Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].[CH3:21][Si:22](Cl)([CH2:24][CH2:25][Si:26](Cl)([CH3:28])[CH3:27])[CH3:23]>O1CCCC1>[F:13][C:14]1[CH:15]=[C:16]([N:17]2[Si:26]([CH3:28])([CH3:27])[CH2:25][CH2:24][Si:22]2([CH3:23])[CH3:21])[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cccc(F)c1
Reactant: C[Si](C)(Cl)CC[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si]1(C)CC[Si](C)(C)N1c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of freshly distilled diisopropylamine (22.9 mL) in dry tetrahydrofuran (175 mL) at −78° C. under N2 is treated with n-butyllithium (1.6M in hexanes, 109 mL) dropwise over 15 minutes, and the resulting mixture is stirred at −78° C. for 45 minutes and is then added over ten minutes via cannula to a solution of 3-fluoroaniline (8.00 mL) in dry tetrahydrofuran (166 mL) at −78° C. under N2. The resulting reaction mixture is stirred at −78° C. for 50 minutes and is then treated with a solution of 1,1,4,4-tetramethyl-1,4-dichlorodisilethylene (18.3 g) in dry tetrahydrofuran (85 mL). The mixture is allowed to slowly warm to ambient temperature over four hours with stirring and is then washed with water (2×200 mL) and saline (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, NMR (CDCl3, 400 MHz) 7.12, 6.65, 6.58, 0.86, 0.24δ.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[O:9])[CH:2]=1.[C:11]1([CH3:39])[C:12]([C:17]([CH2:19][N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[N:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:23][CH:22]([NH2:37])[C:21]2=[O:38])=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=1>O1CCCC1>[C:11]1([CH3:39])[C:12]([C:17]([CH2:19][N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[N:24]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:23][CH:22]([NH:37][C:8]([NH:7][C:3]3[CH:4]=[CH:5][CH:6]=[C:1]([CH3:10])[CH:2]=3)=[O:9])[C:21]2=[O:38])=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1ccccc1C(=O)CN1C(=O)C(N)CN(c2ccccc2)c2ccccc21
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NC2CN(c3ccccc3)c3ccccc3N(CC(=O)c3ccccc3C)C2=O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.6 %

Procedure:
m-Tolyl isocyanate (34 mg) was added to a solution of 1-(2-toluoylmethyl)-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (90 mg) obtained from Step 2 of Example 18 in tetrahydrofuran (10 ml), the mixture was stirred for 10 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby obtain 100 mg of the title compound (Yield: 83%).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C@@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([NH2:23])=[O:22]>>[C:21]([C@@H:20]([NH:19][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH2:24][CH:25]([CH3:27])[CH3:26])(=[O:22])[NH2:23]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: CC(C)C[C@H](NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 6, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g) and (2S)-2-amino-4-methyl-pentanamide hydrochloride (1:1) (CAN 10466-61-2) as starting materials, and isolated (46 mg, 62%) as light yellow gum; LC-MS (UV peak area, ESI) 100%, 347.2081 (M+H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1.[C:23]([O:38][CH3:39])(=[O:37])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O-:36])=O>C(Cl)Cl>[C:23]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:36])([O:38][CH3:39])=[O:37]
Reactant: CNc1ccccc1OCc1ccccc1
Reactant: COC(=O)CCCCCCCCCCC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CCCCCCCCCCC(=O)N(C)c1ccccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a stirred ice-cold solution of (27) (0.21 g., 1.0 mM) in dried methylene chloride (10 mL) containing anhydrous pyridine (0.3 mL) is added (7) (0.27 g., 1.03 mM), dissolved in 5 methylene chloride (5 mL), dropwise over 1 minute (some methylene chloride used as a rinse). After stirring cold for 30 minutes, the mixture is allowed to stir at ambient temperature for completion of the reaction. The reaction mixture is washed 1× with , 1N HCL, dried (Na2SO4) and filtered. Flash chromatography (silica gel, 20% ethyl acetate/hexane as eluant) of the residue obtained gives the title compound (28) (0.33 g) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([CH:7]1[CH2:16][CH2:15][C:14]2[CH:13]=[N:12][C:11]([Cl:17])=[CH:10][C:9]=2[C:8]1=O)=O)[CH3:2].[NH2:20][NH2:21].O>CCO>[CH2:1]([O:3][C:4]([C:5]1[NH:20][N:21]=[C:8]2[C:9]3[C:14](=[CH:13][N:12]=[C:11]([Cl:17])[CH:10]=3)[CH2:15][CH2:16][C:7]=12)=[O:19])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(=O)C1CCc2cnc(Cl)cc2C1=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1[nH]nc2c1CCc1cnc(Cl)cc1-2

Procedure:
(3-Chloro-5-oxo-5,6,7,8-tetrahydro-isoquinolin-6-yl)-oxo-acetic acid ethyl ester (1.4 g; 4.8 mmol) in EtOH (15 ml) is combined with H2NNH2.H2O (242 mg; 4.8 mmol) and refluxed for 1 hour. The mixture is left over night at room temperature and delivers the title compound as yellowish crystals. 1H-NMR (400 MHz; DMSO-d6): 8.37 (s, 1H); 7.68 (s, 1H); 4.36 (q, 2H); 3.5 (bs, 1H); 2.99 (m, 2H); 2.97 (m, 2H); 1.35 (t, 3H). MS (m/z) ES+: 278 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([C@@H:19]([NH:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=1)[CH3:20])=[CH:7]2.O.[OH-].[NH4+:31]>O1CCOCC1.[Cl-].[Na+].O>[NH2:31][C:26]1[N:25]=[CH:24][N:23]=[C:22]([NH:21][C@H:19]([C:8]2[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10](=[O:12])[C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[Cl:1])[CH3:20])[CH:27]=1
Reactant: C[C@H](Nc1cc(Cl)ncn1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1cc(N)ncn1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A heavy-wall glass tube with stir bar and FEP-encapsulated-silicone o-ring seal was charged with 77 (ca. 300 mg, 0.73 mmol) in 1,4-dioxane (12 mL) and concentrated ammonium hydroxide solution (10 mL), then sealed tightly and heated at 120° C. After 16 h, more ammonium hydroxide (6 mL) was added and heating continued at 150° C. during 6 h, then 160° C. during 24 h. A third portion of ammonium hydroxide (8 mL) was added and heating continued at 150° C. during 3 days. The reaction mixture was poured into a mixture of water and brine (35 mL each), stirred about 1 h at 0° C., and the resulting precipitate collected by filtration and washed with ice-water. This material was dried in vacuo to give (S)-3-(1-(6-aminopyrimidin-4-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one 78. ESI-MS m/z: 392.15 [M+H]+.
Reaction SMILES: C(O)CC.Cl[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>O>[N:18]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: N#Cc1ccc(OCCCCl)cc1
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CCCO
Product: N#Cc1ccc(OCCCn2ccnc2)cc1
Yield: 82.3 %

Procedure:
To 30 ml of n-propanol, there were added 2.695 g of 4-(3-chloropropoxy)benzonitrile and 10.21 g of imidazole and the resulting mixture was heated under reflux for 24 hours. After concentration of the reaction mixture, water was added to the residue obtained, followed by extraction with chloroform, washing of the resulting extract with water and then drying the same. After concentration of the extract, the residue obtained was recrystallized from a mixture of ether and n-hexane, followed by addition of n-hexane, filtration and drying to give 2.575 g (yield 75.3%) of 4-[3-(1H-imidazolyl)propoxy]benzonitrile having a melting point of 60.0°-61.5° C.
Reaction SMILES: [B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.[OH:21][CH:22]([C:24]1[CH:25]=[C:26]([C:41]([OH:43])=O)[CH:27]=[C:28]2[C:33]=1[O:32][C:31]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[CH:30][C:29]2=[O:40])[CH3:23].CCN(C(C)C)C(C)C.[CH3:53][N:54]([CH3:58])[CH2:55][CH2:56][NH2:57]>C(Cl)Cl>[CH3:53][N:54]([CH3:58])[CH2:55][CH2:56][NH:57][C:41]([C:26]1[CH:27]=[C:28]2[C:33](=[C:24]([CH:22]([OH:21])[CH3:23])[CH:25]=1)[O:32][C:31]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[CH:30][C:29]2=[O:40])=[O:43]
Reactant: CC(O)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: CN(C)CCN
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(O)c1cc(C(=O)NCCN(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.3 %

Procedure:
TSTU (104 mg, 0.34 mmol) at 25° C., was added portionwise to 8-(1-hydroxyethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (110 mg, 0.34 mmol) and DIPEA (0.066 mL, 0.38 mmol) suspended in DCM (1 mL) under nitrogen. The resulting mixture was stirred at 25° C. for 1.5 hrs. N1,N1-dimethylethane-1,2-diamine (0.038 mL, 0.34 mmol) was then added and the mixture stirred at 25° C. for 30 minutes. The mixture was poured onto a silica gel column and purified by flash chromatography eluting with 5% methanolic ammonia (7 N) in DCM. The solvent was evaporated to dryness, the residue was triturated in diethyl ether, collected by filtration and dried to afford N-(2-(dimethylamino)ethyl)-8-(1-hydroxyethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide (80 mg, 0.205 mmol, 59.6%) as a off-white solid. Mass Spectrum: M+H+ 390.
Reaction SMILES: [CH3:1][CH:2]1[CH:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:4][N:3]1[C:17](Cl)=[O:18].[OH-].[NH4+:21]>O1CCCC1.O>[CH3:1][C@H:2]1[C@@H:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:4][N:3]1[C:17]([NH2:21])=[O:18]
Reactant: CC1C(Oc2cccc(C(F)(F)F)c2)CN1C(=O)Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](Oc2cccc(C(F)(F)F)c2)CN1C(N)=O
Reaction time: 6 h
Yield: 87 %

Procedure:
A solution of 4.02 g (0.01 mole) of crude (73%) 2-methyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride cis isomer in 20 ml of tetrahydrofuran was treated while stirring with 2 ml (0.02 mole) of 57% aqueous ammonium hydroxide. After stirring for 6 hr, the reaction mixture was diluted with 100 ml of water and the oil which separated was extracted into methylene chloride (2×50 ml). The combined extracts were dried over magnesium sulfate and concentrated in vacuo to give 4.2 g. A sample of the oil crystallized at -78° C. and was used to seed the bulk of the material. The resulting solid was recrystallized from benzene/isooctane to yield 2.35 g (87%) of white crystalline product, m.p. 107°-108° C.
Reaction SMILES: Cl.CN.[CH2:4]([N:6](CC)CC)C.Br[C:12]1[N:16]([C@H:17]2[O:29][C@@H:28]([CH2:30][O:31]C(=O)C)[C@H:23]([O:24]C(=O)C)[C@@H:18]2[O:19]C(=O)C)[C:15]2[CH:35]=[C:36]([Cl:40])[C:37]([Cl:39])=[CH:38][C:14]=2[N:13]=1.C(O)C>CN(C=O)C>[Cl:39][C:37]1[C:36]([Cl:40])=[CH:35][C:15]2[N:16]([C@H:17]3[O:29][C@@H:28]([CH2:30][OH:31])[C@H:23]([OH:24])[C@@H:18]3[OH:19])[C:12]([NH:6][CH3:4])=[N:13][C:14]=2[CH:38]=1
Reactant: CCN(CC)CC
Reactant: CC(=O)OC[C@@H]1O[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CN
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: CNc1nc2cc(Cl)c(Cl)cc2n1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Methylamine hydrochloride (3.0 g, 45 mmol), triethylamine (3 mL), and 2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (0.6 g, 1.1 mmol) were combined with absolute ethanol (25 mL) and stirred at 80° C. for 24 h. The reaction mixture was separated between saturated sodium bicarbonate (50 mL) and ethyl acetate (150 mL). The organic layer was dried with sodium sulfate, concentrated and absorbed onto silica gel (15 g). This material was dry loaded onto a silica gel column (5 cm×10 cm, 230-400 mesh) with 1:10 methanol:dichloromethane. The main product came off the column as a white solid (0.22 g, 0.62 mmol, 54%) m.p. 238-240° C.; [a]20D=(−) 15.2 (c=0.5 DMF).
Reaction SMILES: C(OC(=O)C1C=CC(S)=CC=1)C.[H-].[Na+].CS(OCC[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][C:23]=1[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)(=O)=O.CCOCC>CN(C)C=O>[N:33]1[CH:34]=[CH:35][CH:36]=[C:31]([C:23]2[NH:24][C:25]3[C:30]([CH:22]=2)=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:32]=1
Reactant: CS(=O)(=O)OCCc1c(-c2cccnc2)[nH]c2ccccc12
Agent: CCOC(=O)c1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: c1cncc(-c2cc3ccccc3[nH]2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5.9 g of p-mercaptobenzoic acid ethyl ester (prepared according to the procedure found in J. Chem. Soc., 1963, 1947-1954) in 30 ml of dimethylformamide is added dropwise to a slurry of 1.55 g of 50% sodium hydride (dispersion in mineral oil) in 30 ml of dimethylformamide. This mixture is stirred at room temperature for 0.5 hour under nitrogen atmosphere, and added dropwise to a solution of 9.78 g of 3-(2-methylsulfonyloxyethyl)-2-(3-pyridyl)-indole in 60 ml of dimethylformamide at -10°. This mixture is stirred at room temperature overnight and poured into 1 liter of ice-water. This is extraced several times with ether. The ether extract is washed with water, dried over MgSO4 and evaporated in vacuo to give 3-[2-(4-ethoxycarbonylphenylthio)-ethyl]-2-(3-pyridyl-indole.
Reaction SMILES: [C:1]12([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]45[CH2:28][CH:23]6[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]6)[CH2:20]4)[CH2:26]5)[CH:15]=[C:14]([N:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(=O)([O-])[O-].[K+].[K+].BrC1C=CC(S(O[CH2:52][C:53](=[O:75])[C@@H:54]2[C@:71]3([CH3:72])[C@H:57]([C@H:58]4[C:68](=[CH:69][CH2:70]3)[C@:66]3([CH3:67])[C:61](=[CH:62][C:63](=[O:73])[CH:64]=[CH:65]3)[CH2:60][CH2:59]4)[CH2:56][C@H:55]2[CH3:74])(=O)=O)=CC=1>C(#N)C>[C:1]12([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]45[CH2:28][CH:23]6[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]6)[CH2:20]4)[CH2:26]5)[CH:15]=[C:14]([N:29]4[CH2:30][CH2:31][N:32]([CH2:52][C:53](=[O:75])[C@@H:54]5[C@:71]6([CH3:72])[C@H:57]([C@H:58]7[C:68](=[CH:69][CH2:70]6)[C@:66]6([CH3:67])[C:61](=[CH:62][C:63](=[O:73])[CH:64]=[CH:65]6)[CH2:60][CH2:59]7)[CH2:56][C@H:55]5[CH3:74])[CH2:33][CH2:34]4)[N:13]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)COS(=O)(=O)c1ccc(Br)cc1
Reactant: c1c(NC23CC4CC(CC(C4)C2)C3)nc(NC23CC4CC(CC(C4)C2)C3)nc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CN1CCN(c2cc(NC34CC5CC(CC(C5)C3)C4)nc(NC34CC5CC(CC(C5)C3)C4)n2)CC1
Temperature: 65 °C
Reaction time: 5 h

Procedure:
After adding 1.88 g (4.07 mmoles) of 2,4-bis(1-adamantylamino)-6-(1-piperazinyl)pyrimidine and 0.56 g of potassium carbonate to a solution containing 2.00 g (3.57 mmoles) of 21-(4-bromobenzenesulfonyloxy)-16α-methylpregna-1,4,9(11)-triene-3,20-dione in 100 ml of acetonitrile, the reaction mixture is stirred at a temperature of 65° C. for 5 hours, then evaporated. The residue is distributed between 40 ml of chloroform and 10 ml of water. After separation the chloroform layer is dried and evaporated. The residue is purified by chromatography on a silica gel column by using a 98:2 mixture of chloroform/methanol as eluent. After recrystallization from ether the title compound is obtained in a yield of 2.48 g (88.5%), m.p.:210°-220° C.
Reaction SMILES: C(N)C1C=CC=CC=1.O1CC1COC1C2C3C(=CC=CC=3)NC=2C=CC=1.[CH3:27][O:28][C:29]1[C:34]([O:35][CH2:36][CH2:37][N:38]([CH2:46][CH:47]([OH:63])[CH2:48][O:49][C:50]2[C:55]3[C:56]4[C:61]([NH:62][C:54]=3[CH:53]=[CH:52][CH:51]=2)=[CH:60][CH:59]=[CH:58][CH:57]=4)CC2C=CC=CC=2)=[CH:33][CH:32]=[CH:31][CH:30]=1>[Cl-].[Cl-].[Zn+2].C(OC(=O)C)C>[CH3:27][O:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=1[O:35][CH2:36][CH2:37][NH:38][CH2:46][CH:47]([OH:63])[CH2:48][O:49][C:50]1[CH:51]=[CH:52][CH:53]=[C:54]2[NH:62][C:61]3[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=3[C:55]=12
Reactant: COc1ccccc1OCCN(Cc1ccccc1)CC(O)COc1cccc2[nH]c3ccccc3c12
Agent: [Cl-]
Agent: [Zn+2]
Agent: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12
Solvent: NCc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To 400 ml ethylacetate, 70 g (0.27 moles) of anhydrous N-2-[2-(methoxy)-phenoxy]-ethyl]-benzylamine, 10.25 g (0.075 moles) of anhydrous ZnCl2 and 50 g (0.21 moles) of 4-(oxiranylmethoxy)-9H-carbazole are added and the reaction mixture is heated to 70-75° C. for 3 hrs (TLC control for checking conversion to N-benzylcarvedilol). The reaction mixture is cooled to ambient temperature and quenched into 100 ml of ˜12-15% aqueous ammonia. The aqueous layer separated, and the product enriched organic layer is washed with water till neutral pH. The organic layer is charcoalised, filtered. To this solution of N-benzyl carvedilol in ethylacetate, (7 g) of wet Pd/C catalyst (5% Pd content and 50% moisture content) is added. The reaction mixture is hydrogenated at 3.5-4.5 Kg/cm2 at temperature of 60-70° C. for a period of about 10 hours. The reaction mixture is filtered and filtrate concentrated to remove ethylacetate. To the resultant syrupy mass n-butanol (100 ml) is added and the solution is stirred for about 10 hours, the crystals separated by filtration, washed successively with n-butanol (50 ml) and toluene (50 ml) to obtain carvedilol (47 g). The product is recrystallized from 3 volumes of ethyl acetate to obtain carvedilol (42 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([OH:26])[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2].F[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([O:26][C:28]4[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=4)[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(O)ccc(F)c32)cc1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(Oc4ccc(C#N)cc4)ccc(F)c32)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 33.1 %

Procedure:
(1S,2S)-2-[4-((R)-7-Fluoro-4-hydroxy-indan-1-yloxy)-phenyl]-cyclopropanecarboxylic acid ethyl ester (Intermediate 5, 146 mg, 0.41 mmol), 4-fluorobenzonitrile (55 mg, 0.45 mmol), and cesium carbonate (145 mg, 0.45 mmol) are suspended in dry dimethylformamide (10 mL) and stirred for 3 hours at 100° C. followed by room temperature overnight. The mixture is diluted with water and extracted with ethyl acetate. The organic extract is dried over sodium sulfate, filtered and the solvent removed. The residue is purified by flash chromatography (10% ethyl acetate in cyclohexane) to give the title compound (Yield 62 mg). LC (METHOD 5): tR=1.54 min; Mass spectrum (ES+): m/z=458 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[S:4]([C:7]1[C:8]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][CH:10]=[CH:11][CH:12]=1)(=[O:6])=[O:5])[CH3:2].C(N=[C:24]=[O:25])CCC.C(Cl)(Cl)=O>>[CH2:17]([N:3]([CH2:1][CH3:2])[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([N:16]=[C:24]=[O:25])(=[O:14])=[O:15])(=[O:6])=[O:5])[CH3:18]
Reactant: CCCCN=C=O
Reactant: CCN(CC)S(=O)(=O)c1ccccc1S(N)(=O)=O
Agent: O=C(Cl)Cl
Product: CCN(CC)S(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Reaction time: 0.5 h

Procedure:
A solution of 13.2 g of N,N-diethyl-1,2-benzenedisulfonamide, 4.5 g of n-butylisocyanate, and 0.2 g of 1,4-diaza[2,2,2]bicyclooctane (DABCO) in 90 ml of mixed xylenes was heated to 135°. To this solution was added 3.3 ml of liquid phosgene at such a rate that the temperature was maintained between 125° and 135° (about 2 hours). The temperature was kept at 130° for 1/2 hour after the addition. The solution was cooled and filtered to remove a small amount of insoluble solid then concentrated at 60°-70° in-vacuo. The residue of o-N,N-diethylsulfamoylbenzenesulfonyl isocyanate was an oil weighing 16.8 g and was sufficiently pure for further reaction.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:19])[NH:6][N:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH2:16][CH2:15][C:14]=3[CH:18]=2)[CH:9]=1)([OH:3])=[O:2].S(Cl)(Cl)=O.[CH3:24]O>>[O:17]1[C:13]2[CH:12]=[CH:11][C:10]([C:8]3[CH:9]=[C:4]([C:1]([O:3][CH3:24])=[O:2])[C:5](=[O:19])[NH:6][N:7]=3)=[CH:18][C:14]=2[CH2:15][CH2:16]1
Reactant: CO
Reactant: O=C(O)c1cc(-c2ccc3c(c2)CCO3)n[nH]c1=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(-c2ccc3c(c2)CCO3)n[nH]c1=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
4-Carboxy-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one (5.9 g, 22.8 mmol) was suspended in methanol (100 mL), and thionyl chloride (3 g, 25.1 mmol) was added dropwise to the suspension under cooling with ice, followed by stirring for three hours at 80° C. The temperature of the reaction mixture was reduced to room temperature, and the solvent was removed under reduced pressure. Water was added to the residue under cooling on ice, and the formed precipitates were collected through filtration and washed with water, followed by drying, to thereby yield 4.90 g of the title compound as pale yellow micro-needles (78.8%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:9]=1[NH:10][CH:11]1[CH2:13][CH2:12]1)=[O:4].N#N.[Cl:22][C:23]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>ClC(Cl)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:9]=1[N:10]([CH:11]1[CH2:13][CH2:12]1)[C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:23]=1[Cl:22])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC1CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: N#N
Solvent: CC(Cl)Cl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)C1CC1
Reaction time: 16 h
Yield: 100.2 %

Procedure:
To a solution of 3-Cyclopropylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester (52 mg, 0.19 mmol) in dichloroethane (10 ml) in an atmosphere of N2 was added 2,4-dichlorobenzoyl chloride (45 mg, 0.21 mmol). The reaction mixture was stirred for 16 h at reflux. Then, the solvant was removed and the residue was purified by flash chromatography (8:2 Hexane/EtOAc) to obtain 85 mg (99%) of 3-[Cyclopropyl-(2,4-dichloro-benzoyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): 7.64 ppm (d, 2H, Haro); 7.47 ppm (m, 2H, Haro); 7.44-7.33 ppm (m, 3H, Haro); 7.21-7.12 ppm (m, 2H, Haro); 3.89 ppm (s, 3H); 3.33 ppm (m, minor rotamer); 3.13 ppm (m, 1H, major rotamer) 1.01-0.49 ppm (m, 4H).