Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][P:2]([CH3:5])(=[O:4])[OH:3].[OH-].[CH2:7]([N+:11]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH3:10]>O.CC(O)C>[CH3:1][P:2]([CH3:5])(=[O:3])[O-:4].[CH2:20]([N+:11]([CH2:7][CH2:8][CH2:9][CH3:10])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:21][CH2:22][CH3:23]
Reactant: CP(C)(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CP(C)(=O)[O-]

Procedure:
To a flask were added 1.0 g dimethylphosphinic acid, 4.5 g of a 55-60% solution of tetrabutylammonium hydroxide in water and 20 ml 2-propanol. After heating to 50 C under nitrogen for 1 hour, the solvent was removed and another 20 ml of 2-propanol were added and removed by distillation under reduced pressure. After drying, a yellow partially solidified product was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.Br[CH2:37][CH2:38][OH:39]>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][N:26]([CH2:37][CH2:38][OH:39])[CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C1CCNCC1
Reactant: OCCBr
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C1CCN(CCO)CC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[1-(2-hydroxyethyl)piperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-piperidin-4-yl-1,3-thiazolidine-2,4-dione (Example 113) and 2-bromoethanol following General Procedure S.
Reaction SMILES: Br.[CH3:2][O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[S:8][C:7]1=[NH:15].[CH2:16]1[CH:23]2[C:19]3([C:25](O)=[O:26])[CH2:20][CH:21]([CH2:24][CH:17]1[CH2:18]3)[CH2:22]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:2][O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[S:8]/[C:7]/1=[N:15]\[C:25]([C:19]12[CH2:20][CH:21]3[CH2:24][CH:17]([CH2:16][CH:23]1[CH2:22]3)[CH2:18]2)=[O:26]
Reactant: O=C(O)C12CC3CC(CC1C3)C2
Reactant: COCCn1c2c(sc1=N)CCCC2
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCn1c2c(s/c1=N\C(=O)C13CC4CC(CC1C4)C3)CCCC2

Procedure:
A mixture of the product of Example 68A (293 mg, 1.00 mmol), hexahydro-2,5-methano-pentalene-3a-carboxylic acid (199 mg, 1.20 mmol), HATU (570 mg, 1.50 mmol) and triethylamine (836 mL, 6.00 mmol) in 15 mL of DMF was processed according to the method of Example 3B to afford the title compound: 1H NMR (500 MHz, DMSO-d6) δ 1.53-1.62 (m, 4H) 1.67-1.82 (m, 8H) 2.07-2.12 (m, 2H) 2.23-2.27 (m, 2H) 2.45-2.49 (m, 3H) 2.54-2.59 (m, 2H) 3.23 (s, 3H) 3.63 (t, J=5.3 Hz, 2H) 4.16 (t, J=5.5 Hz, 2H); MS (DCI/NH3) m/z 361 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][CH:6]=1.[C:20]([C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[O:24][CH2:25][CH:26]1[O:28][CH2:27]1)#[N:21]>C(O)(C)C>[C:20]([C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[O:24][CH2:25][CH:26]([OH:28])[CH2:27][NH:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:9][CH:10]=1)#[N:21]
Reactant: CC(C)(N)CNc1ccc(C2=NNC(=O)CC2)cc1
Reactant: N#Cc1ccccc1OCC1CO1
Solvent: CC(C)O
Product: CC(C)(CNc1ccc(C2=NNC(=O)CC2)cc1)NCC(O)COc1ccccc1C#N
Reaction time: 24 h
Yield: 78.6 %

Procedure:
2.6 g of 6-[4-(2-amino-2-methylpropylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone and 1.5 g of 1-(2-cyanophenoxy)-2,3-epoxypropane obtained in Example 1, (3) were dissolved in 20 ml of isopropanol, and heated with stirring for 24 hours. The solution was then worked up in the same way as in Example 1, (5). Recrystallization from dichloromethane-ether gave 2.93 g of 6-[4-[2-[3-(2-cyanophenoxy)-2-hydroxypropylamino]-2-methylpropyl-amino]phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:21])[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1.O>[CH2:29]([N:26]([CH2:27][CH3:28])[CH2:25][CH2:24][CH2:23][NH:22][C:20](=[O:21])[CH2:19][N:11]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:3][CH:4]=2)[CH:9]=[N:10]1)[CH3:30]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CCCNC(=O)Cn1ncc(-c2ccc(N)cc2)c1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CCN(CC)CCCNC(=O)Cn1ncc(-c2ccc(NS(C)(=O)=O)cc2)c1-c1ccccc1

Procedure:
A solution of 8 lg (0.02 mol) of 4-(4-aminophenyl)-N-[3-(diethylamino)propyl]-5-phenyl-1H-pyrazole-1-acetamide of example 46 in 50 mL of pyridine was cooled to 5° C. and 4.6 g (0.04 mol) of methanesulfonyl chloride was added dropwise below 10° C. The reaction was stripped below 60° C. in vacuo, dissolved in about 75 mL of water, treated with excess saturated aqueous sodium bicarbonate, extracted into methylene chloride and stripped. The product was recrystallized from acetonitrile, 7.2 g, mp 179°-180° C.
Reaction SMILES: [C:1]([NH:9][NH:10][C:11](=O)[C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1.C(OCC)(=O)C>CCCCCCC>[C:2]1([C:1]2[S:32][C:11]([C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])=[N:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: C[C@H](NC(=O)OC(C)(C)C)c1nnc(-c2ccccc2)s1
Yield: 75.1 %

Procedure:
To a solution of (S)-tert-butyl (1-(2-benzoylhydrazinyl)-1-oxopropan-2-yl)carbamate (155 mg, 0.5 mmol, 1.0 equv. in 5 ml of THF) was added Lawesson's reagent (36.4 mg, 0.5 mmol, 1.0 equv.) the reaction mixture was stirred at reflux for 3 hours, the reaction mixture was filtered and the solvent was removed to yield the crude product. Silica gel column chromatography (ethyl acetate in heptane 10 to 50%) to provide (S)-tert-butyl (1-(5-phenyl-1,3,4-thiadiazol-2-yl)ethyl)carbamate (114.6 mg, white solid) in 70.7% yield. 1H NMR (400 MHz, CD2Cl2) δ 7.94-7.72 (m, 2H), 7.52-7.26 (m, 3H), 5.59 (b, 1H), 5.11 (b, 1H), 1.57 (d, J=7.0 Hz, 3H), 1.34 (s, 9H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][N:12]=[C:13]([C:16]3[C:21]([CH2:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:24][CH3:25])[CH:14]=2)[N:9]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[CH:8]=1)C.CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(Cl)Cl>[CH2:22]([C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:24][CH3:25])[C:16]=1[C:13]1[CH:14]=[C:15]2[C:7]([CH2:6][CH2:5][CH2:4][OH:3])=[CH:8][N:9]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=3)[C:10]2=[CH:11][N:12]=1)[CH3:23]
Reactant: CCOC(=O)CCc1cn(-c2ccc(C(C)C)cc2)c2cnc(-c3c(CC)cccc3CC)cc12
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCc1cccc(CC)c1-c1cc2c(CCCO)cn(-c3ccc(C(C)C)cc3)c2cn1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of 3-[5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-propionic acid ethyl ester (220 mg, 0.47 mmol, prepared by the procedure described in Example 11, Step 5) in DCM (4 mL) at −78° C., DIBAL (1M solution in toluene, 2.35 mL, 2.3 mmol) is added, and the mixture is stirred at −78° C. for 3 h. Reaction is warmed up to room temperature, and a saturated aqueous Rochelle's salt solution (6 mL) is carefully added. Stirring is continued for another 1 hour. The organic layer is separated, and the aqueous phase is extracted with DCM. The combined organic solutions are washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Chromatography of the residue affords 3-[5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-propan-1-ol as a colorless oil. 1H NMR: (CDCl3) 8.97 (s, 1H), 7.49 (s, 1H), 7.48 (d, J=12 Hz, 2H), 7.42 (d, J=10 Hz, 2H), 7.32 (s, 1H), 7.27 (t, J=10 Hz, 1H), 7.15 (d, 12 Hz, 2H), 3.76 (t, J=6 Hz, 2H), 3.01 (m, 1H), 2.89 (t, J=6 Hz, 2H), 2.35 (m, 4H), 2.01 (m, 2H), 1.33 (d, J=10 Hz, 6H), 1.073 (t, J=10 Hz, 6H); LCMS m/z 427.32 (2.32 min).
Reaction SMILES: [CH2:1](I)[CH2:2][CH2:3][CH2:4][CH3:5].[NH:7]1[CH2:12][CH:11]=[C:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:8]1>CC(C)=O.[Ag]=O>[CH2:1]([N:7]1[CH2:8][CH:9]=[C:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:11][CH2:12]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCI
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: O=[Ag]
Solvent: CC(C)=O
Product: CCCCCN1CC=C(c2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5.18 g of silver oxide and then 20 ml of pentyl iodide were added to a solution of 10 g of 3-(1,2,3,6-tetrahydropyridin-4yl)-1H-indole in 100 ml of acetone and after stirring the mixture for 4 hours at room temperature, another 2.5 ml of pentyl iodide were added thereto. The mixture was stirred for one hour and was filtered and the filter was rinsed with a 1-1 methylene chloride-methanol mixture. The filtrate was evaporated to dryness under reduced pressure at 40° C. and the residue was chromatographed over silica gel. Elution was effected with a 7-2-1 chloroform-methanol-triethylamine mixture and the residue from evaporation of the solvents was extracted with 250 ml of refluxing ethanol. The organic extract was filtered and crystallization of the filtrate was effected at 0° to 5° C. to obtain 7.9 g of 3-(1-pentyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole melting at about 180° C.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH2:4][CH2:5][C@@H:6]3[C@@H:15]([C:16]=2[CH:17]=[CH:18][CH:19]=1)[CH2:14][CH2:13][C@@:11]1([CH3:12])[C@H:7]3[CH2:8][CH2:9][C@@H:10]1[OH:20]>CC(C)=O.S([O-])([O-])(=O)=O.[NH4+].[NH4+].[O-2].[O-2].[O-2].[Cr+6]>[F:1][C:2]1[C:3]2[CH2:4][CH2:5][C@@H:6]3[C@@H:15]([C:16]=2[CH:17]=[CH:18][CH:19]=1)[CH2:14][CH2:13][C@@:11]1([CH3:12])[C@H:7]3[CH2:8][CH2:9][C:10]1=[O:20]
Reactant: C[C@]12CC[C@@H]3c4cccc(F)c4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: [Cr+6]
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: CC(C)=O
Product: C[C@]12CC[C@@H]3c4cccc(F)c4CC[C@H]3[C@@H]1CCC2=O
Temperature: 0 °C

Procedure:
To a solution of 4-fluoroestra-1,3,5-(10)-trien-17β-ol IV as prepared in Example 2 (100 mg, 0.36 mmol) in 1.5 ml of acetone at 0° C. is added, dropwise with stirring, a solution of (95ml) of 8N chromium trioxide in ammonium sulfate. After approximately 5 min. the reaction mixture is poured into 75 ml of ice-water and the solids are collected. The filter cake is stirred with methanol, the inorganic salts are removed and the filtrate is evaporated to dryness to give the crude product, 4-fluoroestra-1,3,5-(10)-trien-17-one as a tan solid. The latter crystallizes from ether-petroleum ether (30°-60°) as a colorless solid (60 mg, 61% yield), mp 139°-141° C. Ir (KBr)cm-1 1724 (C17C=O), 1230 (aryl fluoride); 1H NMR δ7.21-6.81 (m, 3, H1, H2, H3 aromatic) 2.91-1.54 (m, 15), 0.92 (s, 3, C18CH3). Anal. Calc'd. for C, 79.38; H, 7.77; F, 6.98. Found: C, 79.53; H, 7.76; F, 7.13.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:29])[N:12]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH:25]=O)=[C:19]([O:27][CH3:28])[CH:18]=4)[CH:13]=[CH:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.CC(O)=O.[OH-].[Na+]>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:29])[N:12]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)=[C:19]([O:27][CH3:28])[CH:18]=4)[CH:13]=[CH:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1CCC=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1CCCN1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Dissolve 3-{4-[2-(4-chloro-phenyl)-4-oxo-4H-thiazolo[5,4-c]pyridin-5-yl]-2-methoxy-phenyl}-propionaldehyde (94 mg, 0.22 mmol) in 1,2-dichloroethane (2.2 mL) and add pyrrolidine (20 μL, 0.24 mmol), AcOH (19 μL, 0.33 mmol), and NaHB(OAc)3 (70 mg, 0.33 mmol). Stir the yellow solution at room temperature for 1 h, then add 1N NaOH (5 mL), and extract the mixture with CH2Cl2 (2×10 mL). Combine the organic portions, then dry, filter, and concentrate. Purify the crude material by flash chromatography, using 8% 2N NH3 in MeOH/CHCl3 as eluent, to give the title compound (75 mg, 71%). MS (ES+) 480.1 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 8.03 (d, 2H, J=8.3 Hz), 7.48 (d, 2H, J=8.8 Hz), 7.43 (d, 1H, J=7.5 Hz), 7.25 (t, 1H, J=3.7 Hz), 6.97 (d, 1H, J=7.5 Hz), 6.93-6.88 (m, 2H), 3.83 (s, 3H), 2.70 (t, 2H, J=7.7 Hz), 2.60 (br s, 6H), 1.96-1.79 (m, 6H).
Reaction SMILES: [N+](C1C=C(C=O)C(O)=CC=1)([O-])=[O:2].C(C[C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19])#N.C(COC1C=CC=CC=1C([O-])=O)#N.B#B>O1CCCC1>[C:21]1(=[O:2])[O:20][C:18](=[O:19])[C:17]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:16]12
Reactant: COC(=O)c1ccccc1CC#N
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Agent: B#B
Agent: N#CCOc1ccccc1C(=O)[O-]
Solvent: C1CCOC1
Product: O=C1OC(=O)c2ccccc21

Procedure:
The intermediates for reacting with 5-nitrosalicylaldehyde to prepare compounds wherein --Y-- contains an ethylbenzyl or ethoxybenzyl group were prepared by the reduction of the appropriate methyl cyanomethylbenzoate or cyanomethoxybenzoate with diborane in tetrahydrofuran solution, followed by the reaction of the amino compound thus obtained with phthalic anhydride at 100° C. and then with phosphorus tribromide also at 100° C. The various intermediates which were characterised have melting points as follows: 4-(2-aminoethyl)benzyl alcohol hydrochloride m.p. 160°-162° C. 3-(2-aminoethyl)benzyl alcohol hydrochloride m.p. 115°-118° C. 2-(2-aminoethyl)benzyl alcohol hydrochloride m.p. 103°-104° C. 4-(2-aminoethoxy)benzyl alcohol m.p. 92°-94° C. 3-(2-aminoethoxy)benzyl alcohol hydrochloride m.p. 143°-145° C. 4-(2-phthalimidoethyl)benzyl bromide 158°-161° C. 3-(2-phthalimidoethyl)benzyl bromide 93°-94° C. 2-(2-phthalimidoethyl)benzyl bromide 140°-141° C. 3-(2-phthalimidoethoxy)benzyl bromide 116°-117° C. 4-(2-phthalimidoethoxy)benzyl chloride 109°-112° C. (prepared by reacting with mesyl chloride and triethylamine in place of phosphorus tribromide).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[CH:4][CH:3]=1.B1([C:22]2[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=2)OCCCO1.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>[CH3:14][N:13]([CH2:12][CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:10]=2)[CH:6]=[CH:7]1)[CH3:15]
Reactant: c1cncc(B2OCCCO2)c1
Reactant: CN(C)CCn1ccc2ccc(Br)cc21
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
Product: CN(C)CCn1ccc2ccc(-c3cccnc3)cc21
Yield: 81.5 %

Procedure:
In a 25 mL round bottom flask equipped with a stir bar was added 6-Bromo-1-(2-(N,N-dimethylamino)ethyl)-1H-indole (0.10 g; 0.37 mmol), pyridine-3-boronic acid-1,3-propanediol cyclic ester (0.12 g; 0.74 mmol), toluene (10 mL), sodium carbonate (2M) (4 mL) and tetrakis(triphenylphosphine)palladium(0) (0.02 g; 0.04 mmol). The reaction mixture was refluxed overnight, filtered through a pad of celite and the solvent evaporated in vacuo. The residue was dissolved in ethyl acetate (30 mL) and successively washed with water (2×20 mL) and brine (20 mL). The organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuo. The crude residue was purified by column chromatography on silica gel using chloroform:ammonialmethanol (2N) (98:2) to yield the title compound as yellow oil (0.08 g; 85%). 13C NMR (CDCl3): δ 148.6, 147.8, 137.9, 136.5, 134.5, 131.4, 129.3, 128.5, 123.5, 121.6, 118.9, 107.9, 101.3, 59.1, 45.8, 44.8.
Reaction SMILES: [O:1]([CH:8]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=1)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].O1CCC[CH2:24]1.Cl>O.CO>[CH3:24][C:19]1[CH:18]=[C:13]([CH:12]=[CH:11][C:10]=1[CH2:8][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]([OH:16])=[O:15]
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc(C(C)Oc2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)O)ccc1COc1ccccc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
A mixture of methyl 4-(1-phenoxyethyl)benzoate (0.32 g, 1.2 mmol), lithium hydroxide monohydrate (571 mg, 13.6 mmol), tetrahydrofuran (15 mL), methanol (5 mL) and water (5 mL) was stirred at 20° C. for 4 hours. The mixture was neutralized to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (15 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to give 3-methyl-4-(phenoxymethyl)benzoic acid (0.21 g, 72%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:25][C:10]3=[CH:11][C:12]4[C:13]([CH2:23][CH3:24])([CH2:21][CH3:22])[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:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:29]([CH:26]5[CH2:28][CH2:27]5)=[O:30])=[CH:6][NH:5][N:4]=4)[NH:25][C:10]3=[CH:11][C:12]=2[C:13]([CH2:23][CH3:24])([CH2:21][CH3:22])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(CC)(CC)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(Cl)C1CC1
Product: CCN1C(=O)C(CC)(CC)c2cc3[nH]c(-c4n[nH]cc4NC(=O)C4CC4)nc3cc21
Yield: 34.5 %

Procedure:
Cyclopropanecarboxylic acid[3-(5,7,7-triethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5,7,7-triethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (137.7 mg, 0.407 mmol) and cyclopropanecarbonyl chloride (46.8 mg, 0.448 mmol). 57 mg (34%) of the title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:14](I)[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.C(O)C>C(OCC)C.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>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:14]1[CH:13]=[C:12]([Cl:11])[CH:17]=[CH:16][C:15]=1[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Clc1ccc(OCc2ccccc2)c(I)c1
Reactant: OB(O)c1ccccc1Br
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: Cc1ccccc1
Solvent: CCOCC
Product: Clc1ccc(OCc2ccccc2)c(-c2ccccc2Br)c1
Yield: 55.1 %

Procedure:
A mixture of 2-bromophenylboronic acid (2.01 g, 10 mmol), 4-chloro-2-iodo-1-[(phenylmethyl)oxy]benzene (3.445 g, 10 mmol), potassium carbonate (5.52 g, 40 mmol) and tetrakis(triphenylphosphine)palladium(0) (580 mg, 0.5 mmol) in 1:1 toluene/ethanol (45 ml) was stirred and heated at 90° C. under nitrogen for 2 hours when a further 1 g (4.98 mmol) of 2-bromophenylboronic acid and 0.2 g (0.17 mmol) of tetrakis(triphenylphosphine)palladium(0) were added. The mixture was heated for 6 hours then cooled, diluted with diethyl ether/water and the organic phase separated, dried (magnesium sulphate) and evaporated. The residue was purified by chromatography on silica eluting with ethyl acetate/iso-hexane (1:49) then rechromatographed eluting with dichloromethane/iso-hexane (1:9) to give 2.06 g of colourless gum which slowly crystallised.
Reaction SMILES: CO[C:3](=[O:19])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][O:7]1.[CH3:20][NH:21][C:22]([NH2:24])=[O:23].C[O-].[Mg+2].C[O-].CO>>[Cl:18][C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][O:7]2)[C:3]([NH:24][C:22]([NH:21][CH3:20])=[O:23])=[O:19])[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: COC(=O)C(CC1CCCO1)c1ccc(Cl)c(Cl)c1
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCO1)c1ccc(Cl)c(Cl)c1

Procedure:
A solution of 2-(3,4-dichloro-phenyl)-3-(tetrahydro-furan-2-yl)-propionic acid methyl ester (617 mg, 2.04 mmol), methylurea (302 mg, 4.07 mmol), and a solution of magnesium methoxide in methanol (7.4 wt. % , 4.63 mL, 3.06 mmol) was heated at 100° C. for 8 h. After this time, the reaction mixture was concentrated in vacuo, dissolved in ethyl acetate (50 mL), and then filtered through a pad of silica gel. The organics were then concentrated in vacuo to give the crude product. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 1-[2-(3,4-dichloro-phenyl)-3-(tetrahydro-furan-2-yl)-propionyl]-3-methyl-urea as a white solid: EI-HRMS m/e calcd for C15H18Cl2N2O3 (M+) 344.0694. found 344.0699.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]([CH3:36])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([N:21]1[CH2:35][C:24]2=[C:25]3[N:30]([N:31]=[C:23]2[CH2:22]1)[C:29]([CH3:32])=[C:28]([Cl:33])[C:27]([CH3:34])=[N:26]3)=[O:20])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>CC(=O)OCC>[Cl:33][C:28]1[C:27]([CH3:34])=[N:26][C:25]2[N:30]([N:31]=[C:23]3[CH2:22][N:21]([C:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[O:12][CH2:11][CH2:10][N:9]([CH2:8][CH2:7][OH:6])[CH3:36])=[O:20])[CH2:35][C:24]3=2)[C:29]=1[CH3:32]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OCCN(C)CCO[Si](C)(C)C(C)(C)C)C3
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OCCN(C)CCO)C3
Yield: 38.6 %

Procedure:
A mixture of [2-(2-{[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-methyl-amino}-ethoxy)-phenyl]-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]inden-2-yl)-methanone (40 mg; 0.07 mmol; 1 eq.) and a 1M solution of tetrabutyl-ammonium fluoride in THF (0.09 mL; 0.09 mmol; 1.2 eq.) was stirred at room temperature for 3 hours. The solution was diluted with EA, washed with water, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (EA to 20% MeOH in EA) afforded the title compound (12 mg, 38%) as a colourless oil. HPLC (max plot) 95.8%, Rt 2.56 min. UPLC/MS: (MS+) 444.3 ([M+H]+).