Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:3]1[C:15]2[C:6](=[C:7]3[C:12](=[C:13]([CH3:16])[CH:14]=2)[NH:11][C:10](=[O:17])[CH:9]=[CH:8]3)[O:5][CH2:4]1)=[O:2].[BH4-].[Na+].O>CO>[OH:2][CH2:1][CH:3]1[C:15]2[C:6](=[C:7]3[C:12](=[C:13]([CH3:16])[CH:14]=2)[NH:11][C:10](=[O:17])[CH:9]=[CH:8]3)[O:5][CH2:4]1
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OCC2C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OCC2CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
To 3-formyl-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (1.0 g) in methanol (80 ml), sodium borohydride (1.0 g) was added and stirred at room temperature for 30 minutes. After completion of the reaction, water was added and extracted with chloroform-methanol (4:1). The extract was dried and the solvent was evaporated. The residue was recrystallized from methanol-ether to obtain 0.59 g of 3-hydroxymethyl-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one was obtained as colorless needles (58.5%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][O:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1>>[CH3:28][O:29][C:30]1[CH:35]=[C:34]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)[CH:33]=[N:32][CH:31]=1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Product: COc1cncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(C)(=O)=O)CC4)cc3n2)c1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 3-methoxypyridine-5-boronic acid pinacol ester in General Procedure A. Purification on silica and ether trituration gave 243. NMR (CDCl3): 2.68-2.72 (4H, m), 2.82 (3H, s), 3.29-3.33 (4H, m), 3.90 (2H, s), 3.90-3.94 (4H, m), 4.00 (3H, s), 4.05-4.10 (4H, m), 7.35 (1H, s), 8.23 (1H, s), 8.38 (1H, s), 9.26 (1H, s). MS (ESI+): MH+ 505.19 (100%)
Reaction SMILES: [CH2:1]([N:4]([CH2:13][CH2:14][CH3:15])[C:5](/[CH:7]=[C:8](\[CH3:12])/[C:9]([OH:11])=O)=[O:6])[CH2:2][CH3:3].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:38]([O:42][C:43]([N:45]1[C@@H:50]([C@@H:51]([OH:63])[C@@H:52]([NH2:62])[CH2:53][C:54]2[CH:59]=[C:58]([F:60])[CH:57]=[C:56]([F:61])[CH:55]=2)[CH2:49][O:48][C@@H:47]([CH2:64][O:65][CH:66]2[CH2:71][CH2:70][CH2:69][CH2:68][CH2:67]2)[CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>ClCCl>[C:38]([O:42][C:43]([N:45]1[C@@H:50]([C@@H:51]([OH:63])[C@@H:52]([NH:62][C:9](=[O:11])/[C:8](/[CH3:12])=[CH:7]/[C:5](=[O:6])[N:4]([CH2:1][CH2:2][CH3:3])[CH2:13][CH2:14][CH3:15])[CH2:53][C:54]2[CH:59]=[C:58]([F:60])[CH:57]=[C:56]([F:61])[CH:55]=2)[CH2:49][O:48][C@@H:47]([CH2:64][O:65][CH:66]2[CH2:71][CH2:70][CH2:69][CH2:68][CH2:67]2)[CH2:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CCCN(CCC)C(=O)/C=C(\C)C(=O)O
Reactant: CC(C)(C)OC(=O)N1C[C@H](COC2CCCCC2)OC[C@@H]1[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCN(CCC)C(=O)/C=C(\C)C(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](COC2CCCCC2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
Dissolve (E)-3-dipropylcarbamoyl-2-methylacrylic acid (0.029 g, 0.134 mmol) in dichloromethane (1.3 mL). Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (0.028 g, 0.148 mmol) then 1-hydroxybenzotriazole (HOBT) (0.023 g, 0.148 mmol). Stir at room temperature for 30 minutes. To this stirring solution add (2R,5R)-5-[(1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2-cyclohexyloxymethylmorpholine-4-carboxylic acid tert-butyl ester (0.065 g, 0.134 mmol) in dichloromethane (1.5 mL). Stir for 2.5 hours, quench with 10% aqueous potassium carbonate (20 mL), and dilute with dichloromethane (75 mL). Extract the organic layer, wash with 5% aqueous citric acid (25 mL), saturated aqueous sodium chloride (30 mL), dry (magnesium sulfate) and purify (silica gel chromatography, eluting with 30:70 to 70:30 ethyl acetate:hexanes) to give the title compound as a white foam (0.041 g, 45.2%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)[C:5]([C:21]#[N:22])=[C:4]([S:23][CH2:24][C:25]2[N:26]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[S:28][CH:29]=2)[N:3]=1.O.[C:38]1(C)C=CC(S(O)(=O)=O)=C[CH:39]=1.CO>C(=O)C>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([C:27]2[S:28][CH:29]=[C:25]([CH2:24][S:23][C:4]3[C:5]([C:21]#[N:22])=[C:6]([C:11]4[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][OH:20])=[CH:15][CH:16]=4)[C:7]4[C:8](=[O:9])[NH:10][CH:38]([CH3:39])[NH:1][C:2]=4[N:3]=3)[N:26]=2)=[CH:35][CH:34]=1
Reactant: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc(N)c(C(N)=O)c1-c1ccc(OCCO)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CC=O
Solvent: CO
Solvent: O
Product: CC1NC(=O)c2c(nc(SCc3csc(-c4ccc(Cl)cc4)n3)c(C#N)c2-c2ccc(OCCO)cc2)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon, 138 mg (0.256 mmol) of the compound from Example 22A were initially charged in 3 ml of acetaldehyde, a spatula tip of 4-toluenesulfonic acid monohydrate was added and the mixture was stirred at RT for 1 h. 2.5 ml of methanol were then added to the reaction solution, and after 2 h the mixture was concentrated and the residue was purified by column chromatography (silica gel, toluene/acetonitrile 2:1→1:1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:4][N:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][C:2]1[C:6]([C:7]([N:16]2[CH2:20][CH2:19][CH2:18][CH:17]2[CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:9])=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:4][N:3]=1
Reactant: Cc1noc(-c2ccccc2)c1C(=O)O
Reactant: c1cncc(CC2CCCN2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccccc2)c1C(=O)N1CCCC1Cc1cccnc1
Temperature: 25 °C

Procedure:
3-Methyl-5-phenyl-4-isoxazolecarboxylic acid (40 mg, 0.197 mmol), 3-(pyrrolidin-2-ylmethyl)pyridine (50.5 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.0 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H21N3O2: 347.1634, found 347.1642.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:10]Cl)=[CH:4][CH:3]=1.C(N(CC)CC)C>O1CCCC1.C(OCC)C>[C:15]1([S:12]([C:9]([S:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[CH2:10])(=[O:14])=[O:13])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=S(=O)(c1ccccc1)C(CCl)Sc1ccc(Br)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(Sc1ccc(Br)cc1)S(=O)(=O)c1ccccc1

Procedure:
A solution of 10.2 g (26.1 mmoles) of 2-chloro-1-(phenylsulfonyl)ethyl p-bromophenyl sulfide in 50 ml of tetrahydrofuran was diluted with 50 ml of diethyl ether and treated with 3.63 ml (2.65 g, 26.2 mmoles) of triethylamine. After 20 minutes the triethylamine hydrochloride was removed by filtration. The filtrate was freed of solvent by evaporation under reduced pressure to leave a viscous, pale yellow oil of n20 1.6338.
Reaction SMILES: C([O:8][C:9]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][C:12]([C:13]([N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[S:17](=[O:25])(=[O:24])[CH2:16]2)=[O:14])=[CH:11][C:10]=1[O:32][CH3:33])C1C=CC=CC=1>O1CCCC1.[C].[Pd]>[OH:8][C:9]1[C:27]([C:28]([F:31])([F:29])[F:30])=[CH:26][C:12]([C:13]([N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[S:17](=[O:25])(=[O:24])[CH2:16]2)=[O:14])=[CH:11][C:10]=1[O:32][CH3:33]
Reactant: COc1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(C(F)(F)F)c1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(C(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 22 h
Yield: 75.8 %

Procedure:
3-(4-benzyloxy-3-methoxy-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (574 mg) was dissolved in tetrahydrofuran (6 mL), and 5% palladium-carbon (310 mg) was added to the solution, and then the mixture was stirred at room temperature for 22 hours under a hydrogen atmosphere. The reaction solution was filtered, and then the solvent was distilled off under reduced pressure and the obtained residue was crystallized from n-hexane-chloroform to obtain the title compound (353 mg) as a colorless crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([N:21]4C(=O)C5C(=CC=CC=5)C4=O)[CH3:20])=[CH:15][CH:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1.O.NN>C(Cl)Cl.C(O)C>[CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([NH2:21])[CH3:20])=[CH:15][CH:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2ncc(-c3ccc(C(C)N4C(=O)c5ccccc5C4=O)cc3)s2)cc1
Agent: NN
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(Oc2ncc(-c3ccc(C(C)N)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.5 %

Procedure:
To a solution of Example 11C (770 mg, 1.69 mmol) in methylene chloride (20 mL) and ethanol (2 min) was added hydrazine monohydrate (540 μL, 11.1 mmol, 6.6 eq.) at room temperature. The mixture was stirred at room temperature overnight. The mixture was filtered. The filtrate was concentrated. The residue was dissolved in methylene chloride again, which was filtered and the filtrate was concentrated to give the title compound (615 mg), which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([Br:13])=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Li+].[CH3:15][CH:16]([N-]C(C)C)C.O1CC1.O>C1COCC1>[Br:13][C:4]1[S:3][C:2]([Br:1])=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]=1[CH2:15][CH3:16]
Reactant: Brc1cc(-c2ccccc2)c(Br)s1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: C1CO1
Product: CCc1c(Br)sc(Br)c1-c1ccccc1
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,5-dibromo-3-phenylthiophene (2.54 g, 8.0 mmol) in dry THF (30 mL) at −65° C. was added LDA (8.8 mmol) dropwise. After stirring for 30 min at −65° C., oxirane (20.0 mmol) was added and the reaction was stirred for 2 h. The reaction mixture was then warmed to room temperature and water was added. The resulting mixture was extracted with EtOAc (3×100 mL), washed with brine, and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound.
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].O[C@@H](C)CNC(=O)OC(C)(C)C.CI>>[CH3:1][O:2][C@@H:3]([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:9])[CH3:11]
Reactant: CO[C@H](C)CNC(=O)OC(C)(C)C
Agent: C[C@H](O)CNC(=O)OC(C)(C)C
Solvent: CI
Product: CO[C@@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized by using the method analogous to the synthesis of Intermediate 277 starting with tert-butyl [(2S)-2-hydroxypropyl]carbamate and alkylating it with methyl iodide.
Reaction SMILES: N#N.Br[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1.[Li]CCCC.[NH4+].[Cl-].C1C[O:21][CH2:20][CH2:19]1>CCCCCC>[Br:10][C:6]1[CH:5]=[C:4]([C:20](=[O:21])[CH3:19])[CH:9]=[CH:8][CH:7]=1
Reactant: Brc1cccc(Br)c1
Reactant: C1CCOC1
Agent: N#N
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 1,3-dibromobenzene (2.45 g, 10.07 mmol) in THF (25.0 mL) was treated at −78° C. with n-BuLi (4.0 mL of a 2.5M solution in hexane, 10.00 mmol). The reaction mixture was stirred for 30 min before N,N-dimethylacetaminde (1.50 mL, 16.13 mmol) was added and the solution was then allowed to warm to rt over 1 h. Sat. aq. NH4Cl was then added and the aq. layer was extracted with Et2O (3×50 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (20:1 hept-EA) gave the title compound as a white solid: TLC:rf (10:1 hept-EA)=0.28. LC-MS-conditions 02: tR=0.95 min.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH:43][C:44]([NH2:46])=[NH:45])[CH:34]=[CH:35][C:36]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1>>[C:17]([C:13]1[CH:12]=[C:11]([C:10]2[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][N:46]=[C:44]([NH:43][C:33]3[CH:34]=[CH:35][C:36]([N:37]4[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]4)=[C:31]([O:30][CH3:29])[CH:32]=3)[N:45]=2)[CH:16]=[CH:15][CH:14]=1)#[N:18]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cccc(C#N)c1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: CCOC(=O)c1cnc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc1-c1cccc(C#N)c1

Procedure:
The title compound was prepared from ethyl 3-dimethylamino-2-(3-cyano-benzoyl)-acrylate (85 mg, 0.31 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (116 mg, 0.31 mmol) using in analogous manner the procedure described in example 28b). Obtained as a pale-yellow solid (41 mg, 29%). Mp 195-197° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[CH:45][C:46]([N:49]3[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]3)=[N:47][CH:48]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)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>[F:23][C:21]1[CH:22]=[C:17]([CH:18]=[C:19]([F:24])[CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:43]4[CH:44]=[CH:45][C:46]([N:49]5[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]5)=[N:47][CH:48]=4)[CH:3]=3)[N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:9]=2)[CH:12]=[N:13]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Yield: 101.9 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (STEP 1 example 71) (1 g, 1.515 mmol) was coupled with tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (intermediate 69C) (581 mg, 1.818 mmol) using sodium carbonate (481 mg, 4.545 mmol) and Pd(PPh3)2Cl2 (53 mg, 0.075 mmol) in toluene/ethanol/water (10/15/2 ml). This afforded 1.12 g (100% yield) of the titled compound after purification by column (Silica gel 60/120) using 40% ethyl acetate in hexane as eluent. MS: m/z=726.3 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([C:18]([NH:20][C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)=[O:19])[CH2:3]1.[CH2:27]=[O:28].[OH-].[Na+]>C(O)(=O)C.O>[OH:28][CH2:27][N:12]1[C:11]2[C:17]3[C:14]([CH2:15][C@@H:16]4[C@@H:6]([C:7]=3[CH:8]=[CH:9][CH:10]=2)[CH2:5][C@@H:4]([C:18]([NH:20][C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)=[O:19])[CH2:3][N:2]4[CH3:1])=[CH:13]1
Reactant: CN1C[C@H](C(=O)Nc2cnccn2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CN1C[C@H](C(=O)Nc2cnccn2)C[C@@H]2c3cccc4c3c(cn4CO)C[C@H]21
Reaction time: 3 h

Procedure:
4 g of 6-Methyl-N-pyrazinylergoline-8β-carboxamide (see Example 1) dissolved in 42 ml of acetic acid are placed in a three-necked bottle and diluted with 200 ml of water. 42 ml of an aqueous formaldehyde solution (35% of weight) are added. The mixture is stirred for three hours at 60°-70°, cooled to 20°, adjusted to a pH-value of 8 with a 5N sodium hydroxide solution and extracted with methylene chloride. After evaporation of the solvent, 3.28 g of the obtained crude product, 1-hydroxymethyl-6-methyl-N-pyrazinylergoline-8β-carboxamide, are dissolved in 270 ml of absolute methanol after which 52 g tartaric acid is added and the mixture is stirred for three hours at 60°. The solvent is evaporated in vacuo. The residue is taken up in water, neutralized with a 2N potassiumbicarbonate solution and extracted with methylene chloride. The crude product, obtained after evaporation of the solvent, is purified by chromatography on a column of silica gel. The product is eluted with 3% methanol in methylene chloride and is dissolved in acetone. Two equivalents of tartaric acid are added to form the tartaric acid addition salt.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3](=[O:11])O1.[NH2:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][CH2:20][NH2:21]>>[O:12]=[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3](=[O:11])[N:13]1[CH2:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][CH2:20][N:21]1[C:3](=[O:11])[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:12]
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: NCCCNCCCN
Product: O=C1Cc2ccccc2C(=O)N1CCCNCCCN1C(=O)Cc2ccccc2C1=O

Procedure:
N,N-Bis-[3-(3,4-dihydro-1,3-dioxo-2(1H)-isoquinolyl)-propyl]-amine was prepared analogous to Example 30 from 2.44 gm of isochroman-1,3-dione and N,N-bis-(3-amino-propyl)-amine. The hydrochloride was precipitated from acetone with ethereal hydrochloric acid. M.p. of the hydrochloride: 135° -140° C; yield: 0.17 gm (2.5% of the theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.CON(C)[C:13]([C:15]1[CH:19]=[CH:18][N:17]([S:20](=[O:25])(=[O:24])[N:21]([CH3:23])[CH3:22])[N:16]=1)=[O:14]>C1COCC1>[CH3:22][N:21]([CH3:23])[S:20]([N:17]1[CH:18]=[CH:19][C:15]([C:13](=[O:14])[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[N:16]1)(=[O:24])=[O:25]
Reactant: Clc1cccc([Mg]Br)c1
Reactant: CON(C)C(=O)c1ccn(S(=O)(=O)N(C)C)n1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1ccc(C(=O)c2cccc(Cl)c2)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
A solution of 3-chlorophenylmagnesium bromide (0.5 M in THF) (15.89 mL, 7.95 mmol) was added to a solution of 1-dimethylsulfamoyl-1H-pyrazole-3-carboxylic acid methoxy-methyl-amide (1.60 g, 6.11 mmol) in THF (20 mL) at −78° C. and under nitrogen. The mixture was stirred at −78° C. for 1 hour and then further stirred at room temperature for 5 hours. The mixture was quenched with NH4Cl (aq. sat. solution) and the product was extracted with AcOEt. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; AcOEt in DCM 0/100 to 10/90). The desired fractions were collected and concentrated in vacuo to yield 3-(3-chloro-benzoyl)-1H-pyrazole-1-sulfonic acid dimethylamide (1.68 g, 88% yield) as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([CH:8]([CH3:22])[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[O:5][N:4]=1.[NH3:23]>>[NH2:23][CH2:2][C:3]1[N:7]=[C:6]([CH:8]([CH3:22])[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[O:5][N:4]=1
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CCl)no1
Reactant: N
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CN)no1
Reaction time: 8 h

Procedure:
A mixture of 6.0 g of 3-chloromethyl-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole and 50 ml of liquid ammonia was allowed to stand in an autoclave at room temperature overnight. After evaporation of ammonia, the residue was chromatographed over silica gel using chloroform to give 4.05 g of 3-aminomethyl-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole as a light brown oil, nD22 1.5878.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][CH2:10][C@@H:11]2[C@@H:16]([C:17]([F:20])([F:19])[F:18])[O:15][CH2:14][C@:12]2([C:21]2[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:22]=2[F:28])[N:13]=1)(C)(C)C.[F:30][C:31]([F:42])([F:41])[C:32]1[N:33]=[CH:34][C:35]([C:38](O)=[O:39])=[N:36][CH:37]=1>>[NH2:7][C:8]1[S:9][CH2:10][C@@H:11]2[C@@H:16]([C:17]([F:20])([F:19])[F:18])[O:15][CH2:14][C@:12]2([C:21]2[CH:26]=[C:25]([NH:27][C:38]([C:35]3[CH:34]=[N:33][C:32]([C:31]([F:41])([F:30])[F:42])=[CH:37][N:36]=3)=[O:39])[CH:24]=[CH:23][C:22]=2[F:28])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Reactant: O=C(O)c1cnc(C(F)(F)F)cn1
Product: NC1=N[C@@]2(c3cc(NC(=O)c4cnc(C(F)(F)F)cn4)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1

Procedure:
Synthesized from tert-butyl[(4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-trifluoromethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate and 5-trifluoromethylpyrazine-2-carboxylic acid according to the general procedure. 1H NMR (400 MHz, CDCl3) δ ppm 2.80 (dd, J=13 0.6, 3.8 Hz, 1 H), 3.11 (dd, J=13.8, 2.9 Hz, 1 H), 3.30-3.44 (m, 1 H), 3.87 (d, J=8.3 Hz, 1 H), 4.25-5.14 (m, 4 H), 7.07 (dd, J=11.9, 8.8 Hz, 1 H), 7.57 (dd, J=6.8, 2.8 Hz, 1 H), 7.86 (dt, J=8.4, 3.6 Hz, 1 H), 8.89 (s, 1 H), 9.53 (s, 2 H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[CH2:7][C@H:8]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C@@H:11]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[N:10]([C@@H:28]([CH2:34][CH3:35])[C:29](OCC)=[O:30])[C:9]1=[O:36])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+]>CCOCC>[Cl:20][C:16]1[CH:15]=[C:14]([C@@H:12]2[C@@H:11]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[N:10]([C@@H:28]([CH2:34][CH3:35])[CH2:29][OH:30])[C:9](=[O:36])[C@@H:8]([CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:37])[CH2:13]2)[CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)[C@H](CC)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Product: CC[C@@H](CO)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-ethyl 2-((3R,5R,6S)-3-(2-tert-butoxy-2-oxoethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoate (1.94 g, 3.54 mmol, Example 21, Step A) in Et2O (35.4 mL) was added 90% lithium borohydride (0.154 g, 7.07 mmol) at 0° C. After being stirred at 0° C. for 30 min, the reaction was quenched (ice cold 10% citric acid), extracted (2×EtOAc) and washed (sat. aq. NaCl solution). The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification by chromatography on silica gel (50% to 100% EtOAc/Hexanes, gradient elution) provided the title compound.