N:34]([C:28]5[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=5[F:26])[N:21]=[CH:20][CH:19]=4)=[N:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc3c(c2)OC(F)(F)O3)ccc1=O
Reactant: NNc1cc(F)ccc1F
Product: O=c1ccn(-c2ccc3c(c2)OC(F)(F)O3)nc1-c1ccnn1-c1cc(F)ccc1F

Procedure:
The product was obtained starting from 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-11) and 2,5-difluoro-phenylhydrazine according to the method described for example 91. MS: M=431.2 (M+H)+