Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9](Cl)=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH2:28][CH2:29][N:30]([C:9]([C:8]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:7]=2[N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:10])[CH2:31][CH2:32]1
Reactant: Fc1ccc(N2CCNCC2)c(Cl)c1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2ccc(F)cc2Cl)CC1

Procedure:
The title compound was prepared according to the procedure described for example 46 from 2-Morpholin-4-yl-5-nitro-benzoyl chloride and 1-(2-Chloro-4-fluoro-phenyl)-piperazine (70%, yellow solid, MS (m/e): 449.2 (M+H, 100%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[C:6](=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].S(=O)(=O)(O)O>>[CH2:1]([O:3][C:4]([C:5]1[O:13][C:14]2[CH:15]=[C:16]([O:20][CH3:21])[CH:17]=[CH:18][C:19]=2[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:22])[CH3:2]
Reactant: CCOC(=O)C(=O)C(Oc1cccc(OC)c1)C(=O)OCC
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1oc2cc(OC)ccc2c1C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(3-Methoxy-phenoxy)-3-oxo-succinic acid diethyl ester (23) (60 g, 193.4 mmol) is dissolved in 32 ml of cooled (−15° C.) cone, sulfuric acid and stirred for 3 h whereas the reaction mixture slowly warmed up to room temperature. Then the mixture is poured onto 1 kg of ice and extracted with diethyl ether. The organic layers are washed with brine, dried over sodium sulfate, filtrated and evaporated. The crude product is purified by Flash-chromatography (silica gel, ethyl acetate/hexanes 1:9).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[N:4]=1)#[N:2].C[O-].[Na+].[Cl-].[NH4+:24].C(O)(=O)C>CO>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][N:5]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:11]2[C:3]([C:1](=[NH:24])[NH2:2])=[N:4]1
Reactant: N#Cc1nn(Cc2ccccc2F)c2ncccc12
Reactant: [NH4+]
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
108.00 g (0.43 mol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (example I, step 4) are dissolved in one liter of methanol and added dropwise to a solution of 94.73 g (1.67 mol; purity: 95%) of sodium methoxide in 3 l of methanol. After stirring at RT for 2 hours, 28.83 g (0.54 mol) of ammonium chloride are added, and subsequently 100.03 g (1.67 mol) of glacial acetic acid are added dropwise. This solution is stirred under reflux overnight. The solvent is removed in vacuo, the residue is twice suspended in acetone and the insoluble solid is filtered off with suction. The latter is dissolved in 1.5 l of ethyl acetate, and 590 ml of an aqueous 20% strength sodium carbonate solution are added. Stirring for 20 minutes is followed by dilution with 200 ml of 1N sodium hydroxide solution. The organic phase is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered. The solvent is removed in vacuo. 99.10 g (86% of theory) of the product are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:39]=[CH:38][C:6]2[N:7](C(C3CCOCC3)=O)[C:8](=[O:29])[C@@H:9]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C@H:10]([CH3:20])[N:11]([C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])[C:5]=2[CH:4]=1)#[N:2].[OH-].[Na+]>CO.CCOC(C)=O>[C:1]([C:3]1[CH:39]=[CH:38][C:6]2[NH:7][C:8](=[O:29])[C@@H:9]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:25])[CH3:26])[C@H:10]([CH3:20])[N:11]([C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])[C:5]=2[CH:4]=1)#[N:2]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N(C(=O)C2CCOCC2)c2ccc(C#N)cc2N1C(=O)C1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)Nc2ccc(C#N)cc2N1C(=O)C1CCOCC1
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
To a rt solution of tert-butyl(3S,4S)-7-cyano-4-methyl-2-oxo-1,5-bis(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (0.707 g, 1.31 mmol) in MeOH (13.1 ml) was added 1 M aq. sodium hydroxide (1.44 ml, 1.44 mmol), dropwise. The reaction was stirred for 30 min, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(2S,3S)-8-cyano-2-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (289 mg, 52%) as a white solid. MS m/z 451 (MNa)+.
Reaction SMILES: CNCC1C=CC(C2C=CC=CC=2)=CC=1.[CH3:16][C:17]([CH3:39])([CH3:38])[C:18]#[C:19]/[CH:20]=[CH:21]/[CH2:22][N:23]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)[CH3:24]>>[CH3:16][C:17]([CH3:39])([CH3:38])[C:18]#[C:19]/[CH:20]=[CH:21]\[CH2:22][N:23]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:30][CH:31]=1)[CH3:24]
Reactant: CN(C/C=C/C#CC(C)(C)C)Cc1ccc(-c2ccccc2)cc1
Agent: CNCc1ccc(-c2ccccc2)cc1
Product: CN(C/C=C\C#CC(C)(C)C)Cc1ccc(-c2ccccc2)cc1

Procedure:
N-methyl-4-phenylbenzylamine (0.75 g) was processed in a similar manner as in Synthesis Example 5, whereby trans-N-(6,6-dimethyl-2-hepten-4-yn-1-yl)-N-methyl-4-phenylbenzylamine (Compound 9) and cis-N-(6,6-dimethyl-2-hepten-4-yn-1-yl)-N-methyl-4-phenylbenzylamine (Compound 10) were obtained in amounts of 0.52 g (yield: 45%) and 0.12 g (yield: 10.4%), respectively. The followings are their NMR spectrum data:
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[NH:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][C:46]=2B(O)O)[CH:41]=[CH:40]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][C:46]=2[C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:41]=[CH:40]1
Reactant: OB(O)c1cccc2cc[nH]c12
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cccc5cc[nH]c35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 84.9 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.17 mmol) was treated with (1H-indol-7-yl)boronic acid (65 mg, 0.28 mmol), sodium carbonate (43 mg, 0.40 mmols) and bis(triphenylphosphine)palladium(II) dichloride (12 mg, 0.02 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 25%, hexane-ethyl acetate) to give 91 mg (81% yield) of the title compound. Purity 94%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][S:19][CH2:20][CH2:21][NH2:22]>>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][S:19][CH2:20][CH2:21][NH:22][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH3:12])[CH:5]=1
Reactant: COc1ccc(C(=O)O)cc1C
Reactant: NCCSCc1ccco1
Product: COc1ccc(C(=O)NCCSCc2ccco2)cc1C
Yield: 58 %

Procedure:
Prepared in a similar manner as described in example 4 from 4-methoxy-3-methylbenzoic acid and 2-(furan-2-ylmethylthio)ethanamine. Yield 58%. 1H NMR (500 MHz, CDCl3) 2.23 (s, 3H), 2.76 (t, 2H, J=6.37 Hz), 3.59 (q, 2H, J=12.2 Hz), 3.76 (s, 2H), 3.86 (s, 3H), 6.22 (dd, 1H, J=3.49 Hz, J=2.67 Hz), 6.30 (dd, 1H, J=3.04 Hz, J=1.78 Hz), 6.46 (m, 1H, broad), 6.83 (d, 1H, J=8.51 Hz), 7.34(dd, 1H, J=1.97 Hz, J=1 Hz), 7.56 (d, 1H, J=1.72 Hz), 7.61(dd, 1H, J=8.53 Hz, J=2.25 Hz). MS (M+H, 306).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[C:3]=1[F:12].[CH2:13]([CH2:15][NH2:16])[OH:14]>C(O)C>[F:12][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[C:5]([N+:8]([O-:10])=[O:9])[C:4]=1[NH:16][CH2:15][CH2:13][OH:14]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: NCCO
Solvent: CCO
Product: O=[N+]([O-])c1ccc(F)c(F)c1NCCO
Reaction time: 5 h

Procedure:
A solution of 1,2,3-trifluoro-4-nitrobenzene (5.0 g, 28.2 mmol) and ethanolamine (1.72 g, 28.2 mmol) in 100 ml of ethanol is stirred over night at room temperature then at 70° C. for 5 hours. The reaction is concentrated to dryness and purified by silica gel flash chromatography using a gradient of 80/20 to 20/80 heptane/ethyl acetate providing an orange solid. Yield (3.8 g, 62%). 1H NMR (400 MHz, CDCl3) δ ppm 1.67 (t, J=5.08 Hz, 1H) 3.77-3.83 (m, 2H) 3.88-3.94 (m, 2H) 6.51 (ddd, J=9.77, 8.59, 7.03 Hz, 1H) 8.02 (ddd, J=9.77, 5.66, 2.34 Hz, 1H) 8.21 (s, 1H)
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:18](Cl)(=[O:20])[CH3:19]>C(#N)C>[Br:1][C:2]1[N:7]=[C:6]([S:8]([NH:11][C:18](=[O:20])[CH3:19])(=[O:9])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: NS(=O)(=O)c1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)NS(=O)(=O)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-Bromopyridine-2-sulphonamide (0.5 g, 2.11 mmol, prepared by the methods described in WO2005/058299) and potassium carbonate (2.92 g, 21.1 mmol) were initially charged in acetonitrile (10 ml). While cooling with ice, acetyl chloride (1.16 g, 14.8 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure, and the residue was taken up in water and acidified with dilute hydrochloric acid solution. It was extracted with ethyl acetate and the solvent was removed under reduced pressure. This gave 0.54 g (85% of theory) of N-[(6-bromopyridin-2-yl)sulphonyl]-acetamide.
Reaction SMILES: [F:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([C:28]#[N:29])=[N:9][C:10]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:21]=[N:22][C:23]([CH2:26]O)=[CH:24][CH:25]=4)[N:14]=3)=[CH:11][CH:12]=2)[CH2:3]1.P(Br)(Br)Br.[O:34]=[C:35]1[CH2:40][NH:39][CH2:38][CH2:37][NH:36]1>CC#N>[F:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([C:28]#[N:29])=[N:9][C:10]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:21]=[N:22][C:23]([CH2:26][N:39]5[CH2:38][CH2:37][NH:36][C:35](=[O:34])[CH2:40]5)=[CH:24][CH:25]=4)[N:14]=3)=[CH:11][CH:12]=2)[CH2:3]1
Reactant: N#Cc1nc(-c2ccnc(Nc3ccc(CO)nc3)n2)ccc1N1CC[C@H](F)C1
Reactant: O=C1CNCCN1
Agent: BrP(Br)Br
Solvent: CC#N
Product: N#Cc1nc(-c2ccnc(Nc3ccc(CN4CCNC(=O)C4)nc3)n2)ccc1N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.3 %

Procedure:
Compound 82 (40 mg, 0.10 mmol) was dissolved in MeCN (5 mL). Phosphorous tribromide (50 μL, 0.53 mmol) was added and the reaction mixture was heated under reflux for 0.5 hours. The reaction was cooled to rt and 2-oxopiperazine (100 mg, 0.99 mmol) was added and the reaction mixture stirred at rt for 16 hours. The solvent was removed in vacuo and the residue purified by reverse phase preparative LC-MS. Fractions contained the desired product were combined and the MeOH removed in vacuo. The resulting aqueous solution was frozen (−78° C.) and the solvent evaporated in vacuo (freeze dried). The title compound (3 mg, 6%) was obtained as an off-white solid. LCMS, Rt=6.15 min (MeOH-FA method), m/z 474 (MH+).
Reaction SMILES: C1C([C:7]2[O:17][C:16]3[CH:15]=[C:14]([OH:18])[CH:13]=[C:12]([OH:19])[C:11]=3[C:9](=[O:10])[CH:8]=2)=CC=C(O)C=1.Cl.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1>N1C=CC=CC=1>[C:22]([O:19][C:12]1[CH:13]=[C:14]([O:18][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=2)[CH:15]=[C:16]2[C:11]=1[C:9](=[O:10])[CH:8]=[CH:7][O:17]2)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1
Reactant: O=c1cc(-c2ccc(O)cc2)oc2cc(O)cc(O)c12
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Oc1cc(OC(=O)c2cccnc2)c2c(=O)ccoc2c1)c1cccnc1
Temperature: -10 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
In a 500 mL round-bottomed flask fitted with magnetic stirrer were placed apigenin (4′,5,7-trihydroxyflavone (5 g, 18.50 mmol)) and pyridine (250 mL). The mixture was cooled at −10° C. and nicotinoyl chloride HCl (16.5 g, 92.70 mmol) was added. Then the reaction mixture was stirred for 24 h at rt under nitrogen. The solvent was removed under reduced pressure and the residue was dissolved in chloroform, which was washed with water and evaporated. The crude product was purified by crystallization from DCM-MeOH to give 7.5 g of 2-(4-nicotinoyloxy)phenyl)-oxo-4H-chromene-5,7-diyl dinicotinate (69%). MS (ES) m/z: 586.17 (M+1), 481.11, 293.70.
Reaction SMILES: [C:1]1([N:7]2[C:11]3=[N:12][C:13]([Cl:17])=[N:14][C:15](Cl)=[C:10]3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][C@@H:19]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][OH:21]>C(O)C>[C:1]1([N:7]2[C:11]3=[N:12][C:13]([Cl:17])=[N:14][C:15]([NH:18][C@@H:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][OH:21])=[C:10]3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: Clc1nc(Cl)c2cnn(-c3ccccc3)c2n1
Solvent: CCO
Product: OC[C@H](Cc1ccccc1)Nc1nc(Cl)nc2c1cnn2-c1ccccc1
Reaction time: 24 h
Yield: 97 %

Procedure:
2.5 g of the starting material 1-phenyl-4,6-dichloropyrazolo[3,4-d]pyrimidine was suspended in 60 ml of ethanol. Next, 4.28 g of (S)-(-)-2-amino-3-phenyl-1-propanol was added and the reaction was allowed to stir for 24 hours. The solvent was then removed under vacuum and the crude oil was purified by flash chromatography (10-15-20% isopropyl alcohol/hexane) to yield 3.5 g of (S)-β-[(1-phenyl-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]benzenepropanol (97%).
Reaction SMILES: [Cu](C#N)C#N.[C:6]([Mg]Cl)([CH3:9])([CH3:8])[CH3:7].[Br:12][C:13]1[CH:14]=[CH:15][C:16](I)=[N:17][CH:18]=1>C1COCC1>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:6]([CH3:9])([CH3:8])[CH3:7])=[N:17][CH:18]=1
Reactant: CC(C)(C)[Mg]Cl
Reactant: Brc1ccc(I)nc1
Agent: N#C[Cu]C#N
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(Br)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a THF (40 ml) suspension of copper cyanide (1.79 g, 20 mmol) which was dried under reduced pressure for 4 hours was added 1.0 M THF solution of tert-butylmagnesium chloride (40 ml, 40 mmol) dropwise at −78° C. over 30 minutes and the mixture was stirred for 1 hour at −78° C. 5-Bromo-2-iodopyridine (2.83 g, 10 mmol) was added at −78° C. and the mixture was stirred for 1 hour at −78° C., followed by additional stirring for 16 hours at room temperature. Then, the reaction was quenched with 25% aqueous ammonia solution (40 ml) and the precipitates were removed by filtration and washed with EtOAc. The filtrate and washings were combined and concentrated in vacuo. Then, filtration, evaporation, and purification by silica gel column chromatography, eluting with hexane/EtOAc (20:1), gave the title compound (1.07 g, 50% yield) as a colorless oil.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[C:14]([N+:15]([O-])=O)=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[N+:18]([O-])=O>CO.[Pd]>[NH2:15][C:14]1[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[CH:7]=[C:6]2[C:5]=1[CH:4]=[CH:3][NH:18]2
Reactant: COC(=O)c1cc([N+](=O)[O-])c(/C=C/N(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)c2cc[nH]c2c1
Reaction time: 7 h
Yield: 77.3 %

Procedure:
To a solution of methyl 4-[(E)-2-(dimethylamino)ethenyl]-3,5-dinitrobenzoate (D200) (10 g, 34 mmol, 1 equiv) in MeOH (250 ml) was added 10% palladium on charcoal (50% wet, 1.0 g, 5% w/w) and the resulting mixture was stirred under an atmosphere of hydrogen for 7 h. The catalyst was removed by filtration through a pad of celite and the solution concentrated in vacuo. The residue was triturated with AcOEt/iso-hexane to give methyl 4-amino-1H-indole-6-carboxylate (D201) (5 g, 77%) as a dark pink solid. [M+H]+=191.0, RT=1.20 min.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[O:10][CH3:11].Br[CH:13]([OH:16])[CH2:14][CH3:15]>>[NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:15][CH2:14][CH2:13][OH:16])=[CH:5][C:4]=1[O:10][CH3:11]
Reactant: CCC(O)Br
Reactant: COc1cc(O)ccc1CN
Product: COc1cc(OCCCO)ccc1CN

Procedure:
3-(4-Aminomethyl-3-methoxy-phenoxy)-propan-1-ol is prepared starting from 4-aminomethyl-3-methoxy-phenol and 1-bromo-propanol in analogy to the procedures given in Example 18, steps a to c. LC-MS: tR=0.67 min, [M+1]+=212.16.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([F:30])=[C:13]([CH:29]=1)[CH:14]([C:16]1[CH:28]=[CH:27][C:19]([C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[CH3:35][C@H:36]1[CH2:41][NH:40][C@H:39]([CH3:42])[CH2:38][NH:37]1.CO>ClCCl>[CH3:35][C@H:36]1[CH2:41][NH:40][C@H:39]([CH3:42])[CH2:38][N:37]1[CH:14]([C:16]1[CH:28]=[CH:27][C:19]([C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)[C:13]1[CH:29]=[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:10]=[CH:11][C:12]=1[F:30]
Reactant: CCN(CC)C(=O)c1ccc(C(O)c2cc(O[Si](C)(C)C(C)(C)C)ccc2F)cc1
Reactant: C[C@@H]1CN[C@@H](C)CN1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CO
Product: CCN(CC)C(=O)c1ccc(C(c2cc(O[Si](C)(C)C(C)(C)C)ccc2F)N2C[C@@H](C)NC[C@@H]2C)cc1
Yield: 20 %

Procedure:
The benzhydrol from above (1.77 g, 4.1 mmol) was treated with thionyl chloride (0.45 mL, 6.2 mmol) by the method in Example 1. The crude product (approximately 4.1 mmol) was treated with trans-2,5-dimethylpiperazine (1.64 9, 14.3 mmol) as in Example 1. Chromatography on silica gel with 1-7% methanol in dichloromethane gave 0.44 g (20% from benzhydryl chloride) of (±)-4-(α-(trans-2,5-dimethyl-1-piperazinyl)-5-(tert-butyldimethylsilyloxy)-2-fluorobenzyl)-N,N-diethylbenzamide as a yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:17])[NH:11][NH:12][C:13]=2[CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1.N1C=CN=C1.[CH:23]([Si:26](Cl)([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])([CH3:25])[CH3:24].O>CN(C)C=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([O:17][Si:26]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:23]([CH3:25])[CH3:24])=[N:11][NH:12][C:13]=2[CH:14]([CH3:15])[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CC(C)c1[nH][nH]c(=O)c1Cc1ccc(I)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1[nH]nc(O[Si](C(C)C)(C(C)C)C(C)C)c1Cc1ccc(I)cc1
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a solution of 1,2-dihydro-4-[(4-iodophenyl)methyl]-5-isopropyl-3H-pyrazol-3-one (5 g) and imidazole (1.19 g) in N,N-dimethylformamide (20 mL) was added triisopropylsilyl chloride (3.1 g) at room temperature, and the mixture was stirred for 3 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 4-[(4-iodophenyl)methyl]-5-isopropyl-3-triisopropylsilyloxy-1H-pyrazole (7.27 g). To a solution of obtained 4-[(4-iodophenyl)methyl]-5-isopropyl-3-triisopropylsilyloxy-1H-pyrazole (3 g) in N,N-dimethylformamide (10 mL) was added sodium hydride (55%, 0.33 g) under ice-cooling, and the mixture was stirred for 20 minutes. To the reaction mixture were added a solution of 1-benzoyloxy-3-chloropropane (3.0 g) in N,N-dimethylformamide (10 mL) and potassium iodide (0.25 g) at the same temperature, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=20/1-10/1) to give 1-(3-benzoyloxypropyl)-4-[(4-iodophenyl)methyl]-5-isopropyl-3-triisopropylsilyloxy-1H-pyrazole (2.55 g). This material was dissolved in tetrahydrofuran (3 mL). To the solution was added 4 mol/L hydrochloric acid (1,4-dioxane solution, 10 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was poured into water. The organic layer was separated, and the organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. To the residue was added a mixed solvent of n-hexane and ethyl acetate (20/1) (10 mL), and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, and washed with a mixed solvent of n-hexane and ethyl acetate (20/1) and dried under reduced pressure to give the title compound (0.85 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[Li]CCCC.[CH3:23][Sn:24](Cl)([CH3:26])[CH3:25]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([Sn:24]([CH3:26])([CH3:25])[CH3:23])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-n2ccc3cc(Br)ccc32)cc1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1ccc2c(ccn2-c2ccc(F)cc2)c1
Reaction time: 1 h

Procedure:
1-(4-Fluorophenyl)-5-bromo-1H-indole (5 g, 17.2 mmol) in THF (20 mL) was added during 3 minutes to a solution of n-BuLi (1.6 M, 26 mmol) in THF (200 mL) at −78° C. The solution was stirred for 4 minutes at −78° C. before addition of trimethylstannyl chloride (10 g, 50 mmol) in THF (10 mL). The reaction mixture was allowed to warn up to room temperature and stirred for 1 h. After evaporation of the solvent the crude product was purified by flash chromatography (EtOAc/Heptane 5/100). Yield: 3.6 g. Mp 61-63° C. (EtOAc/Heptane).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6]Cl.[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([Si:15]([CH3:18])([CH3:17])[CH3:16])[O:13][CH:14]=1.CN(C)C1C=CC=CC=1>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:8][CH2:9][C:10]1[CH:11]=[C:12]([Si:15]([CH3:18])([CH3:17])[CH3:16])[O:13][CH:14]=1
Reactant: COCCOCCl
Reactant: C[Si](C)(C)c1cc(CO)co1
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: COCCOCOCc1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Methoxyethoxymethyl chloride (0.11 ml, 0.96 mmol) was added to a solution of 4-hydroxymethyl-2-trimethylsilylfuran, also known as (2-trimethylsilyl-4-furyl)methanol, (162.8 mg, 0.96 mmol) and dimethylaniline (0.13 ml, 0.1 mmol) in dichloromethane (5 ml) at 0°. After stirring at room temperature overnight (ca. 16 hours), the reaction mixture was washed successively with water, dilute hydrochloric acid and water. Evaporation of the dried (magnesium sulfate) dichloromethane layer gave an oil, which was purified by preparative silica TLC (developed with 30% ethyl ether/hexane) to give the title ether as a colorless oil.