Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[C:8]2[CH:12]=[C:11]([CH3:13])[S:10][C:9]=2[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[OH-].[Na+]>CN(C)C=O.C(O)C.O1CCCC1.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([NH:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:21])=[CH:23][CH:24]=2)[C:8]2[CH:12]=[C:11]([CH3:13])[S:10][C:9]=2[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)c(C)s1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)c(C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a mixture of 4-{[cyclohexyl(2,5-dimethylthiophen-3-yl)methyl]amino}benzoic acid (250 mg) synthesized above, ethyl β-alaninate hydrochloride (134 mg), 1-hydroxybenzotriazole monohydrate (134 mg) and triethylamine (122 μL) in N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (168 mg), and the mixture was stirred at room temperature overnight. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography (ethyl acetate) to give a colorless oil. To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (10 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (250 mg, 83%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])[NH2:8])([CH3:4])([CH3:3])[CH3:2].[N:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:16]=[O:17]>O1CCOCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:8][C:16](=[O:17])[NH:15][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(I)cc(N)cc1C(C)(C)C
Reactant: CCOC(=O)CN=C=O
Solvent: C1COCCO1
Product: CCOC(=O)CNC(=O)Nc1cc(I)c(OC)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-tert-butyl-5-iodo-4-methoxyaniline (458 mg, 1.5 mmol) in dioxane (5 mL) was added ethyl isocyanatoacetate (0.168 mL, 1.500 mmol) dropwise producing a solution that was stirred at room temperature for 16 hours. The reaction mixture was concentrated and the product was triturated in 9:1 hexane/ethyl acetate. The resulting solid was collected by filtration and dried to give the title compound.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[F-].[Cs+].[C:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)#[N:10].Br[C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH3:30])[C:25]([CH2:31][CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][CH:34]1[CH3:38])=[CH:24]2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1.O>[CH3:30][N:26]1[C:27]2[C:23](=[CH:22][C:21]([C:14]3[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=3)=[CH:29][CH:28]=2)[CH:24]=[C:25]1[CH2:31][CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][C@H:34]1[CH3:38]
Reactant: CC1CCCN1CCc1cc2cc(Br)ccc2n1C
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H]1CCCN1CCc1cc2cc(-c3ccc(C#N)cc3)ccc2n1C
Temperature: 65 °C
Yield: 44.8 %

Procedure:
A reaction flask was charged with Cs2CO3 (1.14 g, 3.5 mmol), CsF (0.38 g, 2.5 mmol), 4-cyanophenylboronic acid (425 mg, 2.5 mmol), and H2O (10 mL) followed by a toluene solution (10 mL) of 5-bromo-1-methyl-2-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-1H-indole (320 mg, 1.0 mmol). The resulting mixture was purged with nitrogen. To the reaction mixture was then added Cy2PPh2(5-bromo-2-[2-(R)-methyl-pyrrolidin-1-yl)-ethyl]-1H-indole) (35 mg, 0.1 mmol) and Pd2(dba)3 (46 mg, 0.05 mmol). The resulting reaction mixture was then heated to 65° C. overnight under nitrogen. HPLC indicated that all of the 5-bromo-1-methyl-2-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-1H-indole was consumed. The reaction mixture was cooled to room temperature and IPAc (20 mL) was added. The organic layer was separated and concentrated. The residue was purified by column chromatograph eluting with heptane/acetone/CH2Cl2/Et3N (600 mL/40 mL/5 mL/2 mL). The fractions containing product were conbined and concentrated under reduced pressure to provide the title compound as a semi-solid (154 mg). 1H NMR (400 MHz, CDCl3) δ 7.57-7.66 (m, 5H), 7.30 (dd, J=1.7, 8.6 Hz, 1H), 7.25 (d, J=8.51 Hz, 1H), 6.27 (S, 1H), 3.63 (S, 1H), 3.21-3.25 (m, 1H), 3.06-3.13 (m, 1H), 2.87-2.93 (m, 2H), 2.33-2.40 (m, 2H), 2.16 (q, J=8.78 Hz, 1H), 1.84-1.91 (m, 1H), 1.65-1.76 (m, 2H), 1.36-1.44 (m, 1H), 1.07 (d, J=6.1 Hz, 3H). 13C NMR (400 MHz, CDCl3) δ 146.80, 140.39, 137.11, 132.04, 130.19, 128.11, 127.27, 119.86, 119.08, 118.43, 109.18, 99.37, 60.15, 54.19, 53.24, 32.89, 29.91, 26.85, 21.98, 19.32. [M+H]+ at m/z 344.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH2:9][CH2:8][N:7]([CH3:19])[CH2:6]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH3:19][N:7]1[CH2:8][CH2:9][C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C@H:5]([CH2:3][OH:2])[CH2:6]1
Reactant: COC(=O)[C@@H]1CN(C)CC[C@@H]1c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CC[C@H](c2ccc(Cl)c(Cl)c2)[C@H](CO)C1
Temperature: -30 °C
Reaction time: 3 h

Procedure:
A solution of (1) (5.0 g, 17 mmol) in tetrahydrofuran (50 ml) at −50° C. was added LiAlH4 (0.50 g, 13 mmol). Stirred at −30° C. for three hours, then quenched by addition of water and evaporated to a solid. The residue was dissolved in dichloromethane, dried with magnesium sulfate and evaporated to dryness. Yield 4.6 g of (3) (100%). Mp. 127-129° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH:13]=[C:14]([CH:16]=[N:17]O)[N:15]=[C:5]2[C:4]1=[O:19])[CH3:2]>C(OC(=O)C)(=O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH:13]=[C:14]([C:16]#[N:17])[N:15]=[C:5]2[C:4]1=[O:19])[CH3:2]
Reactant: CCn1c(=O)c2nc(C=NO)cn2c2ccccc21
Solvent: CC(=O)OC(C)=O
Product: CCn1c(=O)c2nc(C#N)cn2c2ccccc21
Yield: 103.5 %

Procedure:
A solution of 0.4 g of the product of Step A in 5 ml of acetic anhydride was refluxed for 21/2 hours and was then cooled during which it solidified into a buff crystalline solid. The solid was triturated with aqueous sodium carbonate solution and was filtered. The product was washed with water and dried in vacuo to obtain 0.385 g of 4,5-dihydro-5-ethyl-4-oxo-imidazo-[1,2-a]-quinoxaline-2-carbonitrile in the form of a crystalline solid melting at >330° C.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:26][C:16]3=[C:17]4[C:21](=[C:22]([CH3:24])[CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:25])[CH2:18]4)(=O)=O)=CC=1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CS(C)=O>[CH2:28]([NH:35][CH2:11][CH:12]1[O:26][C:16]2=[C:17]3[C:21](=[C:22]([CH3:24])[CH:23]=[C:15]2[O:14][CH2:13]1)[NH:20][C:19](=[O:25])[CH2:18]3)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3cc(C)c4c(c3O2)CC(=O)N4)cc1
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc2c(c3c1NC(=O)C3)OC(CNCc1ccccc1)CO2
Temperature: 85 °C

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-6-methyl-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.57 g, 4.04 mmole) and benzylamine (2.18 g, 5.6 mmole) were combined in 10 ml of dry DMSO and heated to 85° C. for 3 hours under a nitrogen atmosphere. After cooling to room temperature, 150 ml of water was added and the mixture was extracted twice with 250 ml portions of 35% ethyl acetate in hexane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuum to yield an orange oil. Column chromatography on silica gel using 2% methanol/CH2Cl2 as eluant gave 1.08 g of the free base of the title compound as a light beige solid. This was crystallized from isopropanol with the addition of fumaric acid (0.42 g, 3.7 mmole) to give 0.49 g of the (S) enantiomer of the title compound as a beige solid fumarate, m.p. 219-220° C.
Reaction SMILES: [CH2:1]([N:5]([CH2:28][CH3:29])[C:6]1[C:7]2[C:15]([CH3:17])([CH3:16])[CH:14]([OH:18])[N:13]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[C:8]=2[N:9]=[C:10]([CH3:12])[N:11]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH3:32]I>C1COCC1>[CH2:1]([N:5]([CH2:28][CH3:29])[C:6]1[C:7]2[C:15]([CH3:16])([CH3:17])[CH:14]([O:18][CH3:32])[N:13]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[C:8]=2[N:9]=[C:10]([CH3:12])[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CI
Reactant: CCCCN(CC)c1nc(C)nc2c1C(C)(C)C(O)N2c1c(C)cc(C)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCN(CC)c1nc(C)nc2c1C(C)(C)C(OC)N2c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 4-(butyl-ethyl-amino)-2,5,5-trimethyl-7-(2,4,6-trimethylphenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-6-ol] (20 mg, 0.05 mmol) in 1 ml of dry THF was treated with sodium hydride (60% in oil, 4 mg, 0.1 mmol) and then methyl iodide (0.3 ml) was added at room temperature. After stirring at room temperature for 2.5 hours, the mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give 26 mg of crude material. After silica gel column purification with 10% ethyl acetate in hexane, 19 mg of a colorless oil of the title compound was obtained. 1H NMR (CDCl3) δ 6.92 (s, 1H), 6.89 (s, 1H), 4.48 (s, 1H), 3.1–3.3 (m, 4H), 3.11 (s, 3H), 2.32 (s, 3H), 2.28 (s, 3H), 2.20 (s, 3H), 2.19 (s, 3H), 1.45 (s, 3H), 1.44 (s, 3H), 1.4–1.52 (m, 2H), 1.2–1.4 (m, 2H), 1.10 (t, 3H), 0.90 (t, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([C:14]=2[C:16]([OH:18])=[O:17])=[C:12]([CH3:19])[CH:11]=[C:10]([CH3:20])[CH:9]=3)[CH:5]=[C:4]([CH3:21])[CH:3]=1.[C:22]1(O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.CN(C)C1C=CN=CC=1>[C:22]1([O:17][C:16]([C:14]2[C:13]3[C:8]([N:7]=[C:6]4[C:15]=2[C:2]([CH3:1])=[CH:3][C:4]([CH3:21])=[CH:5]4)=[CH:9][C:10]([CH3:20])=[CH:11][C:12]=3[CH3:19])=[O:18])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cc(C)c2c(C(=O)O)c3c(C)cc(C)cc3nc2c1
Reactant: Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: Cc1cc(C)c2c(C(=O)Oc3ccccc3)c3c(C)cc(C)cc3nc2c1
Yield: 55 %

Procedure:
In step 1, 1,3,6,8 tetramethylacridine-9-carboxylic acid was esterified with phenol in THF and 4-dimethylamino-pyridine [DMAP]. Phenyl-1,3,6,8-tetramethylacridine-9-carboxylate was obtained in about 55% yield after recrystallization from benzene.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]1[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:28][C@@H:29]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[CH2:30][OH:31].[Cl-].[NH4+]>C(#N)C>[CH:33]1([CH2:32][C@H:29]([NH:28][CH2:2][C:3]([N:5]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]2[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:4])[CH2:30][OH:31])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: N[C@H](CO)CC1CCCCC1
Reactant: O=C(CCl)N1CCc2ccccc2C1C1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: O=C(CN[C@H](CO)CC1CCCCC1)N1CCc2ccccc2C1C1CCCCC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 24.2 %

Procedure:
To a solution of 2-(chloroacetyl)-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (12 mg) in acetonitrile (0.5 mL) were added potassium carbonate (3 mg) and (S)-(+)-2-amino-3-cyclohexyl-1-propanol hydrochloride (15 mg), followed by stirring at 80° C. for 4 hours. Thereafter, a saturated aqueous ammonium chloride solution was added to the reaction liquid, followed by extraction with chloroform. The solvent was evaporated and the resulting residue was purified by preparative HPLC to obtain (2S)-3-cyclohexyl-2-{[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amino}propan-1-ol (4.1 mg).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1.Cl[C:30]1[S:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1>CN(C=O)C>[S:31]1[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=[C:30]1[NH:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1
Reactant: Clc1nc2ccccc2s1
Reactant: Cc1c(N)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1c(Nc2nc3ccccc3s2)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12

Procedure:
6-Amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile hydrochloride (9.5 mg, 0.024 mmol) and 2-chlorobenzothiazole (4.4 mg, 0.026 mmol) in DMF (0.1 ml) were stirred at 100° C. for 12 hrs. The reaction mixture was concentrated and purified by silica gel flash chromatography to isolate 379 as a yellow film (3.3 mg, 28%). [M+H]+489.14
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:19]=[CH:18][N:17](COCC3C=CC=CC=3)[N:16]=2)[CH:12]=[CH:11][C:10]=1[N:29]1[S:33](=[O:35])(=[O:34])[NH:32][C:31](=[O:36])[CH2:30]1)C1C=CC=CC=1>CCO.O.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[CH:12]=[CH:11][C:10]=1[N:29]1[S:33](=[O:35])(=[O:34])[NH:32][C:31](=[O:36])[CH2:30]1
Reactant: O=C1CN(c2ccc(-c3ccn(COCc4ccccc4)n3)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: O=C1CN(c2ccc(-c3cc[nH]n3)cc2O)S(=O)(=O)N1

Procedure:
A solution of 5-[2-benzyloxy-4-(1-benzyloxymethyl-1H-pyrazol-3-yl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one in 10 mL of EtOH/water (1:1) is hydrogenated over 10% Pd/C (15 mg) at 1 atm for 18 h. The catalyst is filtered and the filtrate evaporated. The residue is re-dissolved in EtOH/HOAc (3:1) and hydrogenated over 10% Pd/C for 18 h. The catalyst is filtered and the filtrate evaporated to give the title compound: (M−1)−=293.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:32])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=4[O:30][CH3:31])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:33][NH2:34]>>[CH3:31][O:30][C:23]1[C:24]([O:28][CH3:29])=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:34][CH3:33])[CH2:17][C:16]=2[CH:18]=[C:19]([F:32])[CH:20]=1
Reactant: COc1cccc(-c2cc(F)cc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)c1OC
Reactant: CN
Product: CNCC1Cc2cc(F)cc(-c3cccc(OC)c3OC)c2O1

Procedure:
The title compound was prepared (0.103 g, 74%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.18 g, 0.39 mmol) and methylamine (0.139 g, 3.9 mmol). mp 85-89° C.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[S:26]([C:30]1[CH:31]=[C:32]([NH2:36])[CH:33]=[CH:34][CH:35]=1)(=[O:29])(=[O:28])[NH2:27]>>[S:26]([C:30]1[CH:31]=[C:32]([NH:36][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:33]=[CH:34][CH:35]=1)(=[O:28])(=[O:29])[NH2:27]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 510.2 [(M−H)−]; mp 258° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][CH2:32][C:33](=[O:45])[CH2:34][C:35](=[O:44])[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:10]([CH:28]([CH3:30])[CH3:29])=[C:11]([C:19](=[O:27])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C>C(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][CH2:32][C@@H:33]([OH:45])[CH2:34][C@@H:35]([OH:44])[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:10]([CH:28]([CH3:30])[CH3:29])=[C:11]([C:19](=[O:27])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CCC(=O)CC(=O)CC(=O)OC(C)(C)C
Solvent: O=CO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)C[C@@H](O)CC(=O)OC(C)(C)C
Reaction time: 24 h

Procedure:
An argon inerted reactor was charged with 7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dioxo-heptanoic acid, t-butyl ester (V-A, 100.0 mmol, prepared as indicated in U.S. Pat. No. 6,476,235) and toluene (245 ml). To the reaction mixture was added triethyl amine (55 ml), followed by slow addition of formic acid (7.5 ml). The vessel and its contents was degassed via three vacuum/argon purges. Under a steady flow of argon, the complex of Ruthenium, [N-[(1R,2R)-2-(amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN]chloro[(1,2,3,4,5,6-η)-1,3,5-trimethylbenzene]-(1.25 g) was added, and the vessel and its contents were degassed via one vacuum/argon purge. The reaction mixture was stirred for 24 hours and condensed to a foamy solid. The crude (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid, t-butyl ester may be carried on through subsequent steps without purification, or optionally, can be isolated via flash column chromatography on silica gel, eluting with ethyl acetate-heptane mixtures. HPLC analysis (YMC ODS AQ S5; 1 ml/min; 30° C.; 254 nm: CH3CN/H2O w/0.1% formic acid, 60:40 (0-5 min) to 100:0 (15-22 min) to 60:40 (25 min) indicated a syn:anti ratio of 6:1 tr(syn)=13.9 min tr(anti)=13.5 min
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:7]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:6]2[S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27].C(N(CC)CC)C.[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1>ClCCl>[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:7]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:6]2[S:26]([N:29]1[CH2:30][CH2:31][N:32]([S:50]([C:47]2[CH:46]=[CH:45][C:44]([O:43][CH3:42])=[CH:49][CH:48]=2)(=[O:52])=[O:51])[CH2:33][CH2:34]1)(=[O:27])=[O:28]
Reactant: CCOC(=O)c1c(S(=O)(=O)N2CCNCC2)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(OC)cc3)CC2)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution ethyl 5-bromo-1-(phenylsulfonyl)-3-(piperazin-1-ylsulfonyl)-1H-indole-2-carboxylate hydrochloride (20 mg, 0.034 mmol) in 1.0 mL of dichloromethane at room temperature was added triethylamine (0.019 mL, 0.14 mmol), followed by 4-(methoxy)benzenesulfonyl chloride (8.0 mg, 0,041 mmol). After stirring overnight, the solvent was removed under a stream of nitrogen to provide the titled compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]([NH:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[N:26][CH:25]=[CH:24]3)=[O:19])[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.C(Cl)CCl.[CH3:35][C:36]1([C:39](O)=[O:40])[CH2:38][CH2:37]1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:35][C:36]1([C:39]([O:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH2:9][NH:10][C:11]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:17])[C:18]([NH:20][C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[CH:27]=[N:26][CH:25]=[CH:24]4)=[O:19])=[CH:4][CH:3]=2)=[O:40])[CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(O)cc1
Reactant: CC1(C(=O)O)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(OC(=O)C2(C)CC2)cc1
Reaction time: 8 h

Procedure:
To tert-butyl 2-(4-hydroxyphenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E8) in pyridine was added EDC, DMAP, and 1-methylcyclopropanecarboxylic acid, and the solution was flushed with N2, capped, and stirred overnight. The mixture was poured into EtOAc/NaHCO3(sat) and the aqueous layer was further extracted with EtOAc. The organics were dried (Na2SO4), filtered, and evaporated. Column chromatography 5% MeOH/CH2Cl2 gave pure 4-(3-(tert-butoxycarbonylamino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)phenyl 1-methylcyclopropanecarboxylate (E11).
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][O:7][C:8]2[C:17]3[C:16]([CH3:19])([CH3:18])[CH2:15][CH2:14][C:13]([CH3:21])([CH3:20])[C:12]=3[CH:11]=[C:10]([C:22]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH:30]=[C:29]([C:34]([O-:36])=[O:35])[CH:28]=[CH:27]4)=[O:23])[CH:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[NH4+]>C1COCC1.CO>[F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][O:7][C:8]2[C:17]3[C:16]([CH3:19])([CH3:18])[CH2:15][CH2:14][C:13]([CH3:20])([CH3:21])[C:12]=3[CH:11]=[C:10]([CH:22]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH:30]=[C:29]([C:34]([OH:36])=[O:35])[CH:28]=[CH:27]4)[OH:23])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CCC(C)(C)c2c(OCc3ccc(F)cc3)cc(C(=O)c3ccc4cc(C(=O)[O-])ccc4c3)cc21
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CCC(C)(C)c2c(OCc3ccc(F)cc3)cc(C(O)c3ccc4cc(C(=O)O)ccc4c3)cc21
Reaction time: 1 h
Yield: 89 %

Procedure:
245 mg (0.5 mmol) of 6-{1-[4-(4-fluorobenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]methanoyl}-2-naphthalenecarboxylate are dissolved in 5 mL of THF and 5 mL of methanol, and 28 mg (0.7 mmol) of sodium borohydride are added. The medium is stirred for 1 hour, and then treated with saturated ammonium chloride solution. The residue obtained after extraction is purified by chromatography: a white solid is obtained (m=220 mg; yield=89%; m.p.=212° C.).
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:25]=[N:26][CH:27]=[C:28]([S:30]CC[Si](C)(C)C)[CH:29]=4)[CH:19]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].[CH2:37]([O:39][C:40](=[O:45])[C:41](Br)([F:43])[F:42])[CH3:38].CCOC(C)=O>CCOCC>[CH2:37]([O:39][C:40](=[O:45])[C:41]([F:43])([F:42])[S:30][C:28]1[CH:27]=[N:26][CH:25]=[C:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:16]3[CH:17]=[C:8]([C:5]([S:2]([CH3:1])(=[O:4])=[O:3])([CH3:6])[CH3:7])[CH:9]=[C:10]4[C:15]=3[N:14]=[CH:13][CH:12]=[CH:11]4)[CH:19]=2)[CH:29]=1)[CH3:38]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CC(C)(c1cc(-c2cccc(-c3cncc(SCC[Si](C)(C)C)c3)c2)c2ncccc2c1)S(C)(=O)=O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)C(F)(F)Sc1cncc(-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 24 (Step 5) but using 6-(1-methanesulfonyl-1-methyl-ethyl)-8-{3-[5-(2-trimethylsilanyl-ethylsulfanyl)-pyridin-3-yl]-phenyl}-quinoline from EXAMPLE 24 (Step 2) and bromo-difluoro-acetic acid ethyl ester as starting materials. Flash chromatography (Hex:EtOAc; 1:4) and stirring in Hex:Et2O afforded the title compound as a white solid after filtration.