Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][C:12]1[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][C:13]=1[NH:20][CH2:21][CH3:22])=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:24][C:25](OCC)=[O:26].C1CCN2C(=NCCC2)CC1>C(O)C>[CH2:1]([N:8]1[C:25](=[O:26])[CH2:24][S:10][C:9]1=[N:11][C:12]1[CH:17]=[C:16]([CH:15]=[CH:14][C:13]=1[NH:20][CH2:21][CH3:22])[C:18]#[N:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNc1ccc(C#N)cc1NC(=S)NCc1ccccc1
Reactant: CCOC(=O)CCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCNc1ccc(C#N)cc1N=C1SCC(=O)N1Cc1ccccc1
Temperature: 80 °C
Yield: 87.4 %

Procedure:
To a solution of 1-benzyl-3-(5-cyano-2-ethylaminophenyl)thiourea (1.0 g, 3.2 mmol) in ethanol (40 mL, anhyd) was added ethyl chloroacetate (0.39 g, 3.2 mmol) and then DBU (0.58 g, 3.8 mmol). The reaction mixture was heated at 80° C. with stirring. After 1 h the reaction mixture was cooled, concentrated under reduced pressure, and chromatographed (silica gel, 1:1 EtOAc/Hex) to afford the title product (0.98 g, 87%). 1H-NMR (CDCl3): δ 7.38 (6H, m), 7.11 (1H, d), 6.50 (1H, d), 5.05 (2H, s), 3.96 (2H, s), 3.01 (2K, m), 1.03 (3H, t).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][CH:9]=[CH:10][C:5]2=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:3]=1[CH2:18][C:19]([O:21][CH3:22])=[O:20].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:33]1[CH2:37]OC[CH2:34]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][CH:9]=[CH:10][C:5]2=[C:4]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[C:3]=1[CH:18]([CH2:34][CH2:33][CH3:37])[C:19]([O:21][CH3:22])=[O:20]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sccc2c1-c1ccc(C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sccc2c1-c1ccc(C)cc1
Yield: 58.8 %

Procedure:
This compound was prepared according to the procedure C from methyl 2-(6-methyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate (0.078 g; 0.250 mmol), LHMDS 1N in THF (0.276 mL; 0.276 mmol), 1-iodopropane (0.041 mL; 0.420 mmol) in DMF (3.6 mL) for 4 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-15%) in heptane furnished 0.052 g (59%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(=[CH:29][C:30]([O:32][CH3:33])=[O:31])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:33][O:32][C:30](=[O:31])/[CH:29]=[CH:8]/[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/Cc1ccccc1
Yield: 80.5 %

Procedure:
To a solution of phenyl acetaldehyde (5.0 g, 41.61 mmol) in toluene (500 mL) was added methyl (triphenylphosphoranylidene)acetate (13.9 g, 41.61 mmol). The reaction mixture was stirred at reflux for 3 h. The resulting mixture was diluted with EtOAc, washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was added ether/hexane (=1:1, v/v) at 0° C. then stirred for 30 min. The filtrate was concentrated then purified by a silica gel column to produce the title compound (5.9 g, 70˜90%)
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[Cl:18][S:19]([OH:22])(=O)=[O:20]>>[NH2:1][C:2]1[CH:3]=[C:4]([S:19]([Cl:18])(=[O:22])=[O:20])[C:5]2[CH:6]=[CH:7][C:8]3[C:17]4[C:16]=2[C:15]=1[CH:14]=[CH:13][C:12]=4[C:11]([S:19]([Cl:18])(=[O:22])=[O:20])=[CH:10][C:9]=3[S:19]([Cl:18])(=[O:22])=[O:20]
Reactant: O=S(=O)(O)Cl
Reactant: Nc1ccc2ccc3cccc4ccc1c2c34
Product: Nc1cc(S(=O)(=O)Cl)c2ccc3c(S(=O)(=O)Cl)cc(S(=O)(=O)Cl)c4ccc1c2c43
Temperature: 0 °C
Yield: 69 %

Procedure:
Dyes 2a, 2d and 3 were obtained from Eastman, and the following dyes were prepared as described previously: 2c (8); 2g (9). The syntheses of 2e, 2f, 2h, 2I and 2j were modeled after the sulfonation procedures described in (10). Thus, for 2f, a solution of finely powdered 1-aminopyrene (869 mg, 4 mmol) in 10 ml chlorosulfonic acid was stirred under argon atmosphere for 10 hours at room temperature. The solution was poured on 30 g of crushed ice and the crude product was collected by filtration, washed with 20 mL cold water and dried under argon to give 1.4 g of 8-amino-1,3,6-pyrenetrisulfonylchloride (69%). Hydrolysis of this chloride in basic water (NaOH, pH 8) gave a solution of 2f (8-amino-1,3,6-pyrenetrisulfonate). Analogous procedures were used to prepare 2g-2j, except replacing the 1-aminopyrene with the appropriate substituted pyrene starting material.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH:10]=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC=O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 95.1 %

Procedure:
A mixture of (3-hydroxy-propyl)-carbamic acid tert-butyl ester (3.0 g, 0.017 mol), N,N-diisopropylethylamine (7.31 mL, 0.042 mol), and dimethyl sulfoxide (1.84 mL, 0.026 mol) in dichloromethane (100 mL) was cooled to 0° C. and flushed with nitrogen. Sulfur trioxide-pyridine complex (6.68 g, 0.042 mol) was added under a stream of nitrogen and the reaction mixture was stirred for 2.5 h. The reaction mixture was quenched using 0.1 N HCl. The aqueous layer was discarded. The organic extract was washed with additional 0.1N HCl (2×) and brine(2×), dried with Na2SO4, filtered, and concentrated to dryness to provide the title compound (2.8 g) as a clear oil which was used without further purification. 1H NMR (DMSO, 400 mHz) δ (ppm): 9.57 (s, 1H), 6.81 (bs, 1H), 3.19-3.14 (m, 2H), 2.49-2.44 (m, 2H), 1.3 (s, 9H).
Reaction SMILES: C(O[C:4]1[C:11](C)=[CH:10][C:7]([CH:8]=O)=[C:6]([OH:13])[CH:5]=1)C.[C:14]([O-:17])(=[O:16])C.[Na+].C(O)(=O)C.[N+:23](CC)([O-])=O>>[OH:13][C:6]1[CH:5]=[CH:4][C:11]([O:16][CH2:14][OH:17])=[CH:10][C:7]=1[C:8]#[N:23]
Reactant: CC[N+](=O)[O-]
Reactant: CCOc1cc(O)c(C=O)cc1C
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1cc(OCO)ccc1O
Temperature: 115 °C
Yield: 60.1 %

Procedure:
A mixture of 4-ethoxy-2-hydroxy-5-methyl-benzaldehyde (2.4 g, 14.6 mmol), sodium acetate (2.40 g, 29.25 mmol, 2.0 eq), acetic acid (3.4 g, 57.1 mmol, 3.9 eq), and nitroethane (2.2 g, 29.25 mmol, 2.0 eq) was heated in a sealed tube at 115° C. for 18 h. The black reaction mixture was poured into 40 g of ice and extracted 5 times with diethyl ether (100 mL). The organic layers were combined, washed 3 times with sat. sodium bicarbonate solution (25 mL), one time with brine, dried with sodium sulfate an finally concentrated in vacuo to give a black colored oil. Purification by MPLC chromatography (Biotage) using a hexane-ethyl acetate gradient gave 1.45 g (61%) of 2-hydroxy-5-hydroxymethoxy-benzonitrile as an orange solid. 1H-NMR (DMSO-d6) δ 10.69 (s, 1H), 7.04 (s, 1H), 6.51 (1, 2H), 6.01 (s, 2 H); TLC Rf=0.73, 50% ethyl acetate-hexanes.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].C(N(CC)CC)C.[N+:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20])([O-:15])=[O:14]>ClCCl>[CH3:1][S:2]([NH:5][C:19]([C:18]1[CH:22]=[CH:23][CH:24]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=1)=[O:20])(=[O:4])=[O:3]
Reactant: CS(N)(=O)=O
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 32.6 %

Procedure:
A solution of methylsulphonamide (5.37 g, 57 mmol) in anhydrous dichloromethane (100 ml), cooled to 0° C. was treated with triethylamine (7.9 ml, 57 mmol) followed by a solution of 3-nitrobenzoyl chloride (10 g, 54 mmol) in anhydrous dichloromethane (100 ml) dropwise. After stirring for 2 h at 0° C., the reaction mixture was washed with 1M HCl (100 ml). The precipitate which formed was collected by filtration and triturated with diethyl ether and was then recrystallised from methanol to afford the title compound (4.3 g, 31%) as a colourless crystalline solid. mp 175°-178° C. 1H NMR (360 MHz, D6 -DMSO) δ 3.42 (3H, s), 7.82 (1H, dd, J=8.0 and 8.0 Hz), 8.38 (1H, d, J=8.0 Hz), 8.49 (1H, d, J=8.0 Hz), 8.80 (1 H,s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1.O=[C:19]([CH2:26][CH2:27][CH3:28])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH3:1][O:2][C:3]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([CH2:26][CH2:27][CH3:28])[NH:12][C:13]2=[N:14][NH:15][CH:16]=[C:17]12
Reactant: Nc1cc[nH]n1
Reactant: COc1c(C)cccc1C=O
Reactant: CCCC(=O)CC(=O)OCC
Product: CCCC1=C(C(=O)OCC)C(c2cccc(C)c2OC)c2c[nH]nc2N1

Procedure:
A suspension of 2,6-dimethylphenol (19.5 g), iodomethane (31 ml) and potassium carbonate (33.2 g) in dimethylformamide (200 ml) was stirred at 60° C. for 10 hours. The reaction mixture was poured into water (300 ml) and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:hexane) to give 2-methoxy-m-xylene (12 g) as a colorless oil. A suspension of 2-methoxy-m-xylene (5.1 g), N-bromosuccinimide (4.2 g) and bezoyl peroxide (229 mg) in carbon tetrachloride (50 ml) was heated under reflux for 3 hours. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give a yellow solid (5.4 g). The obtained yellow solid (5.4 g) and hexamethylenetetramine (5.1 g) were dissolved in acetic acid-water (1:1, 16 ml) and the mixture was heated under reflux for 2 hours. To the reaction mixture was added concentrated hydrochloric acid (6 ml) and the mixture was heated under reflux for 15 minutes. The reaction mixture was extracted with ethyl acetate. The extract was washed with water, an aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (5:1)) and crystallized (hexane-ethyl acetate (5:1)) to give 2-methoxy-3-methylbenzaldehyde (1.2 g) as yellow crystals. Subsequently, the title compound was prepared from 2-methoxy-3-methylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]1[C:17]([OH:19])=O)=[O:7])(C)(C)C.[N:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1)=C=O.[CH2:30]([N:32]1[C:44]2[CH:43]=[CH:42][C:41]([NH2:45])=[CH:40][C:39]=2[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH3:31]>>[CH2:15]([O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6]([NH:20][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=2)=[O:7])[C@H:9]([C:17]([NH:45][C:41]2[CH:42]=[CH:43][C:44]3[N:32]([CH2:30][CH3:31])[C:33]4[C:38]([C:39]=3[CH:40]=2)=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:19])[CH2:10]1)[CH3:16]
Reactant: Cc1cccc(N=C=O)c1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CCON=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(=O)Nc2cccc(C)c2)C1

Procedure:
Following the general method as outlined in Example 22, staring from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylic acid, 1-isocyanato-3-methylben-zene, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 80% purity by LC/MS. MS(ESI+): m/z=498.4.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([OH:21])[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:26][CH:25]([NH:27][C:28]([CH2:30][NH:31][C:32](=[O:43])[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=2)=[O:29])[CH2:24]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([OH:21])[CH2:19][CH2:18][CH:17]([N:23]3[CH2:26][CH:25]([NH:27][C:28](=[O:29])[CH2:30][NH:31][C:32](=[O:43])[C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:41])([F:42])[F:40])[CH:34]=4)[CH2:24]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2(O)CCC(=O)CC2)cc1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: CC(C)(C)OC(=O)Nc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
The title compound was prepared as a white solid by reductive amination of [4-(1-hydroxy-4-oxo-cyclohexyl)-phenyl]-carbamic acid tert-butyl ester (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6](C3OC(C)(C)C(C)(C)O3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[F:19][C:20]1[CH:21]=[C:22]([CH:32]([NH:34][C:35]([C:37]2[O:38][C:39](Br)=[CH:40][CH:41]=2)=[O:36])[CH3:33])[CH:23]=[C:24]([F:31])[C:25]=1[NH:26][S:27]([CH3:30])(=[O:29])=[O:28].C([O-])([O-])=O.[Cs+].[Cs+]>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:19][C:20]1[CH:21]=[C:22]([CH:32]([NH:34][C:35]([C:37]2[O:38][C:39]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[CH:9]=3)=[CH:40][CH:41]=2)=[O:36])[CH3:33])[CH:23]=[C:24]([F:31])[C:25]=1[NH:26][S:27]([CH3:30])(=[O:29])=[O:28]
Reactant: CC(NC(=O)c1ccc(Br)o1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CC1(C)OC(c2cccc(C3CC3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1ccc(-c2cccc(C3CC3)c2)o1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 45.1 %

Procedure:
2-(3-Cyclopropyl-phenyl)-4,4,5,5-tetramethyl-[1,3]dioxolane (126 mg, 0.52 mmol) and 5-bromo-furan-2-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (110 mg, 0.26 mmol) was reacted using Pd(PPh3)2Cl2 (14 mg, 0.02 mmol), Cs2CO3 (254 mg, 0.78 mmol) as described above to give the title compound (54 mg, 56%) after purification by recrystallization from n-Hex/EtOAc.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.Cl[C:16]1[NH:20][C:19]2[CH:21]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:24]([Cl:25])[C:18]=2[N:17]=1.C(N(CC)C(C)C)(C)C>>[Cl:25][C:24]1[C:18]2[N:17]=[C:16]([N:12]3[CH2:11][CH2:10][N:9]([C:4]4[C:3]([Cl:2])=[CH:8][CH:7]=[CH:6][N:5]=4)[CH2:14][CH2:13]3)[NH:20][C:19]=2[CH:21]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:23]=1
Reactant: FC(F)(F)c1cc(Cl)c2nc(Cl)[nH]c2c1
Reactant: Clc1cccnc1N1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1cc(Cl)c2nc(N3CCN(c4ncccc4Cl)CC3)[nH]c2c1

Procedure:
The reaction of 1-(3-chloropyridin-2-yl)piperazine hydrochloride (99 mg, 0.5 mmol, Example 3b) and 2,4-dichloro-6-trifluoromethyl-1H-benzoimidazole (76 mg, 0.3 mmol, Example 5b) and N,N-diisopropylethylamine (0.17 mL, 1 mmol, Aldrich) under the conditions of Example 3c afforded the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 416 (M+1).
Reaction SMILES: Cl.[CH:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[C:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24][NH2:25])[CH2:19][CH2:18]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>ClCCl>[CH:13]1[C:9]2[CH:10]=[CH:11][C:12]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=3[C:7](=[C:17]3[CH2:18][CH2:19][N:20]([C:23](=[O:26])[CH2:24][NH:25][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:21][CH2:22]3)[C:8]=2[CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reaction time: 0.5 h

Procedure:
100 mg (0.271 mmol) of 2-[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-2-oxoethanamine hydrochloride was dissolved in 1 ml of dichloromethane. 82.3 mg (0.813 mmol) of triethylamine was added to the obtained solution. A solution of 39.2 mg (0.325 mmol) of pivaloyl chloride in 0.5 ml of dichloromethane was slowly added to the obtained mixture. After stirring for 30 minutes, the obtained product was purified by the silica gel chromatography (hexane:ethyl acetate=9:1 to 3:1).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[CH:15][N:16]=[CH:17][CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[C:27](B(O)O)=[C:28]2[CH2:33][CH2:32][CH2:31][N:29]2[N:30]=1>>[C:1]1([S:7]([N:10]2[C:14]3=[CH:15][N:16]=[CH:17][CH:18]=[C:13]3[C:12]([C:27]3[C:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=4)=[N:30][N:29]4[CH2:31][CH2:32][CH2:33][C:28]=34)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1c(-c2ccccn2)nn2c1CCC2
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2ccncc21
Product: O=S(=O)(c1ccccc1)n1cc(-c2c(-c3ccccn3)nn3c2CCC3)c2ccncc21

Procedure:
Using Preparation 3A, 1-benzenesulfonyl-3-iodo-1H-pyrrolo[2,3-c]pyridine (Preparation 8) is reacted with 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (Preparation 2) to provide the titled product. MS (ES) m/z=442 (M+H).
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]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][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]=[C:45]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:46]=[CH:47][CH:48]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(O)C.O>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:14]2[CH:15]=[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:43]5[CH:44]=[C:45]([NH:49][S:50]([CH3:53])(=[O:51])=[O:52])[CH:46]=[CH:47][CH:48]=5)[CH:3]=4)[N:8]([S:25]([C:28]4[CH:29]=[CH:30][C:31]([CH3:32])=[CH:33][CH:34]=4)(=[O:27])=[O:26])[CH:9]=3)[CH:12]=[N:13]2)=[CH:22][CH:21]=1
Reactant: COc1ccc(Cn2cc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Br)cc34)cn2)cc1
Reactant: CC1(C)OB(c2cccc(NS(C)(=O)=O)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2cc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(-c5cccc(NS(C)(=O)=O)c5)cc34)cn2)cc1
Yield: 90.5 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (240 mg, 0.44 mmol) was coupled with N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) methane sulfonamide (intermediate 3) (160 mg, 0.53 mmol) in sodium carbonate (142 mg, 1.34 mmol), bis(triphenyl phosphine)palladium(ii) dichloride (16 mg, 0.022 mmol) and toluene/ethanol/water (7/7/4 ml) to afford 250 mg (89.28% yield) of the pure product after column purification using 35% ethyl acetate in hexane as eluent. MS: m/z=628.3 (M+1).
Reaction SMILES: Cl.Cl.[C:3]1([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@@H:12]3[CH2:19][NH:20][CH2:21][CH2:22][N:11]3[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].Cl>C(Cl)(Cl)Cl.O1CCCC1>[C:30]([N:20]1[CH2:21][CH2:22][N:11]2[CH2:10][C@@H:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:18]3[C:13]([C@@H:12]2[CH2:19]1)=[CH:14][CH:15]=[CH:16][CH:17]=3)(=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCC(=O)Cl
Reactant: c1ccc([C@@H]2CN3CCNC[C@H]3c3ccccc32)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCC(=O)N1CCN2C[C@@H](c3ccccc3)c3ccccc3[C@@H]2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
To a stirred solution of cis-1,3,4,6,7,11b-hexahydro-7-phenyl-2H-pyrazino[2,1-a]isoquinoline dihydrochloride (7.8 g, 0.023 m) and triethylamine (9.4 g, 0.093 m) in chloroform (100 ml) maintained at 0° under nitrogen was added dropwise hexanoyl chloride (4.79 g, 0.0356 m). The mixture was allowed to warm to ambient temperature and stirred for 3 hours, then treated with 10% HCl (25 ml). The layers were separated and the organic phase washed with 10% HCl (2×25 ml), water and dried over MgSO4. Evaporation of the solvent gave an oily residue which was dissolved in tetrahydrofuran and a white solid crystallized which was collected by filtration to give 6.4 g of cis-1,3,4,6,7,11b-hexahydro-2-hexanoyl-7-phenyl-2H-pyrazino[2,1-a]isoquinoline, m.p. 163°-164.5°. An additional 3.1 g of good purity product was recovered from the tetrahydrofuran to give a total of 9.5 g.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:29]([O:12][C:11](=[O:13])[C@H:10]([CH3:14])[CH2:9][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:6][CH:5]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid (prepared using the procedure described in WO 2008083967) (1.0 g, 2.61 mmol) and benzyl bromide (468 mg, 2.74 mmol) in DMF (15 mL) is added potassium carbonate (541 mg, 3.91 mmol) and the mixture is stirred at room temperature for 2 hours. Water is added and the mixture is extracted with ethyl acetate. The combined organic layers are washed with water and dried over magnesium sulfate. The solvent is removed under reduced pressure and the residual oil is purified by column chromatography using heptane/EtOAc (4:1) to furnish (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid benzyl ester.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([S:19]([O-:22])(=O)=[O:20])=[C:10]2[O:15][C:16](=[O:18])[CH3:17])(=[O:3])[CH3:2].[Na+].P(Cl)(Cl)([Cl:26])=O.CNC=O>>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([S:19]([Cl:26])(=[O:22])=[O:20])=[C:10]2[O:15][C:16](=[O:18])[CH3:17])(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Nc1cccc2c(OC(C)=O)c(S(=O)(=O)[O-])ccc12
Agent: [Na+]
Solvent: CNC=O
Product: CC(=O)Nc1cccc2c(OC(C)=O)c(S(=O)(=O)Cl)ccc12
Reaction time: 1 h

Procedure:
The 5-acetamido-1-acetoxynaphthalene-2-sulfonyl chloride was prepared by dropwise treatment of a suspension of dry sodium 5-acetamido-1-acetoxynaphthalene-2-sulfonate in 100 ml. phosphoryl chloride with 5.5 ml. dry methylformamide in a nitrogen atmosphere. The reaction mixture was stirred 1 hour and then poured over 600 ml. of crushed ice. The crude product was filtered and dissolved immediately in 500 ml. chloroform. The solution was treated with activated charcoal and dried over anhydrous magnesium sulfate to give 10.8 g. (44%) of a resinous yellow product which showed a single spot on a thin-layer chromotography.