Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][O:9][N:10]=[C:11]([C:18]2[N:22]([CH3:23])[N:21]=[N:20][N:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:4][CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[CH3:23][N:22]1[C:18]([C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][O:9][CH2:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:7]=2)=[N:19][N:20]=[N:21]1
Reactant: OB(O)c1ccccc1
Reactant: Cn1nnnc1C(=NOCc1cccc(Br)n1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cn1nnnc1C(=NOCc1cccc(-c2ccccc2)n1)c1ccccc1
Temperature: 90 °C
Yield: 96.7 %

Procedure:
In a dried and purged vessel were added N-[(6-bromopyridin-2-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.2 g, 0.536 mmol, 1 eq.), phenylboronic acid (0.072 g, 0.58 mmol, 1.1 eq.), Na2CO3 (0.119 g, 1.12 mmol, 2.1 eq.) and Tetrakis(triphenylphosphine)palladium (0.030 g, 0.027 mmol, 0.05 eq.). A mixture of solvent was added toluene/ethanol/water (4/1/1) was added and the vessel purged with argon and sealed. The reaction was heated to 90° C. for 6 hrs. After cooling, 10 ml of EtOAc were added and the solids were filtered through a “Celite” plug and washed with EtOAc. The organics were separated, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel to give 1-(1-methyl-1H-tetrazol-5-yl)-1-phenyl-N-[(6-phenylpyridin-2-yl)methoxy]methanimine (0.192 g, 91% yield) as a colorless gum.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.C1([Li])C=CC=CC=1.[CH3:17][N:18]=[C:19]=[S:20].Cl>C1C=CC=CC=1.CCOCC.O.C1C=CC=CC=1>[CH3:1][O:2][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[C:19]([NH:18][CH3:17])=[S:20]
Reactant: CN=C=S
Reactant: COCc1ccccn1
Agent: Cl
Agent: [Li]c1ccccc1
Solvent: O
Solvent: c1ccccc1
Solvent: CCOCC
Product: CNC(=S)C(OC)c1ccccn1
Reaction time: 0.5 h

Procedure:
2-(Methoxymethyl)pyridine (4.4 g., 0.036 mole), dissolved in 25 ml. of dry benzene, is added dropwise to 20 ml. of 2M phenyl lithium (0.04 mole) in benzene/ether with cooling. The mixture is stirred for 30 minutes, then methyl isothiocyanate (2.6 g., 0.03 mole), dissolved in 40 ml. of dry benzene, is added dropwise with cooling. The resulting solution is stirred overnight. An equal volume of water is added and the solution is cooled and made acidic with 10% hydrochloric acid. The phases are separated, the organic phase is washed with water and the combined aqueous phases are made basic to about pH 9, then extracted with chloroform. The chloroform extracts are washed with water and dried over magnesium sulfate. Filtration and removal of solvent gives a residue which is recrystallized from isopropyl ether/ethanol to give 2-methoxy-N-methyl-2-(2-pyridyl)thioacetamide, m.p. 104°-105° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:16])[CH2:13][CH2:14]Cl)=[CH:7][CH:6]=1.C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:14][CH2:13][C:12]2=[O:16])=[CH:7][CH:6]=1
Reactant: O=C(CCCl)Nc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: O=C1CCN1c1ccc(C(F)(F)F)cc1
Reaction time: 8 h

Procedure:
Sodium hydride (0.1 mole; 57% dispersion in mineral oil) is charged into a glass reaction flask. The mineral oil is removed by washing the sodium hydride with benzene, and dimethyl sulfoxide (50 ml) is thereafter slowly added with stirring. The mixture is stirred until no more hydrogen gas evolves. A solution of N-(4-trifluoromethylphenyl)-β-chloropropionamide (0.08 mole) in carbon tetrachloride (50 ml) is added dropwise to the reaction flask with stirring while maintaining the temperature of the reaction mixture below about 30°C. After the addition is completed the reaction mixture is allowed to stand at room temperature for a period of about 8 hours. After this time benzene is added and the reaction mixture is washed with water and aqueous sodium bicarbonate. The washed mixture is then dried over anhydrous magnesium sulfate, is filtered, and is stripped of solvents under reduced pressure to yield the desired product N-(4-trifluoromethylphenyl)-2-azetidinone as the residue.
Reaction SMILES: CN1CCOCC1.[Br:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=1.Cl.Cl.[CH3:19][O:20][C:21](=[O:32])[CH:22]([NH:25][C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH2:23][NH2:24].ON1C2C=CC=CC=2N=N1>CN(C=O)C>[CH3:19][O:20][C:21](=[O:32])[CH:22]([NH:25][C:26]1[N:27]=[CH:28][CH:29]=[CH:30][N:31]=1)[CH2:23][NH:24][C:14]([C:12]1[S:13][C:9]([Br:8])=[CH:10][CH:11]=1)=[O:16]
Reactant: COC(=O)C(CN)Nc1ncccn1
Reactant: O=C(O)c1ccc(Br)s1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)C(CNC(=O)c1ccc(Br)s1)Nc1ncccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
4-methylmorpholine (0.23 mL, 2.10 mmol) was added to a mixture of 5-bromothiophene-2-carboxylic acid (124 mg, 0.60 mmol), 3-amino-2-(pyrimidin-2-ylamino)-propionic acid methyl ester bis-hydrochloride salt (161 mg, 0.60 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarboiimide hydrochloride (115 mg, 0.60 mmol) and 1-hydroxybenzotriazole (81 mg, 0.60 mmol) in dry DMF (2 mL). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated, solvent removed in vacuo and the residue chromatographed. Elution with 5% methanol in dichloromethane gave compound G-2 as a yellow foam (186 mg, 81% yield).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[H-].[Na+].[H][H].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([C:1]12[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]1[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [H][H]
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NC2C=CC=CC2(Cc2ccccc2)C(=O)O1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
A solution of isatoic anhydride (4.1 gm) in DMF (30 ml) was added dropwise to a stirred suspension of 60% sodium hydride (1.0 gm) in DMF (20 ml) under nitrogen atmosphere. The reaction mixture was then warmed to 45° C. and stirred until hydrogen evolution ceased. The reaction mixture was then cooled and a solution of benzyl bromide (4.4 gm) in DMF (10 ml) was added slowly. Stirring was continued for one hour at room temperature and the solution was then evaporated under reduced pressure at 45° C. The resulting solid was suspended in methylene chloride, the insoluble inorganic solid was removed by filtration and the filtrate was evaporated to give 1-benzyl-isatoic anhydride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:13]=3[N:14]=2)=[C:7]([NH2:9])[CH:8]=1.[N:21]1([CH2:27][CH2:28][O:29][C:30]2[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.N>O1CCCC1.ClCCl.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:13]=3[N:14]=2)=[C:7]([NH:9][CH2:34][C:33]2[CH:32]=[CH:31][C:30]([O:29][CH2:28][CH2:27][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:37][CH:36]=2)[CH:8]=1
Reactant: O=Cc1ccc(OCCN2CCCCC2)cc1
Reactant: COc1ccc(-c2nc3ccc(OC)cc3s2)c(N)c1
Agent: N
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(-c2nc3ccc(OC)cc3s2)c(NCc2ccc(OCCN3CCCCC3)cc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 15.9 %

Procedure:
To a suspension of 5-methoxy-2-(6-methoxybenzothiazol-2-yl)phenylamine (473 mg) and 4-(2-piperidin-1-ylethoxy)benzaldehyde (484 mg) in tetrahydrofuran (6 ml), dichloromethane (4 ml) and acetic acid (4 ml) was added borane-methyl sulfide complex (0.18 ml), and the solution was stirred for 6 hours at room temperature. The solution was neutralized with ammonia solution on an ice bath, extracted with ethyl acetate, then sequentially washed with water and brine, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (132 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.[N+:13]([CH3:16])([O-:15])=[O:14].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[N+:13]([CH:16]=[CH:6][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=1)([O-:15])=[O:14]
Reactant: C[N+](=O)[O-]
Reactant: COc1cc(C=O)cc(OC)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1cc(C=C[N+](=O)[O-])cc(OC)c1
Temperature: 0 °C

Procedure:
A mixture consisting of 3,5-dimethoxybenzaldehyde (20 g), nitromethane (20 ml), ammonium acetate (8 g) and acetic acid (80 ml) was refluxted for 11/2 hours and the reaction mixture was poured into ice-water. The yellow solid which separated was filtered and dried under high vacuum to yield the title compound (22.3 g).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:10]=1)[CH2:2]2.C(O)(C(F)(F)F)=O.[CH2:45]1[N:50]([CH2:51][CH2:52][NH2:53])[CH2:49][CH2:48][O:47][CH2:46]1>>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:16][CH2:17][CH:18]([NH:53][CH2:52][CH2:51][N:50]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)[CH2:19][CH2:20]3)[N:12]=[C:11]([C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:26][CH:27]=3)[N:10]=1)[CH2:2]2
Reactant: NCCN1CCOCC1
Reactant: O=C1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCC(NCCN4CCOCC4)CC3)nc(N3CC4CCC(C3)O4)n2)cc1

Procedure:
Starting from 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea.TFA (50 mg)and 1-(2-aminoethyl)morpholine (0.031 mL) and following the procedure as outlined in example 118, the titled compound was isolated as its tri-TFA salt after HPLC purification; MS (ES+) 615.9 (M+H)+
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[C:13]([CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22]C[CH2:20]3)[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.FC1C=C(CCC(O)=O)C=CC=1[O:40]C>C(O)C>[CH:19]1([CH2:18][O:17][C:16]2[CH:15]=[CH:14][C:13]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:12][C:11]=2[C:9]2[CH:8]=[CH:7][C:5]3[NH:6][C:2](=[O:40])[S:3][C:4]=3[CH:10]=2)[CH2:24][CH2:23][CH2:22][CH2:20]1
Reactant: COc1ccc(CCC(=O)O)cc1F
Reactant: CCOC(=O)CCc1ccc(OCC2CCCCC2)c(-c2ccc3nc(Br)sc3c2)c1
Agent: Cl
Solvent: CCO
Product: O=C(O)CCc1ccc(OCC2CCCC2)c(-c2ccc3[nH]c(=O)sc3c2)c1
Temperature: 80 °C
Reaction time: 18.5 h

Procedure:
A solution of Intermediate 76 (202 mg) in ethanol (8 ml) was added with 5 N aqueous hydrochloric acid (1.5 ml), and stirred at 80° C. for 18.5 hours. The reaction mixture was concentrated under reduced pressure, and added with water (20 ml) and ethyl acetate (80 ml) for extraction. The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was added with 2 N aqueous sodium hydroxide (1.0 ml), reacted and treated according to the procedure described in the synthesis method of Intermediate 9 provided that the reaction was carried out for 2 hours to obtain the title compound (Compound No. V-89, 250 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C@@H:10]([OH:21])[CH2:11][S:12]([CH2:15][C:16](OCC)=[O:17])(=[O:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(Cl)(Cl)Cl.CO>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1)[C@@H:10]([OH:21])[CH2:11][S:12]([CH2:15][C:16]([NH:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:17])(=[O:14])=[O:13])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: NCCN1CCOCC1
Reactant: CCOC(=O)CS(=O)(=O)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CS(=O)(=O)CC(=O)NCCN1CCOCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1.98 g (4.7 mmole) of ethyl 2-[[(2R,3S) 3-(t butoxycarbonylamino)-4-cyclohexyl-2-hydroxy-1-butyl]sulfonyl]acetate and 2.3 ml of 4-(2-aminoethyl)morpholine was stirred under N2 at room temperature for 2 days. The light amber syrup was dissolved in 75 ml of ethyl acetate and washed with 3×30 ml of saturated aqueous NH4Cl followed by 30 ml of H2O. The ethyl acetate fraction was dried over Na2SO4, filtered, and concentrated. Further drying in vacuo (oil pump) gave 2.19 g (92%) of a nearly colorless, stiff foam or glass. Structure and purity were confirmed by 300 MHz NMR (CDCl3), mass spectrum, and TLC (9:1 CHCl3 --MeOH).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[N:10]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:11]2[C:16]([C:17]=1[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[CH:15][CH:14]=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:12]=2>C1(C)C=CC=CC=1.CO>[Br:8][C:9]1[N:10]([CH2:28][CH2:29][C:30]([O:32][CH3:1])=[O:31])[C:11]2[C:16]([C:17]=1[CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)=[CH:15][CH:14]=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:12]=2
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CCC(=O)O)c2c1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)CCn1c(Br)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
1.6 eq of (Trimethylsilyl)diazomethane (2 M solution in hexanes) was added dropwise to a solution of 3-[2-bromo-3-cyclohexyl-6-(methoxycarbonyl)-1H-indol-1-yl]propanoic acid in a mixture toluene:MeOH (7:3; 0.2 M) and the solution allowed to stir at RT for 1 h. Excess (Trimethylsilyl)diazomethane was quenched with acetic acid and then the solution was concentrated in vacuo. The crude was purified by flash chromatography (Biotage cartridge Si4OS, 1:9 EtOAc/PE) to afford the title compound in 63% yield (over two steps). MS (ES+) m/z 422 (M+H)+, m/z 424 (M+H)+
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([CH3:9])[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>C(Cl)Cl>[S:29]([O:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([CH3:9])[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH3:28])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(C)cn1CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Cc1c(C(=O)OCC)c(C)cn1CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 1-(2-hydroxyethyl)-3-carboethoxy-4-methylpyrrole-2-acetate (101.7 g) in 800 ml of dry methylene chloride at -10° C. was treated with 56 ml of triethylamine followed by addition dropwise 31 ml of methanesulfonyl chloride. After 30 minutes of stirring at room temperature, 250 ml of water was added and the organic layer separated and washed with water (3×300 ml ), dried over Na2SO4 and evaporated under reduced pressure to yield 121.3 g of ethyl 1-(2-mesyloxyethyl)-3-carboethoxy-4-methyl-pyrrole-2-acetate as white crystals from ethylacetate hexane, m.p. 66°-68° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:31]2[CH2:43][CH2:42][N:34]3[C:35]4[CH2:36][CH2:37][CH2:38][CH2:39][C:40]=4[CH:41]=[C:33]3[C:32]2=[O:44])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:28]=[C:22]3[CH2:23][N:24]([CH3:27])[CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:29])[N:14]([CH3:30])[CH:13]=1)(=O)C.O[Li].O>CC(O)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:31]2[CH2:43][CH2:42][N:34]3[C:35]4[CH2:36][CH2:37][CH2:38][CH2:39][C:40]=4[CH:41]=[C:33]3[C:32]2=[O:44])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:28]=[C:22]3[CH2:23][N:24]([CH3:27])[CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:29])[N:14]([CH3:30])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: CN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)cc2C1
Temperature: 30 °C
Reaction time: 2 h
Yield: 32.8 %

Procedure:
A mixture of 113j (300 mg, 0.50 mmol) and LiOH.H2O (120 mg, 2.50 mmol) in iPrOH/THF (1:1, 3 mL) and H2O (1 mL) was stirred at 30° C. for 2 h. The mixture was evaporated in vacuo and the residue was extracted with EtOAc (10 mL×2). The combined EtOAc extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 113 (91 mg, 32%) as a white solid. LCMS: [M+H]+ 555. 1H NMR (500 MHz, CDCl3) δ 8.47 (d, J=5.0, 1H), 7.95 (d, J=5.0, 1H), 7.72 (d, J=2.0, 1H), 7.42 (s, 1H), 7.35 (d, J=5.0, 1H), 6.89 (s, 1H), 5.69 (s, 1H), 5.01-5.02 (m, 1H), 4.61-4.62 (m, 1H), 4.48-4.49 (m, 1H), 4.32-4.33 (m, 1H), 4.15-4.07 (m, 4H), 3.86-3.87 (m, 1H), 3.69 (s, 3H), 3.60-3.59 (m, 2H), 2.88 (t, J=6.0, 2H), 2.61-2.56 (m, 4H), 2.47 (s, 3H), 1.89-1.90 (m, 2H), 1.78-1.79 (m, 2H)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH:24]1([CH2:29][C:30](O)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:29][C:30]([NH:1][C:2]2[C:3]([C:7]3[NH:23][C:10]4=[CH:11][C:12]5[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=5[CH:17]=[C:9]4[N:8]=3)=[N:4][NH:5][CH:6]=2)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)CC1CCCC1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)CC4CCCC4)nc3cc21

Procedure:
2-Cyclopentyl-N-[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-acetamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and cyclopentylacetic acid (111 μl, 0.89 mmol). The title compound was obtained as yellow powder (74 mg, 22%).
Reaction SMILES: [CH:1]([CH:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=C.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH:17](O)(C)C>>[N:11]1([CH2:17][C:7]2[CH:6]=[CH:5][C:4]([CH:3]=[CH2:1])=[CH:9][CH:8]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: CC(C)O
Reactant: C=CC(Cl)c1ccccc1
Reactant: C1CNCCN1
Product: C=Cc1ccc(CN2CCNCC2)cc1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a 500 mL flask was added vinylbenzyl chloride (7.63 g, 0.050 mol), piperazine (8.61 g, 0.100 mol), and isopropanol (50 mL). The resulting solution was heated to 70° C. for 45 minutes and then cooled slowly to room temperature to form a slurry of crystalline material. The slurry was refrigerated for about three hours and then filtered. The solid piperazine hydrochloride salt was vacuum dried and then weighed (5.55 g) and discarded. The mother liquor was concentrated to about 25 mL on a rotary evaporator and ethyl acetate (50 mL) was added). The resulting mixture was refrigerated for about 10 minutes, after which a second crop of piperazine hydrochloride was filtered off and discarded. The mother liquor was then evaporated to dryness on a rotary evaporator to afford 10.35 g of crude 4-(piperazinylmethyl)styrene which was used without further purification to prepare N-(4-methylstyrene)-N'-(3-trimethylammonio-2-hydroxypropyl chloride)piperazine as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].Br[C:31]1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@H]2CC)=N[C:36]=1CC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@H:19]2[CH2:31][CH3:36])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@H]2CC)c(CC)nc1Br
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@H]1CC

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting (+/−)-5-bromo-3,6-diethyl-N-[trans-2-ethyl-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine and making non-critical variations provided the title compound as a light yellow semi-solid. IR (liq.) 3443, 2965, 2934, 2874, 1588, 1566, 1551, 1497, 1470, 1390, 1203, 1186, 1173, 1101, 747 cm−1; OAMS supporting ions at: ESI+ 440.0; MS (EI) m/z 439 (M+); Anal. Calcd for C25H27Cl2N3: C, 68.18; H, 6.18; N, 9.54. Found: C, 68.11; H, 6.17; N, 9.29.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[S:35][C:34]([CH3:36])=[N:33][C:32]=2[C:37](O)=[O:38])=[CH:27][CH:26]=1)[CH3:24]>>[CH2:23]([C:25]1[CH:26]=[CH:27][C:28]([C:31]2[S:35][C:34]([CH3:36])=[N:33][C:32]=2[C:37]([N:6]2[CH2:5][C@H:4]3[C@H:8]([CH2:9][CH:2]([CH3:1])[CH2:3]3)[C@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])=[O:38])=[CH:29][CH:30]=1)[CH3:24]
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Reactant: CCc1ccc(-c2sc(C)nc2C(=O)O)cc1
Product: CCc1ccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)cc1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(4-ethyl-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1)(=O)=O.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19]([C:10]([NH:9][CH2:8][CH2:7][CH2:6][N:32]3[CH2:31][CH2:30][N:29]([C:26]4[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=4)[CH2:34][CH2:33]3)=[CH:11][CH:12]=[N:13]2)=[CH:18][CH:17]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)OCCCNc1ccnc2cc(Cl)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCN(CCCNc3ccnc4cc(Cl)ccc34)CC2)cc1
Temperature: 25 °C
Yield: 10 %

Procedure:
The product of Preparation 2 (0.69 g, 0.00219 mol) and 1-(4-methoxyphenyl)piperazine (0.51 g, 0.00263 mol) were dissolved in THF (15 mL) and triethylamine (0.44 g, 0.00438 mol) was added. The reaction mixture was stirred and heated at reflux for 4 days. After cooling to room temperature, saturated NaHCO3 solution (30 mL) was added, and the mixture was extracted with chloroform (3×10 ml). The organic layer was dried over MgSO4 and evaporated. The resulting powder was dissolved in a mixture of methanol/ethyl acetate (1:3) (10 ml). After filtering, the solution was evaporated to give the title compound (0.09 g, 10%) as a solid.