Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7](O)[C:6]=1[CH3:13])(=[O:3])[CH3:2].[CH3:14][C:15]#N.O([S:25]([C:28](F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>O>[C:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([S:25][CH2:28][C:14]2[CH:15]=[CH:10][C:5]([O:4][CH3:1])=[CH:6][CH:7]=2)[C:6]=1[CH3:13])(=[O:3])[CH3:2]
Reactant: CC#N
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(=O)Oc1cc(C)cc(O)c1C
Solvent: O
Product: COc1ccc(CSc2cc(C)cc(OC(C)=O)c2C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3-hydroxy-2,5-dimethylphenyl acetate (1.04 g) and CH3CN (57 mL) were added TEA (1.61 mL) and Tf2O (1.17 mL) at 0° C. The mixture was stirred at 0° C. for 30 min under nitrogen atmosphere. The mixture was diluted with water at 0° C. and then concentrated in vacuo. The residue was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residual crude material was dissolved in toluene (50 mL). To the solution were added DIPEA (1.79 mL), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.150 g), (4-methoxyphenyl)methanethiol (0.723 mL) and tris(dibenzylideneacetone)dipalladium (0) (Pd2(dba)3, 0.238 g) at room temperature. The mixture was refluxed for 4 h. After cooling, water was added to the mixture, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (1.27 g).
Reaction SMILES: [BH4-].[Na+].[C:3]1([C:9]([C@H:11]2[CH2:15][N:14]([C@@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[C:13](=[O:24])[CH2:12]2)=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[OH:10][CH:9]([C@H:11]1[CH2:15][N:14]([C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[C:13](=[O:24])[CH2:12]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[C@H](c1ccccc1)N1C[C@H](C(=O)c2ccccc2)CC1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H](c1ccccc1)N1C[C@H](C(O)c2ccccc2)CC1=O
Reaction time: 1 h

Procedure:
Under ice-cooling, sodium borohydride (280 mg) was added to anhydrous ethanol (40 ml) solution of 4-(R)-phenylcarbonyl-1-[1-(R)-phenylethyl]-2-pyrrolidone (2.17 g, 7.40 mmol), and the mixture was stirred at the same temperature for 1 hour. The reaction solution was mixed with 10% citric acid (50 ml) under ice-cooling and then ethanol was evaporated under a reduced pressure. The residue was extracted with chloroform (80 ml×2), and the organic layer was washed with saturated brine (100 ml) and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure and the resulting residue was applied to a silica gel column chromatography. By eluting with n-hexane:ethyl acetate (1:3) to ethyl acetate (100%), 892 mg (41%) of the low polarity title compound [F1] and then 1.163 g (53%) of the high polarity title compound [F2] were respectively obtained each as a light yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[O:20][C:19]([CH2:21][CH2:22][NH:23][C:24]([C:26]3[NH:30][N:29]=[C:28]([C:31](O)=[O:32])[CH:27]=3)=[O:25])=[CH:18][CH:17]=2)[CH:12]=[CH:13][C:14]=1[Cl:15]>>[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[O:20][C:19]([CH2:21][CH2:22][NH:23][C:24]([C:26]3[NH:30][N:29]=[C:28]([C:31]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[O:32])[CH:27]=3)=[O:25])=[CH:18][CH:17]=2)[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: O=C(O)c1cc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)[nH]n1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2cc(C(=O)NCCc3ccc(-c4ccc(Cl)c(Cl)c4)o3)[nH]n2)CC1
Yield: 35 %

Procedure:
The title compound was synthesized as in Example 1 starting from 1-methylpiperazine and 5-{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylcarbamoyl}-1H-pyrazole-3-carboxylic acid. Crude product was purified by chromatography (CombiFlash, silica column, eluent 0-10% MeOH/DCM) and crystallized from DCM/heptane to give 1.06 g (35%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.19 (s, 3H), 2.33 (br s, 4H), 2.95 (t, 2H), 3.56 (q, 2H), 3.62 (br s, 2H), 3.85 (br s, 2H), 6.34 (d, 1H), 7.02 (d, 1H), 7.07 (br s, 1H), 7.60 (dd, 1H), 7.63 (d, 1H), 7.84 (d, 1H), 8.61 (s, 1H), 13.92 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH3:10])=[CH:4][C:3]=1[O:12][CH3:13].Br[CH2:15][CH2:16][CH:17]([NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C:18]([O:20]CC)=[O:19].Br.[NH:35]1[CH2:39][CH2:38][N:37]=[C:36]1[NH:40][NH2:41]>CO>[NH:37]1[CH2:38][CH2:39][N:35]=[C:36]1[NH:40][N:41]=[C:9]([CH3:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:15][CH2:16][C@@H:17]([C:18]([OH:20])=[O:19])[NH:23][C:24]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25])=[C:3]([O:12][CH3:13])[CH:4]=1
Reactant: CCOC(=O)C(CCBr)NC(=O)OCc1ccccc1
Reactant: NNC1=NCCN1
Reactant: COc1cc(CC(C)=O)ccc1O
Agent: Br
Solvent: CO
Product: COc1cc(CC(C)=NNC2=NCCN2)ccc1OCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Yield: 0.8 %

Procedure:
The operation is carried out as in Example 1 Stages A, B and C but using 900 mg of 3-(4-hydroxy-3-methoxyphenyl)-2-propanone and 1.80 g of ethyl 4-bromo-2-[[(phenylmethoxy)carbonyl]amino]butanoate (Stage A) then, during Stage B, 1.47 g of 4,5-dihydro-1H-imidazol-2-yl-hydrazine hydrobromide. The saponificaton stage is carried out in the presence of soda in methanol. 20 mg of expected product is obtained in the form of an E/7 mixture 90/10
Reaction SMILES: [C-:1]#[N:2].[Na+].[Br:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[F:14])[C:8](F)=[O:9]>>[F:14][C:13]1[CH:12]=[CH:11][C:7]([C:8]([C:1]#[N:2])=[O:9])=[CH:6][C:5]=1[Br:4]
Reactant: O=C(F)c1ccc(F)c(Br)c1
Reactant: [C-]#N
Agent: [Na+]
Product: N#CC(=O)c1ccc(F)c(Br)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
177 g (3.6 moles) of sodium cyanide and 663 g (3 moles) of 3-bromo-4-fluorobenzoyl fluoride were together initially introduced into the reaction vessel and were heated. At about 80° C., an exothermic reaction started, which had to be restrained somewhat by slight cooling. The temperature was allowed to rise to 100° C. and the mixture was stirred at 100° C. for 1 hour. The exothermic reaction continued for about 10 minutes, and additional heat had then to be supplied to the mixture. The mixture was then cooled and the salts were filtered off and destroyed in saturated iron sulphate solution and the filtrate was distilled on a column. 507 g (74% of theory) of a colorless oil with a boiling point of 126° C./20 mm Hg were thus obtained.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[CH3:31][NH:32][CH2:33][CH2:34][C:35]1[CH:36]=[C:37]([OH:42])[C:38]([OH:41])=[CH:39][CH:40]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([N:32]([CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([OH:41])=[C:37]([OH:42])[CH:36]=3)[CH3:31])[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Reactant: CNCCc1ccc(O)c(O)c1
Product: CN(CCc1ccc(O)c(O)c1)c1nccc(-c2cccc(CN(CCCN)S(C)(=O)=O)c2)n1

Procedure:
Intermediate 4 from above was coupled with 4-(2-Methylamino-ethyl)-benzene-1,2-diol following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 486. 1H NMR (Varian 300 MHz, CDCl3—CD3OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.2 (m, 2H) 8.0 (m, 2H) 7.6 (d, 1H) 7.5 (m, 1H) 6.6 (m, 1H) 6.4 (m, 2H) 4.4 (s, 2H) 4.0 (m, 2H) 3.2 (m, 5H) 2.9 (s, 3H) 2.8 (m, 4H) 1.7 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:27]=[CH:26][C:25]([CH2:28]O)=[CH:24][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH:36]1[CH2:41][CH2:40][CH:39]([C:42]([OH:45])([CH3:44])[CH3:43])[CH2:38][CH2:37]1>C(Cl)Cl>[F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:27]=[CH:26][C:25]([CH2:28][N:36]4[CH2:41][CH2:40][CH:39]([C:42]([OH:45])([CH3:44])[CH3:43])[CH2:38][CH2:37]4)=[CH:24][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CO)cc32)CC1
Reactant: CC(C)(O)C1CCNCC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCC(C(C)(C)O)CC4)cc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
To a 0° C. cooled solution of cis-methyl 4-((E)-2-(4-fluorobenzoylimino)-6-(hydroxymethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate (1 g, 2.350 mmol) in DCM (25 mL) was added thionyl chloride (0.858 mL, 11.75 mmol) dropwise, and the reaction was stirred at 0° C. for 30 minutes. After 30 minutes, the solvent was removed at reduced pressure, and the residue was suspended in ACN (5 mL) and re-concentrated to remove residual thionyl chloride. The residue was resuspended in ACN (15 mL), cooled to 0° C., and 2-(piperidin-4-yl)propan-2-ol (1.010 g, 7.05 mmol) and TEA (0.655 mL, 4.70 mmol) were added. The reaction was stirred overnight at RT. After 16 hours, the reaction mixture was concentrated and partitioned between EtOAc and water. The organic layer was concentrated and the residual product was purified by column chromatography, eluting with 0-100% (90:9:1 DCM/MeOH/NH4OH)/DCM to provide cis-methyl 4-((E)-2-(4-fluorobenzoylimino)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate as a white powder (1.05 g, 81% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (s, 6H), 1.09-1.35 (m, 3H), 1.56-1.91 (m, 8H), 2.21-2.29 (m, 2H), 2.53-2.64 (m, 2H), 2.77-2.95 (m, 3H), 3.50 (s, 2H), 3.77 (s, 3H), 3.99 (s, 1H), 4.74 (br. s., 1H), 7.14 (d, J=6.9 Hz, 1H), 7.26 (dd, J=8.8 Hz, 8.8 Hz, 2H), 7.37-7.58 (m, 2H), 8.26 (dd, J=8.7, 5.9 Hz, 2H), 12.77 (s, 1H). MS, m/z (C31H39FN4O4): calcd, 550.3. found, 551.1 [M+H].
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[C:11]([OH:13])=O.[C:18]([O:22][C:23]([N:25]1[CH2:35][CH2:34][C:28]2[N:29]=[C:30]([NH2:33])[N:31]=[CH:32][C:27]=2[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].[OH-].[Na+]>CN(C=O)C.C(Cl)Cl>[C:18]([O:22][C:23]([N:25]1[CH2:35][CH2:34][C:28]2[N:29]=[C:30]([NH:33][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([Cl:17])[CH:16]=[C:8]([Cl:7])[CH:9]=3)[N:31]=[CH:32][C:27]=2[CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)ncc2C1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2nc(NC(=O)c3cc(Cl)cc(Cl)c3)ncc2C1
Reaction time: 1 h
Yield: 56.5 %

Procedure:
Oxalyl chloride 1184 μl (13.8 mmol) and two drops of DMF were added to a solution of 3,5-dichlorobenzoic acid 527 mg (2.76 mmol) in CH2Cl2 and stirring was performed for 1 h at RT under nitrogen as inert gas. After removal of the solvent, the 3,5-dichlorobenzoyl chloride was dissolved in pyridine (30 ml). 2-Amino-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 599 mg (2.39 mmol) was added to this solution at 0° C. and stirring was performed for 2 h at 0° C. and then for 2 h at RT under nitrogen as inert gas. After the addition of aqueous 1 M NaOH (40 ml) and stirring for 20 minutes, CH2Cl2 (50 ml) was added and the aqueous phase extracted with CH2Cl2 (3×20 ml). The combined organic phases were dried over Na2SO4. After filtration and removal of the solvent, purification was performed by means of column chromatography and the product 2-(3,5-dichloro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 573 mg (1.35 mmol, 57% of theoretical) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[C:7]([CH3:11])=[CH:8][CH2:9][O:10][C:5]=2[CH:4]=1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[CH:7]([CH3:11])[CH2:8][CH2:9][O:10][C:5]=2[CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc2c(c1)OCC=C2C
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1)OCCC2C
Yield: 99.6 %

Procedure:
The alkene mixture of step (b) (29 g) was dissolved in ethanol (300 ml) and hydrogenated in the presence of 5% palladium on charcoal (1.0 g) at 45 psi; until hydrogen uptake had ceased. The catalyst was filtered off through a supercel filter aid and the filtrate was evaporated to give the desired compound 29.2 g (99.4%). NMR and MS analysis were correct for the required compound.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]1[C:14]3[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=3[O:12][CH2:11][C:10]2=1.CCN(CC)CC>C(Cl)Cl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:1](=[O:3])[CH3:2])[C:15]1[C:14]3[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=3[O:12][CH2:11][C:10]2=1
Reactant: COc1ccc2[nH]c3c(c2c1)COc1ccccc1-3
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)c1c(n2C(C)=O)-c2ccccc2OC1
Temperature: 25 °C

Procedure:
Acetyl chloride (0.064 mL, 0.896 mmoL) in CH2Cl2 (2 mL) was treated with 8-methoxy-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene (150 mg, 0.598 mmoL) followed by Et3N (0.896 mmoL, 0.125 mL) at 0° C. The reaction mixture was then slowly warmed to room temperature over 2 hours. The reaction mixture was then partitioned between CH2Cl2 and saturated NaHCO3. The aqueous phase was extracted two times with CH2Cl2. The organic layers from the two extractions were then combined, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material was then purified by column chromatography (silica gel, hexanes:EtOAc 3:1 as eluent) to yield the title compound as a pale solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[Cl:21])=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[CH3:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(Cl)Cl>[Cl:21][C:15]1[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=1[O:13][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][C:7]=1[S:9]([N:26]1[CH2:27][CH2:28][CH:23]([CH3:22])[CH2:24][CH2:25]1)(=[O:11])=[O:10]
Reactant: CC1CCNCC1
Reactant: N#Cc1ccc(Oc2cc(Cl)ccc2Cl)c(S(=O)(=O)Cl)c1
Solvent: ClCCl
Product: CC1CCN(S(=O)(=O)c2cc(C#N)ccc2Oc2cc(Cl)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
Sulfonyl chloride 36 (0.20 g, 0.55 mmol) was combined with 4-methylpiperidine (0.16 g, 1.65 mmol) and TEA (0.17 g, 1.65 mmol) in DCM (5 mL). The solution was stirred overnight at room temperature. Upon consumption of starting material, as determined via TLC (75% EtOAc in hexanes), the reaction mixture was partitioned between DCM and water. After 3 extractions, the combined organic extracts were washed sequentially with saturated aqueous NaHCO3, water, and brine. The crude product was chromatographed on normal-phase silica to yield the desired product 87 (0.167 g, 71.4% yield, 97.1% pure). 1H NMR (500 MHz, DMSO-d6): δ 8.28 (d, J=2 Hz, 1H), 8.07 (dd, J1=9 Hz, J2=2 Hz, 1H), 7.72 (d, J=8 Hz, 1H), 7.46 (dd, J1=5 Hz, J2=2 Hz, 1H), 7.44 (d, J=2 Hz, 1H), 7.10 (d, J=9 Hz, 1H), 3.70 (d, J=12 Hz, 2H), 2.74 (ddd, J1=J2=12 Hz, J3=2 Hz, 2H), 1.65 (dd, J1=13 Hz, J2=2 Hz, 2H), 1.44 (m, 1H), 1.09 (ddd, J1=28 Hz, J2=13 Hz, J3=4 Hz, 2H), 0.87 (d, J=7 Hz, 3H); MS (ESI, EI+): m/z=425.11 (MH+); melting point: 127-130° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:8][CH:9]=1)=O.[BH4-].[Li+]>O1CCCC1>[OH:2][CH2:3][C:5]1[S:6][C:7]([S:10]([NH2:11])(=[O:13])=[O:12])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(S(N)(=O)=O)s1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(CO)s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.7 %

Procedure:
To a solution of 0.442 g 5-sulfamoyl-thiophene-2-carboxylic acid methyl ester in 8 ml tetrahydrofuran was added 0.044 g lithiumborohydride and the mixture was stirred at room temperature for 20 h. To the resulting mixture was added an other 0.088 g lithiumborohydride and the mixture was stirred at room temperature for 2 h and at reflux for 20 h. The resulting suspension was partitioned between water and ethyl acetate. The phases were separated and the organic phase was purified by chromatography on silica gel with ethyl acetate to yield 0.300 g of the title compound as white crystals melting at 70-71° C.
Reaction SMILES: [C:1]([CH2:3][C:4](Cl)=[O:5])#[N:2].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH2:15][CH2:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:10][CH:9]=1>O1CCCC1>[C:1]([CH2:3][C:4]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH2:15][CH2:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:10][CH:9]=1)=[O:5])#[N:2]
Reactant: N#CCC(=O)Cl
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Solvent: C1CCOC1
Product: N#CCC(=O)Nc1ccc(C2=NNC(=O)CC2)cc1
Reaction time: 0.17 h
Yield: 54.2 %

Procedure:
5.9 g (57.0 millimoles) of cyanoacetyl chloride were added dropwise to 6.0 g (31.7 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone in 150 ml of absolute tetrahydrofuran at room temperature, while stirring. After the addition was complete, stirring was continued for a further 10 minutes at 50° C. The product was filtered off under suction at 10° C., washed first with tetrahydrofuran and then with water and recrystallized from dimethylformamide/water. 4.4 g (54%) of 6-[p-(cyanoacetylamino)-phenyl]-4.5,-dihydro-3(2H)-pyridazinone were obtained as pale beige crystals. Mp.: 270° C. (decomposition).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.[H-].[Na+]>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1cccc(O)c1
Reactant: FC(F)(F)c1ccc(-c2ccnc(Cl)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(Oc2cc(-c3ccc(C(F)(F)F)cc3)ccn2)c1

Procedure:
This material was prepared according to the method described in Example 2 (d) using 2-chloro-4-(4-trifluoromethyl-phenyl)-pyridine (Example 410 (c), 129 mg, 0.5 mmol), 3-methoxyphenol (66 uL, 0.6 mmol), and sodium hydride (24 mg, 0.6 mmol) in DMF (1 mL). Purification on a Biotage 40S column (8:1 hexanes: EtOAc), provided the title compound as a white solid. MS (ESI, pos. ion) m/z: 346 (M+1). Mp: 77.5-79.6° C.
Reaction SMILES: [Cl:1][C:2]([C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[Na+].[CH3:23][S:24]([NH-:27])(=[O:26])=[O:25]>O1CCCC1>[Cl:1][C:2]([C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH:27][S:24]([CH3:23])(=[O:26])=[O:25])=[O:4]
Reactant: CS([NH-])(=O)=O
Reactant: COc1cc(OC)nc(C(Cl)(C(=O)Cl)c2ccccc2)n1
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(OC)nc(C(Cl)(C(=O)NS(C)(=O)=O)c2ccccc2)n1
Reaction time: 8 h
Yield: 62.9 %

Procedure:
The product from Stage (b) (3.1 g) in dry tetrahydrofuran (10 ml) was added dropwise to stirred, cooled (5° C.) methanesulfonamide sodium salt (2.8 g) in dry tetrahydrofuran (25 ml). Stirring was continued until most solid had dissolved (2 hours) and the reaction mixture was allowed to stand at room temperature overnight. The solvent was then evaporated off under vacuum and the residue was treated with ether. The precipitated solid was taken up in aqueous potassium bicarbonate, the ether solution extracted again with bicarbonate and then with water. The combined aqueous phases were washed with ether, fresh ether was then added and the whole was acidified to pH=1 with hydrochloric acid as quickly as possible with stirring. The ether solution was separated, and the aqueous phase was extracted twice more. The combined ether solutions were washed with water (5 times), dried over magnesium sulfate and evaporated under vacuum to give 2.3 g of the desired product. Washing with a small volume of diisopropyl ether gave 1.95 g of pure product as a viscous liquid.
Reaction SMILES: CNC(C1C2C=C(C3C(Cl)=CN=C(NCCCN4CCNC[C@H]4C)N=3)SC=2C=CC=1)=O.[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([Cl:53])=[CH:51][N:50]=[C:49](Cl)[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:34][CH2:33]1.C(OC([N:62]1[CH2:67][CH2:66][N:65]([CH2:68][CH2:69][NH2:70])[C@H:64]([CH3:71])[CH2:63]1)=O)(C)(C)C>>[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([Cl:53])=[CH:51][N:50]=[C:49]([NH:70][CH2:69][CH2:68][N:65]5[CH2:66][CH2:67][NH:62][CH2:63][C@H:64]5[CH3:71])[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:34][CH2:33]1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CCN
Agent: CNC(=O)c1cccc2sc(-c3nc(NCCCN4CCNC[C@H]4C)ncc3Cl)cc12
Product: C[C@@H]1CNCCN1CCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1

Procedure:
Using the method of (R)-2-{5-chloro-2-[3-(2-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid methylamide, the title compound is synthesized from 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and (R)-4-(2-aminoethyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester and isolated as a yellow solid. ES+(m/z) 471 (35Cl) and 473 (37Cl) [M+H].
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C@@H:8]([C@@:10]1([CH3:31])[C@H:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([OH:23])[CH:16]=2)[CH2:13][N:12]([C:24](=[O:30])[CH2:25][S:26][C:27](=[O:29])[CH3:28])[CH2:11]1)[CH3:9].[CH:32]1([CH2:35]Br)[CH2:34][CH2:33]1>CN(C=O)C.O>[OH:7][C@@H:8]([C@@:10]1([CH3:31])[C@H:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:35][CH:32]3[CH2:34][CH2:33]3)[CH:16]=2)[CH2:13][N:12]([C:24](=[O:30])[CH2:25][S:26][C:27](=[O:29])[CH3:28])[CH2:11]1)[CH3:9]
Reactant: BrCC1CC1
Reactant: COc1ccc([C@@H]2CN(C(=O)CSC(C)=O)C[C@@]2(C)[C@@H](C)O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc([C@@H]2CN(C(=O)CSC(C)=O)C[C@@]2(C)[C@@H](C)O)cc1OCC1CC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 35.5 %

Procedure:
To a flask containing anhydrous K2CO3 (52 mg, 0.37 mmol, 4.0 eq) under a nitrogen atmosphere was added a solution of Example 118 (34 mg, 0.093 mmol, 1 eq) in anhydrous DMF (1 mL). Cyclopropylmethyl bromide (40 μL, 0.37 mmol, 4.0 eq) was added via syringe to the mixture. The slurry was stirred at 65° C. overnight. The reaction was cooled to room temperature, then diluted with water (50 mL). The aqueous solution was extracted with EtOAc (3×30 mL), and the combined organic layers were washed with brine (50 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The resulting oil was purified by preparative TLC plate (100% EtOAc), yielding a clear, colorless oil (13.9 mg, 36%).
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]2[C:8]=1[CH2:9][CH2:10][C:11](=O)[N:12]2[C:18]1[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=1[CH3:26])[CH2:4][CH3:5])[CH3:2].CSC>C1COCC1>[CH2:1]([CH:3]([O:6][C:7]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]2[C:8]=1[CH2:9][CH2:10][CH2:11][N:12]2[C:18]1[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=1[CH3:26])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1cc(C)nc2c1CCC(=O)N2c1c(C)cc(C)cc1C
Solvent: CSC
Solvent: C1CCOC1
Product: CCC(CC)Oc1cc(C)nc2c1CCCN2c1c(C)cc(C)cc1C
Yield: 86 %

Procedure:
The title compound was prepared in a 86% yield as a clear oil by the method analogous to that described in Example 8 starting from 5-(1-ethyl-propoxy)-7-methyl-1-(2,4,6-trimethyl-phenyl)-3,4-dihydro-1H-[1,8]naphthyridin-2-one and BH3.DMS in THF.