Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:15])=[CH:5][C:6]=1[CH:7]1[CH2:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[CH2:8]1.C1(N=C=NC2CCCCC2)CCCCC1.[C:31](O)(=[O:33])[CH3:32].Cl>CN(C)C1C=CN=CC=1.CN(C)C=O.O>[Cl:1][C:2]1[S:3][C:4]([Cl:15])=[CH:5][C:6]=1[CH:7]1[CH2:12][C:11](=[O:13])[C:10](=[C:31]([OH:33])[CH3:32])[C:9](=[O:14])[CH2:8]1
Reactant: O=C1CC(=O)CC(c2cc(Cl)sc2Cl)C1
Reactant: CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(O)=C1C(=O)CC(c2cc(Cl)sc2Cl)CC1=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 70.2 %

Procedure:
To a solution of 5-(2,5-dichlorothiophen-3-yl)cyclohexane-1,3-dione (3.07 g), 4-dimethylaminopyridine (2.14 g) and dicyclohexylcarbodiimide (3.13 g) in dimethylformamide (10 ml) was added acetic acid (1.26 g), and the mixture was stirred at room temperature for 13 hours. To the mixture were added water (30 ml) and 2N hydrochloric acid (10 ml), and the mixture was extracted with ethyl acetate. The organic layer was extracted with 0.5N sodium hydroxide solution, and to the aqueous layer was added 2N hydrochloric acid to make the solution acidic. The solution was extracted with ethyl acetate, and the organic layer was washed with water. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethyl acetate-hexane to give 5-(2,5-dichlorothiophen-3-yl)-2-(1-hydroxyethylidene)cyclohexane-1,3-dione (2.5 g) as yellow crystals.
Reaction SMILES: [CH2:1]([O:3][P:4](Cl)([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:2].Cl.[NH2:18][CH:19]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:20]1=[O:32].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][P:4]([NH:18][C@H:19]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:20]1=[O:32])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CN1CCCCC(N)C1=O
Reactant: CCOP(=O)(Cl)CCCCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCCC[C@H](NP(=O)(CCCCc2ccccc2)OCC)C1=O
Reaction time: 0.33 h

Procedure:
A mixture of ethoxy(4-phenylbutyl)phosphinyl chloride [4.4 mmole; prepared as set forth in Example 1(f)], dry tetrahydrofuran (10 ml.), and 3-amino-2-oxo-hexahydro-1H-azepine-1-acetic acid, ethyl ester, monohydrochloride (1.0 g., 4.0 mmole) at 0° (ice bath) in an argon atmosphere is treated dropwise with triethylamine (1.7 ml., 3.0 eq.) in tetrahydrofuran (5 ml.) over 2 minutes. After 20 minutes, the ice bath is removed and the reaction mixture is stirred for an additional 1.5 hours. The reaction mixture is diluted with ethyl acetate and washed successively with saturated sodium bicarbonate, 5% potassium bisulfate, and brine, dried (MgSO4) and evaporated. The residue (2.1 g.) is chromatographed on silica (65 g.) eluting with ethyl acetate then acetone to give 1.0 g. of (S)-hexahydro-3-[[ethoxy(4-phenylbutyl)phosphinyl]amino]-2-oxo-1H-azepine-1-acetic acid, ethyl ester as an oil after evaporation. TLC (ethyl acetate) single spot at Rf =0.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[CH3:19][S:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][S:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)=[CH:23][CH:22]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCO
Product: CSc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
The title compound was prepared according to Method C. To a degassed suspension of (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (1.07 g, 3.97 mmol) in 10 ml of 1-propanol were added bis(triphenylphosphine)palladium dichloride (112 mg, 0.16 mmol), 4-(methylthio)phenylboronic acid (1.00 g, 5.95 mmol) and 8 ml of 2N-solution of sodium carbonate. The mixture was stirred at 85° C. for 2 hours. The reaction mixture was diluted with EtOAc, filtered through Celite and washed with water. The organic layer was dried and concentrated. The solid was purified by chromatography on silicagel (EtOAc/MeOH/ammonia:66/33/1) and crystallization from n-hexane. Yield: 1.12 g (79%).
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([I:13])[CH:6]=1.[CH3:16]N(C=O)C.C(Cl)(=O)C(Cl)=O>ClCCl>[CH3:16][O:11][C:10]([C:8]1[S:9][C:5]([C:4]#[C:3][C:2]([CH3:15])([CH3:14])[CH3:1])=[CH:6][C:7]=1[I:13])=[O:12]
Reactant: CC(C)(C)C#Cc1cc(I)c(C(=O)O)s1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1I
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
To a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-iodo-thiophene-2-carboxylic acid (1.0 g, 3.0 mmol) and DMF (20 μL) in dry dichloromethane (10 mL) was added oxalyl chloride (508 μL, 6.0 mmol) at room temperature. After stirring at room temperature for 90 min, the reaction was concentrated in vacuo to remove volatiles. The residue was dissolved in pyridine (5 mL) and methanol (5 mL) and stirred for 2 h. The volatiles were removed in vacuo and the residue was participated between ether (150 mL) and saturated NH4Cl solution (50 mL). The organic layer was washed with saturated NH4Cl solution (50 mL) and dried over Na2SO4. After concentration in vacuo, the residue was purified by silica gel chromatography (EtOAc/hexanes) to give the desired product (835 mg, 80%).
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][CH2:4][CH3:5].CCN(CC)CC.CC(C)(C)C(Cl)=O.[CH3:22][C@H:23]1[C@@H:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:26][C:25](=[O:34])[NH:24]1.[Li+].[Cl-]>C1COCC1>[CH3:22][C@H:23]1[C@@H:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:26][C:25](=[O:34])[N:24]1[C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Reactant: CCCCC(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCC(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0° C. stirred solution of valeric acid (3.83 mL, 35.2 mmol) and Et3N (14.7 mL, 106 mmol) in dry THF (175 mL) was added trimethylacetyl chloride (5.29 mL, 42.3 mmol) dropwise. The mixture was stirred at 0° C. for 1 hour and (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone (7.50 g, 42.3 mmol) was added followed by LiCl (1.79 g, 42.3 mmol). The reaction was warmed to room temperature overnight with good stirring. The mixture was filtered and the filtrate was concentrated under reduced pressure. Et2O (75 mL) was added to the residue, which was washed with sat. NaHCO3 (3×40 mL), 1N HCl (3×40 mL), and brine (2×40 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give a quantitative yield of crude product.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH2:7])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1.CO.[CH:16](=O)[CH3:17].[BH4-].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[C:6]([NH:7][CH2:16][CH3:17])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1
Reactant: CC=O
Reactant: Nc1cn(-c2cccnc2)nc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCNc1cn(-c2cccnc2)nc1Cl
Reaction time: 0.08 h
Yield: 57.3 %

Procedure:
A 3-neck, 100 mL round bottom flask was charged with 3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-amine (5d) (500 mg, 2.57 mmol) and methanol (5 mL). The mixture was stirred for 5 minutes to give a clear solution. Acetaldehyde (136 mg, 3.09 mmol) was added and the reaction was stirred at 20° C. for 6 hours. Sodium borohydride (194 mg, 5.14 mmol) was added and the reaction was stirred at 20° C. for 1 hour, at which point thin layer chromatography analysis [Eluent: ethyl acetate] indicated that some starting material remained and a major product formed. The reaction mixture was quenched with water (10 mL) and concentrated under reduced pressure to remove methanol. Ethyl acetate (10 mL) was added and the organic layer was concentrated to dryness. The residue was purified by flash column chromatography using 20-40% ethyl acetate/hexanes as eluent. The fractions containing pure product were combined and concentrated to afford a white solid (328 mg, 58%). The spectral characterization was in agreement with the product prepared previously.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.[F:24][C:25]1[CH:26]=[C:27]([CH2:33][CH:34]([CH3:40])[C:35]([O:37]CC)=[O:36])[CH:28]=[C:29]([F:32])[C:30]=1O>>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([C:8]2[C:7]([CH2:6][O:5][C:30]3[C:29]([F:32])=[CH:28][C:27]([CH2:33][CH:34]([CH3:40])[C:35]([OH:37])=[O:36])=[CH:26][C:25]=3[F:24])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)=[CH:17][CH:18]=1)[CH3:23]
Reactant: CCOC(=O)C(C)Cc1cc(F)c(O)c(F)c1
Reactant: CCc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)cc1
Product: CCc1ccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CC(C)C(=O)O)cc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-(4-ethylphenyl)-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(3,5-difluoro-4-hydroxyphenyl)-2-methylpropanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CD3OD) δ 7.69 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 6.82-6.88 (m, 2H), 5.19 (s, 2H), 2.89-2.97 (m, 1H), 2.75 (q, J=7.6 Hz, 2H), 2.58-2.65 (m, 2H), 1.30 (t, J=7.6 Hz, 3H), 1.14 (d, J=6.4 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C23H20F5NO3S, 486.1 (M+H). found 486.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6](=O)[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[CH2:12]([NH2:15])[CH2:13][NH2:14]>CO>[CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([NH:14][CH2:13][CH2:12][NH:15][CH:6]2[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3][C:2]([CH3:11])([CH3:1])[CH2:7]2)[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Reactant: NCCN
Solvent: CO
Product: CC1(C)CC(NCCNC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reaction time: 2 h

Procedure:
162.75 g (1.05 moles) of 2,2,6,6-tetramethyl-4-piperidone dissolved in 200 cc of methanol, 30 g (0.5 moles) of ethylenediamine dissolved in 40 cc of methanol, and 0.5 g of Pt (at 10% on carbon) were introduced into a 1 liter autoclave, and the mixture hydrogenated at 80° C and 50 atm pressure for 2 hours.
Reaction SMILES: Cl.[N:2]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[N:19]=[C:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:21][C:22]=3[C:23]([F:26])([F:25])[F:24])=[O:17])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=1.C(N(CC)CC)C>CN(C=O)C>[C:27]1([C:20]2[O:21][C:22]([C:23]([F:26])([F:24])[F:25])=[C:18]([C:16]([NH:15][C:12]3[CH:13]=[CH:14][C:9]([N:2]4[CH2:8][CH2:7][CH2:6][N:5]([CH2:34][C:35]5[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=5)[CH2:4][CH2:3]4)=[CH:10][CH:11]=3)=[O:17])[N:19]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Nc1ccc(N2CCCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(CN2CCCN(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.5 %

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-[1,4]diazepan-1-yl-phenyl)-amide hydrochloride (56 mg, 0.12 mmol), 4-bromomethyl-benzoic acid (28 mg, 0.13 mmol), triethylamine (0.07 mL, 0.50 mmol) in DMF (5 mL) was stirred at room temperature for 0.5 hr then concentrated and the residue was taken up in 50 mL of ethyl acetate and washed with 50 mL of saturated ammonium chloride, water (50 mL), and dried with anhydrous sodium sulfate. The solvent was removed and the residue was triturated with ethyl acetate, followed by filtration, to afford 4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-[1,4]diazepan-1-ylmethyl)-benzoic acid as a yellow solid (20 mg, 29% yield) LCMS for C30H27F3N4O4 calcd. (m/e) 564, observed 565 (M+H).
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:16])[CH:10]([NH2:15])[C:11](=O)[CH2:12][CH3:13])=[CH:5][CH:4]=1.[O-:17][C:18]#[N:19].[K+]>O>[CH2:12]([C:11]1[NH:19][C:18](=[O:17])[NH:15][C:10]=1[CH:9]([OH:16])[C:6]1[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=1)[CH3:13]
Reactant: CCC(=O)C(N)C(O)c1ccncc1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCc1[nH]c(=O)[nH]c1C(O)c1ccncc1
Temperature: 50 °C
Reaction time: 10 h

Procedure:
In 100 ml water is dissolved 29.0 g (0.11 mol) of 1-(4-pyridyl)-1-hydroxy-2-amino-3-ketopentane dihydrochloride and 17.9 g (0.22 mol) of potassium cyanate. The solution is warmed to 50° C. for 10 minutes and then allowed to stand at room temperature for 10 hours, cooled and the solid collected to give the title compound; m.p. 234°-36°.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.[CH2:8]([NH2:10])[CH3:9]>C1COCC1>[CH2:8]([NH:10][CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[CH3:9]
Reactant: O=Cc1nccs1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCc1nccs1

Procedure:
prepared by reaction of thiazole-2-carbaldehyde with 2M ethylamine in THF.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>>[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:10]([CH2:16][C:15]2[CH:18]=[CH:19][C:12]([Br:11])=[CH:13][CH:14]=2)[C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[CH:14][CH:13]=1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Brc1ccc(CN(Cc2ccc(Br)cc2)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), 4-bromobenzylbromide (550 mg; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.153 g (32.5%); MS m/z: 472.3 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 4.63 (s, 4H); 6.66-6.67 (m, 1H); 6.71 (dd, 1H, 4J=2.4 Hz, 3J=8.9 Hz); 7.22-7.24 (m, 4H); 7.34 (d, 1H, 3J=8.9 Hz); 7.48-7.50 (m, 4H); 7.93 (s, 1H); 11.99 (br s, 1H; HPLC (METHOD [A]): rt 18.49 min (98.4%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][N:21]1[CH2:25][C:24](=[O:26])[NH:23][C:22]1=[O:27].N1CCCCC1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=[C:25]4[N:21]([CH3:20])[C:22](=[O:27])[NH:23][C:24]4=[O:26])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cnn2ccc(Nc3cccc(Cl)c3)nc12
Reactant: CN1CC(=O)NC1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CN1C(=O)NC(=O)C1=Cc1cnn2ccc(Nc3cccc(Cl)c3)nc12
Temperature: 70 °C

Procedure:
To 5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (20 mg, 0.074 mmol) in 0.5 mL EtOH was added 1-methylimidazolidine-2,4-dione (8.4 mg, 0.074 mmol) and piperidine (7.5 μL, 0.074 mmol). The mixture was heated at 70° C. overnight. The solid formed was isolated by filtration and air dried to give 5-((5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)-1-methylimidazolidine-2,4-dione. LCMS (M+1=369)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:25])[CH:12]2[CH2:20][CH2:19][C:18]3[NH:17][C:16]4[CH:21]=[CH:22][CH:23]=[N:24][C:15]=4[C:14]=3[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CN(C=O)C.[H-].[Na+].[C:33]([O:37][C:38](=[O:41])[CH2:39]Br)([CH3:36])([CH3:35])[CH3:34]>CO>[C:33]([O:37][C:38](=[O:41])[CH2:39][N:17]1[C:18]2[CH2:19][CH2:20][CH:12]([N:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH3:25])[CH2:13][C:14]=2[C:15]2[N:24]=[CH:23][CH:22]=[CH:21][C:16]1=2)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CN(C1CCc2[nH]c3cccnc3c2C1)S(=O)(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C1CCc2c(c3ncccc3n2CC(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccc(F)cc1
Reaction time: 1 h
Yield: 19 %

Procedure:
A solution of 4-fluoro-N-methyl-N-(6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-8-yl)-benzenesulfonamide (2.8 g, 7.8 mmol) and DMF (22 mL) was cooled to 0° C. Sodium hydride (340 mg, 8.6 mmol, 60% dispersion in mineral oil) was added at 0° C. and after 30 min, tert-butylbromoacetate (1.3 mL, 8.9 mmol) was added at 0° C. After 1 hour, MeOH was added and the reaction mixture was filtered. The organic layer was concentrated and the residue purified by reverse phase preparative HPLC to afford 700 mg of {8-[(4-fluoro-benzenesulfonyl)-methyl-amino]-6,7,8,9-tetrahydro-pyrido[3,2-b]indol-5-yl}-acetic acid tert-butyl ester. Mass spectrometric data [M+H]+=474.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[C:13](=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:29]([N:36]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH:37]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH:38]=[O:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[CH2:47]([N:36]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C@@H:37]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH:38]([CH:12]1[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH2:15][N:14]([CH3:17])[C:13]1=[O:18])[OH:39])[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: O=CC(Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: CN1CCN(C(=O)OCc2ccccc2)CC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(C(=O)OCc2ccccc2)C(C(O)[C@H](Cc2ccccc2)N(Cc2ccccc2)Cc2ccccc2)C1=O
Reaction time: 0.5 h

Procedure:
Treat a solution of 4-benzyloxycarbonyl-1-methylpiperazin-2-one (1.4 g, 5.7 mmol) in THF (4 mL) cooled at −78° C. with lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 5.7 mL, 5.7 mmol) dropwise and stir 30 min. Add 2-(dibenzylamino)-3-phenylpropanal (1 g, 3.1 mmol) in THF (2 mL) and stir at −78° C. for 45 min. Quench with saturated aqueous ammonium chloride solution. Separate organic layer and wash with water, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 1:1 hexanes:ethyl acetate) to provide the title compound as a mixture of four diastereoisomers which are separated by HPLC (normal phase, eluting with 85:15 hexanes:isopropanol) (828 mg, 45% total yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:12][CH:11]2[C:13]#[N:14])=[O:9])=[CH:4][CH:3]=1.[CH3:15][Mg]Br>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:10]2[CH2:12][CH:11]2[C:13]#[N:14])([OH:9])[CH3:15])=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: N#CC1CC1C(=O)c1ccc(Cl)cc1
Solvent: CCOCC
Product: CC(O)(c1ccc(Cl)cc1)C1CC1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
714 mg of the compound from Example 74A with a purity of 54% (1.89 mmol) were introduced into 7 ml of diethyl ether at RT, 0.94 ml (2.83 mmol) of a 3N solution of methylmagnesium bromide in diethyl ether was added, and the mixture was stirred at RT overnight. The reaction mixture was added to a saturated, ice-cold aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient) to result in 257 mg (55% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=O.O=[C:21]([CH2:29][CH3:30])[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].Cl[Si](C)(C)C>CN(C=O)C>[CH2:29]([C:21]1[N:1]=[C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=3[C:3]2=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:22]=1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:30]
Reactant: CCOC(=O)CCC(=O)CC
Reactant: Cc1ccc(C(=O)c2c(N)sc3c2CCCC3)cc1
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1c(CC)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Temperature: 100 °C
Yield: 64.5 %

Procedure:
To a solution of (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(p-tolyl)methanone (0.542 g; 2 mmol) and ethyl 4-oxohexanoate (0.348 g; 2.2 mmol) in dry DMF (8 mL) under a nitrogen atmosphere was added chlorotrimethylsilane (1.02 mL; 8 mmol) dropwise. The mixture was stirred in a sealed tube and heated at 100° C. for 24 h. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic phase was successively washed with a saturated solution of sodium hydrogen carbonate, water, brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using a gradient of ethyl acetate (1-30%) in heptane to afford 0.508 g (64%) of the title compound as a yellow oil.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[CH:18]=[N:17][CH:16]=[C:15]2[Br:20].C([BH3-])#N.[Na+]>CCO.CCOC(C)=O>[CH2:1]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[CH:18]=[N:17][CH:16]=[C:15]2[Br:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc2c(Br)cncc12
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Brc1cncc2c(NCc3ccccc3)cccc12
Temperature: 90 °C

Procedure:
Under argon, benzaldehyde (584 μl, 5.75 mmol) is added to a solution of 8-amino-4-bromoisoquinoline (Intermediate 23.2, 1.11 g, 5 mmol) in absolute EtOH (60 ml). The mixture is heated at 90° C. for 24 h. It is cooled to 0° C. and then sodium cyanoborohydride (NaBH3CN, 3.3 g, 50 mmol) is added in small portions. The stirring is maintained for 2 h at room temperature. The reaction mixture is diluted with AcOEt (600 ml) and is then washed with water. The organic phase is dried over Na2SO4 and then evaporated. The residue is purified on silica gel, eluting with an AcOEt/petroleum ether (1/4) mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:29][C:30](=[NH:34])[CH2:31][CH2:32][CH3:33].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[O:15][N:34]=[C:30]([CH2:31][CH2:32][CH3:33])[N:29]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCCC(=N)NO
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1noc(C=Cc2ccc(OC)c(OC)c2)n1
Temperature: 25 °C

Procedure:
3-(3,4-Dimethoxy-phenyl)-acrylic acid (compound of Example 2, Method A, Step 1; 3.5 g, 16.80 mmol) was dissolved in dry DMF (35 mL). 1,1′-Carbonyldiimidazole (CDI) (3.0 g, 18.48 mmol) was added and the reaction mixture was stirred at room temperature. At the end of 3 h, N-hydroxy-butyramidine (1.88 g, 18.48 mmol) was added and the reaction mixture was stirred at room temperature for 8 h. After completion of the reaction, additional CDI (2.99 g, 18.48 mmol) was added and the reaction mixture was refluxed at 110° C. to 120° C. for 7 h to effect cyclodehydration. DMF was evaporated and the residue obtained was cooled to room temperature followed by addition of water (20 mL). The resulting mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (2×10 mL) and brine (10 mL). The organic phase obtained was dried over anhydrous sodium sulfate and concentrated to afford the title compound.