Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:18])[C@@H:4]1[CH2:8][C@H:7]([C:9]#[N:10])[CH2:6][N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].O[Li].O>CO>[C:14]([O:13][C:11]([N:5]1[CH2:6][C@@H:7]([C:9]#[N:10])[CH2:8][C@H:4]1[C:3]([OH:18])=[O:2])=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)[C@@H]1C[C@H](C#N)CN1C(=O)OC(C)(C)C
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](C#N)C[C@H]1C(=O)O
Reaction time: 4 h

Procedure:
A solution of N-boc-cis-4-cyano-L-proline methyl ester (800 mg, 3.15 mmol) in MeOH (27 mL) was cooled to 0° C. and LiOH.H2O (792 mg, 18.9 mmol) was added. The colorless solution was allowed to reach RT and stirred for 4 h. LiOH.H2O (792 mg, 18.9 mmol) was added and the reaction further stirred at for 1 hour to complete the reaction. MeOH was concentrated and the residue diluted in CH2Cl2 and treated with aqueous 1M HCl adjusting the pH to 1. The layers were separated and the aqueous one re-extracted with CH2Cl2 (×2). The combined organic extracts were dried (Na2SO4), filtered and concentrated to give the desired compound which was used in the next step without further purification. MS (LC/MS): 263.0 [M+Na]+, 503.2 [2M+Na]+, 239.1 [M−H]−.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[S:12][CH:13]=[C:14]([Br:16])[N:15]=1.C1(C)C=CC=CC=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.O.C(O)C>[C:1]1([C:11]2[S:12][CH:13]=[C:14]([Br:16])[N:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1csc(Br)n1
Reactant: OB(O)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: O
Solvent: CCO
Product: Brc1csc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A flask containing 238 mg of tetrakis(triphenylphosphine)palladium, 0.55 g of phenyl boronic acid and 1.00 g of 2,4-dibromothiazole was subjected to nitrogen substitution. To this flask, 30 ml of toluene, 6.1 ml of ethanol, and 9.1 ml of a 2 M sodium carbonate aqueous solution were added, and the obtained mixture was then stirred under reflux for 6 hours. Thereafter, the reaction solution was cooled to a room temperature, and 50 ml of water was then added thereto, followed by extraction with 50 ml of ethyl acetate twice. The organic layer was washed with 30 ml of a saturated brine, and it was then dried over magnesium sulfate. The magnesium sulfate was filtrated, and the organic layer was then concentrated. The residue was then purified by column chromatography (Wako Gel C-200; hexane:ethyl acetate=14:1), so as to obtain 0.71 g of 2-phenyl-4-bromothiazole.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:16]([F:18])[CH3:17])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])[CH2:20][CH3:21].C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:13](=[O:15])[CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH:16]([F:18])[CH3:17])[CH2:27][CH2:26]1)=[O:24])[CH2:20][CH3:21]
Reactant: CC(F)C(NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCCOC(=O)N1CCNCC1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOC(=O)N1CCN(C(=O)C(NC(=O)OCc2ccccc2)C(C)F)CC1
Reaction time: 12 h

Procedure:
To a solution of 500 mg 2-Benzyloxycarbonylamino-3-fluoro-butyric acid in 3 ml DMF were added 310 mg 1-propoxycarbonylpiperazine, 0.50 ml N-ethylmorpholine and 643 mg TOTU. After stirring for 12 h it was diluted with ethyl acetate and extracted with aqueous LiCl (4% w/w), aqueous NaHCO3, 0.1 M HCl and brine. The organic layer was dried over MgSO4 and concentrated to furnish the crude coupling product which was used without further purification in the next step. Yield: 591 mg
Reaction SMILES: [Br:1][C:2]1[C:3](=O)[NH:4][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)[CH3:9])=[N:6][CH:7]=1.P(Cl)(Cl)([Cl:30])=O>>[Br:1][C:2]1[C:3]([Cl:30])=[N:4][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)[CH3:9])=[N:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)N2CCN(C(C)c3ncc(Br)c(=O)[nH]3)CC2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(S(=O)(=O)N2CCN(C(C)c3ncc(Br)c(Cl)n3)CC2)cc1
Temperature: 90 °C

Procedure:
In a flask containing of 5-bromo-2-{1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-3H-pyrimidin-4-one (150.0 mg, 0.33 mmol) in phosphorus oxychloride (2 ml) was heated to 90° C. for 2 hours, then the solvent was concentrated under reduced pressure to give the 5-bromo-4-chloro-2-{1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-pyrimidine that was used in the next step without any purification. MS m/z calc. 524.2 found (ESI); 526.2 (M+1)+. Retention time 2.91 minutes.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:4]1=[O:16].[C:17]([C:19]1[CH:32]=[CH:31][C:22]([CH2:23][N:24]2[C:28]([CH:29]=O)=[CH:27][N:26]=[CH:25]2)=[CH:21][C:20]=1[F:33])#[N:18].C(N(CC)C(C)C)(C)C.[BH3-]C#N.[Na+]>CO>[F:33][C:20]1[CH:21]=[C:22]([CH2:23][N:24]2[C:28]([CH2:29][NH:2][C@@H:3]3[CH2:7][CH2:6][N:5]([CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=4)[C:4]3=[O:16])=[CH:27][N:26]=[CH:25]2)[CH:31]=[CH:32][C:19]=1[C:17]#[N:18]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Reactant: N[C@@H]1CCN(Cc2cccc(O)c2)C1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Cn2cncc2CN[C@@H]2CCN(Cc3cccc(O)c3)C2=O)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-3-Amino-1-(3-hydroxybenzyl)-2-oxopyrrolidine hydrochloride, as described above in Step N, (200 mg, 0.82 mmol) and 1-(4-cyano-3-fluorobenzyl)-5-imidazolecarboxaldehyde, as described above in Step G, (197 mg, 0.86 mmol), were stirred in MeOH (7 mL) and N,N-diisopropylethylamine was added dropwise to adjust the mixture to ca. pH 5, as judged by wetted pH paper. The mixture was stirred for 1 hour at ambient temperature, then NaCNBH3 (54 mg, 0.86 mmol) was added and stirring was continued for 18 hours. The reaction was quenched with saturated aqueous NaHCO3 (2 mL) and most of the MeOH was removed under reduced pressure. The residual solution was partitioned between saturated aqueous NaHCO3 (3 mL) and CH2Cl2 (10 mL). The aqueous layer was extracted further with CH2Cl2 (3×10 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with two column volumes of EtOAc—10% MeOH, then two column volumes of CHCl3—4% MeOH, then CHCl3—4% MeOH—0.4% NH4OH to yield the titled product as a colorless oil.
Reaction SMILES: Br[C:2]1[C:3]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].O.[CH3:28][O:29][C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1>O1CCOCC1.O.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>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:3]2[C:2]([C:35]3[C:30]([O:29][CH3:28])=[N:31][CH:32]=[CH:33][CH:34]=3)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:12])[CH:4]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)c1cc(Br)c(Oc2ccc(Cl)cc2)cc1F
Reactant: COc1ncccc1B(O)O
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cccnc2OC)c(Oc2ccc(Cl)cc2)cc1F
Temperature: 50 °C
Yield: 179.6 %

Procedure:
To a stirred solution of methyl 5-bromo-4-(4-chlorophenoxy)-2-fluorobenzoate (Preparation 32, 199 mg, 0.55 mmol) in dioxane (10 mL) and water (0.5 mL) was added potassium carbonate (158 mg, 1.14 mmol) and 2-methoxypyridin-3-ylboronic acid mono hydrate (147 mg, 0.86 mmol). The reaction was degassed three times followed by the addition of tetrakis(triphenylphosphine)palladium(0) (13.2 mg, 0.012 mmol). The reaction was degassed three times and heated at 50° C. overnight under a nitrogen atmosphere. The reaction was cooled to room temperature, concentrated in vacuo to afford a brown residue. The residue was partitioned between EtOAc (25 mL) and water (25 mL). The aqueous phase was extracted with EtOAc (2×25 mL). The combined organic extracts were washed with water (25 mL), brine (25 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford brown oil (383 mg). The oil was then purified by flash column chromatography using the Biotage System™ (50 g silica column, eluting with DCM). Fractions containing product were combined and concentrated in vacuo to afford the title compound as a grey oil (194 mg, 91%).
Reaction SMILES: CS(O)(=O)=O.C(OC([N:13]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH2:32][CH3:33])[CH:25]=1)[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)=O)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>ClCCl.C(O)(=O)C.CO>[Cl:22][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][NH:13][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH2:32][CH3:33])[CH:25]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CCCOc1cccc(CN(CCc2cccc(Cl)c2)C(=O)OC(C)(C)C)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CCCOc1cccc(CNCCc2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Add methanesulfonic acid (70 uL) to a solution of N-t-Butoxycarbonyl-N-2-(3-chlorophenyl)ethyl-3-propoxybenzylamine in dichloromethane (4 mL) and agitate the mixture for 3 hours at room temperature. Add 10% aqueous Na2CO3 (2 mL), separate the layers, and concentrate the organic layer in a nitrogen stream to give a residue. Dissolve the residue in 4 mL of 5% acetic acid in methanol and pass through a 1 gm SCX column, eluting with 1 M ammonia in methanol to give the title compound: MS (ES+): m/e (M+1). HPLC (10–90% water/acetonitrile over 7.5 min, Tr=4.490 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][NH:23][OH:24].C[Si]([N:29]=[C:30]=[O:31])(C)C.O.C(OCC)(=O)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][N:23]([OH:24])[C:30]([NH2:29])=[O:31]
Reactant: C[Si](C)(C)N=C=O
Reactant: CSc1ccc(/C=C2/C(C)=C(CCNO)c3cc(F)ccc32)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1ccc(/C=C2/C(C)=C(CCN(O)C(N)=O)c3cc(F)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the hydroxylamine intermediate from Step 4 (1.62 g, 4.7 mmol) in THF (15 mL) there was added 85% trimethylsilyl isocyanate (954 mg, 7.25 mmol). The mixture was stirred at room temperature for 30 minutes. Water (10 mL) was added and stirring was continued for a further 10 minutes. Ethyl acetate was then added, the organic layer was decanted, washed with brine, dried over MgSO4 and evaporated to dryness. The residue was triturated with ether and filtered to afford the pure title product as a yellow solid, mp: 149° C. dec.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([O:35][C:36]([CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:37])[CH3:34]>>[CH2:33]([O:35][C:36]([CH:39]1[CH2:38][CH2:43][CH2:42][N:41]([C:30]([C@@H:9]2[CH2:10][C@H:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[CH2:12][N:8]2[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:31])[CH2:40]1)=[O:37])[CH3:34].[CH2:33]([O:35][C:36]([CH:38]1[CH2:43][CH2:42][N:41]([C:30]([C@@H:9]2[CH2:10][C@H:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[CH2:12][N:8]2[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:31])[CH2:40][CH2:39]1)=[O:37])[CH3:34]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Product: CCOC(=O)C1CCCN(C(=O)[C@@H]2C[C@H](NCc3ccc(F)cc3F)CN2Cc2ccccc2)C1
Product: CCOC(=O)C1CCN(C(=O)[C@@H]2C[C@H](NCc3ccc(F)cc3F)CN2Cc2ccccc2)CC1
Yield: 14 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using piperidine-4-carboxylic acid ethyl ester instead of 2-piperazin-1-yl-benzonitrile, to the title product [(2S,4S)-1-benzyl-4-(2,4-difluoro-benzylamino)-pyrrolidine-2-carbonyl]-piperidine-3-carboxylic acid ethyl ester (8.7 mg, 14% yield) as colorless oil. MS m/e=486.6 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]([OH:19])[CH2:10][CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:5]=[CH:6][C:7]=1[F:8].[C:20]([C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])#[CH:21]>>[F:15][C:14]([F:17])([F:16])[C:13]([NH:12][CH2:11][CH2:10][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:21]#[C:20][C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH:3]=1)[OH:19])=[O:18]
Reactant: O=C(NCCC(O)c1ccc(F)c(Br)c1)C(F)(F)F
Reactant: C#CC(O)(CCC)CCC
Product: CCCC(O)(C#Cc1cc(C(O)CCNC(=O)C(F)(F)F)ccc1F)CCC

Procedure:
N-(3-(3-Bromo-4-fluorophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide was coupled with 4-ethynylheptan-4-ol following the method used in Example 7 to give 2,2,2-trifluoro-N-(3-(4-fluoro-3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)-3-hydroxypropyl)acetamide as a pale yellow oil. Yield (1.37 g, 78%): 1H NMR (400 MHz, DMSO-d6) δ 9.31 (t, J=5.0 Hz, 1H), 7.37 (dd, J=6.8, 2.0 Hz, 1H), 7.34-7.30 (m, 1H), 7.18 (t, J=9.0 Hz, 1H), 5.41 (d, J=4.8 Hz, 1H), 5.19 (s, 1H), 4.58-4.54 (m, 1H), 3.28-3.16 (m, 2H), 1.82-1.69 (m, 2H), 1.63-1.41 (m, 8H), 0.89 (t, J=7.2 Hz, 6H).
Reaction SMILES: [CH2:1]([N:4]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH3:3].[C:21]([N:28]1[CH:32]=[CH:31]N=C1)(N1C=CN=C1)=[O:22].[CH2:33](N)[CH2:34][CH2:35][CH2:36][CH2:37]CC.C(=O)(O)[O-].[Na+]>O1CCCC1.O.C(O)(=O)C>[CH2:32]([NH:28][C:21](=[O:22])[O:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([N:4]([CH2:1][CH2:2][CH3:3])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[CH:6]=[CH:7]2)[CH2:31][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCN
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCN(c1ccncc1)n1ccc2cc(O)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCNC(=O)Oc1ccc2c(ccn2N(CCC)c2ccncc2)c1
Reaction time: 24 h

Procedure:
To 1-(propyl-4-pyridinylamino)-1H-indol-5-ol (2.5 g) in 50 ml tetrahydrofuran was added 1,1'-carbonyldiimidazole (1.83 g) portionwise, and the reaction was allowed to proceed for 24 hours. To this mixture was added glacial acetic acid (2.15 ml) followed by a solution of heptylamine (1.45 ml) in tetrahydrofuran which had been treated with 0.56 ml of acetic acid. The reaction mixture was then stirred for 21 hours. The mixture was diluted with water, basified with sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with water and dried (sat. NaCl, anhy. MgSO4). After filtration, the solvent was evaporated to yield an oil (4.6 g), which was eluted with 5% methanol/dichloromethane on a silica gel column via HPLC. The desired fractions were concentrated to yield an oil (4.5 g), which was eluted with 5% methanol/dichloromethane on a silica gel column via HPLC. The desired fractions were concentrated to yield an oil (2.8 g). This material was dissolved in 50 ml of pentane/ether (1:1) and the solution was concentrated to 15 ml, whereupon crystals precipitated out of the solution. These were collected to yield a solid (1.0 g), m.p. 83°-85° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:16]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[CH2:17].[Na]>C(O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:17][CH2:16][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1ccncc1
Agent: [Na]
Solvent: CCO
Product: Cc1ccc2c(c1)c1c(n2CCc2ccncc2)CCN(C)C1
Yield: 2.9 %

Procedure:
The title compound was prepared according to General Method 3. 2,3,4,5-Tetrahydro-2,8-dimethyl-5-(2-(pyridin-4-yl)ethyl)-1H-pyrido[4,3-b]indole was prepared from 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (See Example 1) (100 mg, 0.5 mmol), 4-vinylpyridine (120 mg, 1.14 mmol) and sodium (5 mg, 0.21 g atom) in ethanol (1 mL) at 120° C. for 16 h to obtain 4.5 mg of 2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(pyridin-4-yl)ethyl)-1H-pyrido[4,3-b]indole after purification on silica gel (230-400 mesh) chromatography eluting with methanol-dichloromethane gradient.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([CH3:9])=[CH:4][C:3]=1[C:10](=[O:29])[CH2:11][CH2:12][C:13]1[S:14][C:15]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:16]=2[C:17]=1[CH2:18][CH2:19][CH3:20].[C:30](=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:37][C:38]([O:40][CH3:41])=[O:39]>CC(C)=O>[OH:1][C:2]1[C:3]([C:10](=[O:29])[CH2:11][CH2:12][C:13]2[S:14][C:15]3[CH:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=[CH:21][C:16]=3[C:17]=2[CH2:18][CH2:19][CH3:20])=[CH:4][C:5]([CH3:9])=[C:6]([CH:7]=1)[O:8][CH2:37][C:38]([O:40][CH2:41][CH3:30])=[O:39]
Reactant: O=C([O-])[O-]
Reactant: CCCc1c(CCC(=O)c2cc(C)c(O)cc2O)sc2cc(C(F)(F)F)ccc12
Reactant: COC(=O)CBr
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCCc1c(CCC(=O)c2cc(C)c(OCC(=O)OCC)cc2O)sc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 7 h
Yield: 86 %

Procedure:
In acetone (0.8 mL) was suspended 1-(2,4-dihydroxy-5-methylphenyl)-3-[3-propyl-6-(trifluoromethyl)benzothiophen-2-yl]propan-1-one and cesium carbonate (33 mg, 0.788 mmol). After addition of 1-Methyl bromoacetate in acetone (79 μL), the mixture was stirred for 7 hours at room temperature, diluted with ice-water, and extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. After the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate, 6:1) to give the titled compound as a pale yellow crystal (34 mg, yield 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1[Cl:13].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:18][C:19]1[C:20]([OH:34])=[C:21]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:22]=[CH:23][C:24]=1[OH:25].Cl>C(OCC)(=O)C.ClCCCl>[Cl:13][C:12]1[C:2]([Cl:1])=[CH:3][C:4]([C:9]([OH:8])=[O:10])=[C:5]([C:6]([C:23]2[CH:22]=[C:21]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:20]([OH:34])=[C:19]([Cl:18])[C:24]=2[OH:25])=[O:7])[CH:11]=1
Reactant: COC(=O)CCCCc1ccc(O)c(Cl)c1O
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)CCCCc1cc(C(=O)c2cc(Cl)c(Cl)cc2C(=O)O)c(O)c(Cl)c1O
Temperature: -20 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
In a 2 L 3-neck round-bottomed flask equipped with a stir and addition funnel was added 4,5-dichlorophthalic anhydride (7.13 g, 32.9 mmol) followed by dry 1,2-dichloroethane (120 ml). After stirring for 30 minutes AlCl3 (11.4 g, 85.54 mmol) was added and the mixture was stirred for another 30 minutes. To this mixture was added via the addition funnel a solution of 5b (8.5 g, 32.9 mmol) with stirring. The solution in the flask became slightly warm and turned dark. Hydrogen chloride gas evolved for about 10 to 20 minutes. Stirring was continued overnight (15-18 hours) at room temperature. During this time, a tarry precipitate formed. To this mixture was added ice (160 g) and concentrated HCl (80 ml) followed by ethyl acetate (900 ml). The content of the flask was stirred until all the solids have completely dissolved. The mixture was transferred to a 2-liter separatory funnel. The organic layer was washed with about 300 ml of 1 N HCl, 2×200 ml of saturated NaCl and dried over sodium sulfate. The solution was filtered and evaporated to a solid, which was then triturated in 200 ml of dichloromethane for 30 minutes, and then cooled to −20° C. for at about 2 h. The crystalline precipitate was filtered off and washed with 2:1 hexanes/dichloromethane, followed by 4:1 hexanes/dichloromethane, and dried to afford 10.8 g (69%) of the desired benzophenone 14b. 1H NMR (DMSO-d6) δ: 12.44 (s, 1H), 10.3 (br s, 1H), 8.14 (s, 1H), 7.87 (s, 1H), 6.88 (s, 1H), 3.55 (s, 3H), 2.44 (t, J=6.8 Hz, 2H), 2.25 (t, J=6.9 Hz, 2H), 1.40 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH2:9].[N:10]([O-])=O.[Na+].C([O-])(=O)C.[Na+]>OS(O)(=O)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:9][N:10]=[CH:8]2
Reactant: Cc1cccc(Cl)c1N
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Clc1cccc2cn[nH]c12
Temperature: 7.5 °C
Yield: 40.8 %

Procedure:
A solution of 2-chloro-6-methyl-phenylamine (500 mg, 3.53 mmol) in H2SO4 (1.37 mL) was diluted by adding over 15 min. 2 mL of water in order to maintain a temperature below 90° C. Then the reaction mixture was cooled to 5-10° C. and a solution of sodium nitrite (246 mg, 3.57 mmol) in water (1 mL) was added over 2 hours. The resulting diazonium solution was then added to a solution of sodium acetate (5.21 g, 63.6 mmol) in water (20 mL) at a temperature maintained between 65 to 75° C. The resulting precipitate was filtered and treated with a solution of NaOH (6.00 g) in water (100 mL) at 95-100° C. The aqueous phase was separated while hot from the small amount of black tarry by-products, cooled to 50-60° C. and acidified with HCl (37%, 12.5 mL). The reaction mixture was cooled down to room temperature, the resulting precipitate was filtered, was washed thrice with cold water and was dried under vacuum to yield 7-chloro-1H-indazole (220 mg, 1.44 mmol, 41%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:16]([C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:28]=1[OH:29])[C:23](O)=[O:24])([CH3:19])([CH3:18])[CH3:17].C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[CH3:33][C:30]([C:27]1[CH:26]=[C:22]([C:23]([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)=[O:24])[CH:21]=[C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:28]=1[OH:29])([CH3:31])[CH3:32]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C(=O)N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 89 %

Procedure:
2.07 g (10 mmoles) of 1-(4-nitrophenyl)piperazine, 2.5 cg (10 mmoles) of 3,5-di-tert-butyl-4-hydroxybenzoic acid and 2.26 g (11 mmoles) of dicyclohexylcarbodiimide are introduced into a 100 ml flask containing 25 ml of DMF. The reaction medium is agitated for 15 hours at ambient temperature, the precipitate which appears is filtered out and rinsed with ethyl acetate. After concentration of the filtrate under reduced pressure, the residue is diluted in 20 ml of ethyl acetate and a new insoluble is eliminated by filtration. The solvent is evaporated off under vacuum and the residue is precipitated from diethyl ether. The solid is filtered, rinsed with 2×20 ml of ethyl acetate in order to obtain a yellow powder with a yield of 89%. Melting point: 159.5-160.5° C.