Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]1[C:18]1[CH:19]=[CH:20][C:21]2[C:22]3[CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37][C:23]=3[N:24]([S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:25]=2[CH:26]=1.C(Cl)Cl.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>>[F:54][C:53]([F:56])([F:55])[C:51]([OH:57])=[O:52].[S:27]([N:24]1[C:25]2[CH:26]=[C:18]([N:3]3[CH:4]=[CH:5][C:6]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=4)=[CH:7][C:2]3=[O:1])[CH:19]=[CH:20][C:21]=2[C:22]2[CH2:40][NH:39][CH2:38][CH2:37][C:23]1=2)([C:30]1[CH:31]=[CH:32][C:33]([CH3:34])=[CH:35][CH:36]=1)(=[O:29])=[O:28]
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(-n5ccc(-c6ccc(C(F)(F)F)cn6)cc5=O)cc42)CN(C(=O)OC(C)(C)C)CC3)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(-n5ccc(-c6ccc(C(F)(F)F)cn6)cc5=O)cc42)CNCC3)cc1
Yield: 100 %

Procedure:
tert-Butyl 7-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-5-tosyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (165 mg, 0.248 mmol) was stirred in TFA (3 mL) and methylene chloride (1 mL) for 3 h. Concentration of the solution under reduced pressure provided the title compound (164 mg, 100%) as a yellow oil; ESI MS m/z 565 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:11][C:3]1[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[F:12]
Reactant: O=C(O)c1ccc(F)c(Br)n1
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: O=C(O)c1ccc(F)c(-c2ccccc2F)n1
Yield: 43 %

Procedure:
Method 1 was followed using 6-bromo-5-fluoropicolinic acid (1.0 equiv.) and 2-fluorophenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) to give 5-fluoro-6-(2-fluorophenyl)picolinic acid in 43% yield. LC/MS=236.1 (M+H), Rt=0.72 min.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:9][CH2:8][C:6]=2[N:7]=1.[CH3:20][O:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24].CCOC(C)=O>C(O)(C)C>[CH3:20][O:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: COc1ccccc1N
Reactant: O=C(c1cccnc1)N1CCc2nc(Cl)ncc2C1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COc1ccccc1Nc1ncc2c(n1)CCN(C(=O)c1cccnc1)C2
Temperature: 60 °C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
A solution of (2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyridin-3-yl)methanone, Intermediate 5 (0.025 g, 0.091 mmol) in isopropanol (0.1 mL) was treated with 2-methoxyaniline (0.012 g, 0.100 mmol). The resulting mixture was heated to 60° C. and allowed to stir overnight. After being allowed to cool to room temperature EtOAc (10 mL) was added to the reaction mixture, and the resulting solution was then washed twice with brine (10 mL). The combined aqueous layers were washed once with EtOAc (10 mL). The organic layers were combined, then dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The resulting crude residue was then purified over silica using a MeOH/CHCl3 gradient. The desired product was obtained in 33.5% yield (0.011 g, 0.030 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]3[CH:16]=[CH:15][C:14]([C@@H:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:13][CH:12]=3)[CH2:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:32]([CH3:34])[CH3:33]>CN(C=O)C>[CH:32]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:8][N:9]([C:11]3[CH:16]=[CH:15][C:14]([C@@H:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:13][CH:12]=3)[CH2:10]2)=[CH:23][CH:24]=1)([CH3:34])[CH3:33]
Reactant: CC(C)Br
Reactant: CC(=O)N[C@@H](C)c1ccc(N2CC(Oc3ccc(O)cc3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C)c1ccc(N2CC(Oc3ccc(OC(C)C)cc3)C2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To 0.050 g (0.15 mmol) (S)—N-(1-{4-[3-(4-hydroxy-phenoxy)-azetidin-1-yl]-phenyl}-ethyl)-acetamide (VI.1) in 1.0 mL DMF are added 0.053 g (0.38 mmol) potassium carbonate and 17.2 μL (0.18 mmol) 2-bromopropane. The mixture is stirred for 12 h at 80° C. After cooling the mixture is directly purified by HPLC (XBridge, MeOH/water (+0.3% NH4OH)) to yield the desired product.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[CH:8]=[CH:9][C:10]([N+:16]([O-:18])=[O:17])=[C:11]([C:14]#[N:15])[C:12]=2[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].I[CH2:20][CH2:21][OH:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:5]1[N:6]([CH2:20][CH2:21][OH:22])[C:7]2[CH:8]=[CH:9][C:10]([N+:16]([O-:18])=[O:17])=[C:11]([C:14]#[N:15])[C:12]=2[CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCI
Reactant: CC(C)(C)c1cc2c(C#N)c([N+](=O)[O-])ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2c(C#N)c([N+](=O)[O-])ccc2n1CCO
Temperature: 90 °C
Reaction time: 72 h

Procedure:
A mixture of 2-tert-butyl-5-nitro-1H-indole-4-carbonitrile (200 mg, 0.82 mmol), 2-iodoethanol (77 μL, 0.98 mmol), cesium carbonate (534 mg, 1.64 mmol) and DMF (1.3 mL) was heated to 90° C. overnight. Then more 2-iodoethanol (77 μL, 0.98 mmol) was added and the reaction was stirred at 90° C. for 3 days. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl acetate and then the combined ethyl acetate layers were washed with water (×3) and brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography (50-100% CH2Cl2-Hexanes) to yield the product as a yellow solid (180 mg, ˜25% purity by NMR, product co-elutes with the indole starting material). ESI-MS m/z calc. 287.1. found 288.5 (M+1)+. Retention time 1.59 minutes. 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.14 (d, J=9.1 Hz, 1H), 8.02 (d, J=9.1 Hz, 1H), 6.60 (s, 1H), 5.10 (t, J=5.5 Hz, 1H), 4.55 (t, J=6.3 Hz, 2H), 3.78-3.73 (m, 2H) and 1.49 (s, 9H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([OH:18])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]2[CH3:19])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>>[CH3:27][O:26][C:24](=[O:25])[CH2:23][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH:11]=[C:10]([CH3:19])[N:9]2[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: Cc1cc2c(O)cccc2n1Cc1ccc(F)cc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: COC(=O)COc1cccc2c1cc(C)n2Cc1ccc(F)cc1
Yield: 80.9 %

Procedure:
Using the procedure described in Example 1, Part E, 1-[(4-fluorophenyl)methyl]-4-hydroxy-2-methyl-1H-indole (881 mg, 3.45 mmol) was treated with 138 mg (3.45 mmol) of 60% NaH/mineral oil and then 0.33 mL (3.45 mmol) of methyl bromoacetate. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 914 mg (81% yield) of [[1-[(4-fluorophenyl)methyl]-2-methyl-1H-indol-4-yl]oxy]acetic acid methyl ester, mp, 92-98° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.[S:30]1[CH:34]=[C:33]([C:35](O)=[O:36])[N:32]=[N:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CO>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:35]([C:33]2[N:32]=[N:31][S:30][CH:34]=2)=[O:36])=[C:4]([F:20])[C:5]=1[O:10][C:11]1[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: O=C(O)c1csnn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3csnn3)c2F)c1
Reaction time: 8 h
Yield: 47.3 %

Procedure:
In a 1 dram vial, 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (25 mg, 0.080 mmol), DIPEA (0.014 mL, 0.080 mmol) and 1,2,3-thiadiazole-4-carboxylic acid (10.46 mg, 0.080 mmol) were dissolved in DMF (1 mL). HATU was added (30.6 mg, 0.080 mmol) and the solution stirred overnight. The reaction mixture was diluted to 2 mL with MeOH. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.016 g, 46%) as a white solid. 1H NMR (400 MHz, Acetone-d6): δ ppm 9.55 (s, 1H), 8.94 (br. s., 1H), 7.63 (t, 1H), 7.53 (t, 1H), 7.41-7.46 (m, 1H), 7.37-7.41 (m, 2 H), 4.79 (d, 2H). LCMS m/z 422.8 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH:8]([N:21]1[CH2:24][CH:23](OS(C)(=O)=O)[CH2:22]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C)C=O.C(OCC)(=O)C>[CH:8]([N:21]1[CH2:24][CH:23]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:22]1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc(C(c2ccccc2)N2CC(n3ccnc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
A solution of 3.20 g of imidazole in 25 ml of dimethylformamide was added to 2.10 g of a suspension of sodium hydride (as a 55% w/w dispersion in mineral oil) in 25 ml of dimethylformamide, whilst ice-cooling. The mixture was then stirred at room temperature for 1 hour. A solution of 5.00 g of 1-benzhydryl-3-methanesulfonyloxyazetidine in 50 ml of dimethylformamide was then added to the mixture, after which the mixture was stirred at 70° C. for 17 hours. At the end of this time, the reaction mixture was diluted with ethyl acetate and washed with water and with an aqueous solution of sodium chloride, in that order. The ethyl acetate layer was then dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 2.88 g of the title compound, as a powder, from the fraction obtained by elution with a 95:5 by volume mixture of ethyl acetate and methanol.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][CH:8]([C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)[O:9][CH3:10].[C-:16]#[N:17].[Na+]>CN(C)P(=O)(N(C)C)N(C)C>[C:16]([CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][CH:8]([C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)[O:9][CH3:10])#[N:17]
Reactant: COC(CC#CCCCCl)c1ccco1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(CC#CCCCC#N)c1ccco1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
A stirred mixture of 0.45 g of 7-chloro-1-(2-furyl)-1-methoxy-3-heptyne, 0.20 g of sodium cyanide, and 4.0 ml of hexamethylphosphoric triamide was maintained at 25° C. for 22 hours. The mixture was partitioned with water and 1:1 hexaneether. The organic layer was washed with water and brine, dried and concentrated. The resulting oil was distilled at 0.30 mm on a Kugelrohr at 105°-110° C., giving 0.38 g of the desired compound as an oil; PMR δ 2.36 (2H, t, CH2CN).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH:16]([C:19]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:21]([C:22]([OH:24])=[O:23])[C:20]=1[OH:29])([CH3:18])[CH3:17].Cl>[N+](C1C=CC=CC=1)([O-])=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:26]2[C:25]([CH3:28])=[C:21]([C:22]([OH:24])=[O:23])[C:20]([OH:29])=[C:19]([CH:16]([CH3:18])[CH3:17])[CH:27]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Cc1ccc(C(C)C)c(O)c1C(=O)O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1c(S(=O)(=O)c2ccc(Cl)cc2)cc(C(C)C)c(O)c1C(=O)O
Temperature: 0 °C

Procedure:
4-Chlorophenylsulphonyl chloride (6.3 g.) is added to a mixture of aluminium chloride (8.1 g.) and 3-isopropyl-6-methylsalicylic acid (5.7 g.) in dry nitrobenzene (3 ml.). The mixture is heated at 95°-100° C. for 4 hours and is then stirred into a mixture of ice (250 g.) and concentrated hydrochloric acid (30 ml.). The mixture is subsequently extracted with ethyl acetate (3 × 250 ml.). The extracts are washed with water and are then concentrated in vacuo. Residual nitrobenzene is removed by steam distillation. The oily solid, which remains after decantation of the water from the distillation residue, is crystallised from a mixture of xylene and petroleum ether (b.p. 60°-80° C.) to give 5-(4-chlorophenylsulphonyl)-3-isopropyl-6-methylsalicylic acid, m.p. 165°-166° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[CH3:15][O:16][C:17](=[O:41])[CH2:18][C:19]1[CH:20]=[C:21]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=2[CH2:37][NH:38][CH2:39][CH3:40])[C:22]([O:25][CH3:26])=[CH:23][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:15][O:16][C:17](=[O:41])[CH2:18][C:19]1[CH:20]=[C:21]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:36])[F:35])=[CH:29][C:28]=2[CH2:37][N:38]([C:8](=[O:9])[C:7]([O:6][C:5]2[CH:13]=[CH:14][C:2]([Cl:1])=[CH:3][CH:4]=2)([CH3:12])[CH3:11])[CH2:39][CH3:40])[C:22]([O:25][CH3:26])=[CH:23][CH:24]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)Cl
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)C(C)(C)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-chloro-phenoxy)-2-methyl-propionyl chloride (0.58 mmol) in CH2Cl2 was added (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.200 g, 0.52 mmol) in triethylamine (0.17 mL, 1.23 mmol), and the reaction was stirred at room temperature for 30 minutes. The mixture was concentrated and purified by silica gel chromatography (10-30% EtOAc in hexanes) to give [2′-({[2-(4-chloro-phenoxy)-2-methyl-propionyl]-ethyl-amino}-methyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester. The ester was hydrolyzed according to the procedure described in Example 9, Step 2.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>C1COCC1>[CH3:32][N:33]1[CH2:34][CH2:35][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:41][CH:40]=2)[CH2:37][CH2:38]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(N3CCN(C)CC3)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 31.7 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 69, 100 mg, 0.240 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (50.53 mg, 0.264 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was dissolved in EtOAc. The resulting solution was diluted with Hexanes to initiate the precipitation of the product. The solid precipitate that formed was filtered then washed with ˜1 mL of i-prOH yielding 32% (45 mg, 0.076 mmol) of the title compound.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([N:12]2[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[NH:14][C:13]2=[O:20])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[H-].[Na+].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[CH3:18][C:15]1([CH3:19])[N:14]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:13](=[O:20])[N:12]([C:5]2[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=2)[C:16]1=[O:17]
Reactant: CC1(C)NC(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1=O
Reactant: CCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCCN1C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)C1(C)C

Procedure:
Using the procedure of Example 1, 1 g of 1-(3-trifluoromethyl-4-nitro-phenyl)-4,4-dimethyl-imidazolidine-2,5-dione prepared from a 50% suspension of 170 mg of sodium hydride in oil and 0.7 ml of 1-bromo-nonane were reacted to obtain after chromatography on silica 1.08 g of the desired product melting at 63° C.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:13]([OH:15])=O)[C@@H:10]([CH3:12])[OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:19][CH2:18]1>O>[C:1]([NH:8][C@@H:9]([C:13]([N:26]1[CH2:25][CH2:24][N:23]([CH:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)[CH2:28][CH2:27]1)=[O:15])[C@@H:10]([CH3:12])[OH:11])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: C[C@@H](O)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: O
Product: C[C@@H](O)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(C2CCN(C)CC2)CC1

Procedure:
Prepared from N-Boc-D-allo-threonine and 1-(1-methyl-piperidin-4-yl)piperazine using methods substantially equivalent to General Coupling Method 1. 1H NMR. ES-MS, m/z 385.5 (M+1)+. Analysis For C19H36N4O4.1.0 H2O: Calcd: C 56.69; H 9.52; N 13.92; Found: C 57.18; H 9.59; N 13.85.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[C:5]([CH3:11])=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:5]1[C:6]2[CH:7]=[CH:8][O:9][C:10]=2[C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)c2occc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)c2ccoc12
Yield: 108 %

Procedure:
A mixture of 7-fluoro-4-methyl-benzofuran (14.2 g), N-bromosuccinimide (19.7 g), benzoyl peroxide (0.5 g) and carbon tetrachloride (600 ml) was heated under reflux under the illumination of an 80 W flood lamp for 20 h. The mixture was cooled, and filtered and the filtrate evaporated to dryness to give the title compound as a pale orange oil (23.4 g)
Reaction SMILES: [N:1]1([CH:7]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:41]12[CH2:48][CH2:47][CH:44]([CH2:45][CH2:46]1)[C@@H:43](O)[CH2:42]2>C1COCC1>[N:1]1([CH:7]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[C:8]([O:10][C@@H:43]2[CH:44]3[CH2:47][CH2:48][N:41]([CH2:46][CH2:45]3)[CH2:42]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(c1cccs1)N1CCCCC1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(c1cccs1)N1CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.6 %

Procedure:
A mixture of 2-(piperidin-1-yl)-2-(thiophen-2-yl)acetic acid (250 mg, 1.11 mmol), DCC (458 mg, 2.22 mmol), HOBT (300 mg, 2.22 mmol) and (R)-quinuclidin-3-ol (282 mg, 2.22 mmol) in dry THF (11.1 ml) was stirred at room temperature under nitrogen atmosphere for 24 hours. The pale pink suspension was filtered washing with THF (5 ml) and the pale pink solution was evaporated. The crude was purified by flash chromatography (DCM/MeOH=95/5+0.4% NH4OH) to obtain the title compound (132 mg, 35.6% yield) as a colorless oil.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=O)[CH2:3][CH2:4][C:5](=[O:7])O.[NH2:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15].[C:20](O)(=O)[CH3:21]>>[NH:1]1[C:5](=[O:7])[CH2:4][CH2:3][C@H:2]1[C:8]([NH:11][C@H:12]([C:17]([N:1]1[CH2:21][CH2:20][CH2:4][CH2:3][CH2:2]1)=[O:19])[CH2:13][CH:14]([CH3:15])[CH3:16])=[O:10]
Reactant: CC(=O)O
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)O
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N1CCCCC1

Procedure:
2.0 g (4.51 mmoles) of Z-Glp-Leu-piperidine are dissolved in 40 ml of methanol, 0.4 g of a 10% palladium-on-carbon catalyst are added to the solution, and hydrogen is bubbled through the mixture for one hour. The catalyst is filtered off, the filtrate is evaporated, and the residue is crystallized from ether. 1.12 g (81%) of Glp-Leu-piperidine are obtained; m.p.: 99°-100° C., Rf5 =0.71, [α]D25 =+30.4° (c=1%, in acetic acid). Analysis for amino acids: Glu=0.95 (1.0), Leu=1.00 (1.0).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][CH2:7][CH2:8][S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C.CC(O)=O>C(Cl)Cl>[Br:1][CH2:2][C:3]([NH:6][CH2:7][CH2:8][S:9][C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CBr)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromoacetylbromide (54 μl, 0.62 mmol) was dissolved in 0.5 ml CH2Cl2 and added to a solution of H2N—CH2—CH2-STrt (200 mg, 0.56 mmol) and DIEA (196 μl, 1.1 mmol) in CH2Cl2 (1 ml). The mixture was stirred for 1 h at RT. The reaction mixture was acidified with AcOH (100 μl) and the solvent was removed in vacuo. The residue was purified over silica gel (heptane/EtOAc=1:1) to obtain product Br—CH2—CONH—(CH2)2-STrt.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([S:15]([Cl:18])(=[O:17])=[O:16])=[CH:10][C:11]=3[CH2:12]2)=[CH:4][CH:3]=1.[NH:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(Cl)Cl>[ClH:18].[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([S:15]([N:19]4[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)(=[O:17])=[O:16])=[CH:10][C:11]=3[CH2:12]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: C1CNCCNC1
Solvent: ClCCl
Product: Cl
Product: O=S(=O)(c1ccc2c(c1)Cc1cc(Br)ccc1-2)N1CCCNCC1
Reaction time: 18 h

Procedure:
Add the product of step 1 (1.0 g, 2.9 mmol) in methylene chloride (10 mL) dropwise over 10 minutes to hexahydro-2H-1,4-diazepine (0.35 g) in methylene chloride (20 mL). Stir for 18 hours. Partition the reaction mixture between ethyl acetate (75 mL) and hydrochloric acid (75 mL, 1N). Separate, and adjust the pH of the aqueous layer to alkaline pH (phenolphthalein indicator) with aqueous sodium hydroxide (1N) forming a heavy precipitate. Extract the reaction mixture with methylene chloride (100 mL), wash with saturated aqueous sodium bicarbonate (100 mL), saturated aqueous sodium chloride (100 mL). Dry (MgSO4), filter and concentrate in vacuo to give the title compound free base (0.87 g) as a light yellow solid. Rf=0.52 (450:45:5 methylene chloride:methanol:acetic acid). Chromatograph the free base (120 mg) on a column of silica gel (300 g, 60 micron particle size) eluting with 1:9 methanol:methylene chloride to give a solid. Dissolve the solid in hydrochloric acid (10 mL) and concentrate to give the title compound (110 mg) as a white solid, as the semihydrate. Calculated for C18H21O2.5N2SBrCl: C, 47.76; H, 4.68; N, 6.18. Observed: C, 47.76; H, 4.39; N, 6.14.