Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]Br.[Mg].[CH2:4]([CH2:11][NH:12][CH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[CH2:14]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O1CCCC1>[CH2:4]([CH2:11][NH:12][CH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:1])([OH:22])[CH2:14]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CC(NCCc2ccccc2)c2ccccc21
Reactant: CBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1(O)CC(NCCc2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
In 35 milliliters of tetrahydrofuran, 4 grams methyl bromide is dissolved. One quarter of this solution is then added to 1 gram of magnesium, previously washed with chloroform, and refluxed with tetrahydrofuran for 20 minutes; and this mixture is refluxed 4 hours to initiate reaction. Additional methyl bromide solution is thereafter added to maintain the refluxing without further heating. After the addition has been completed 10 grams of 3-benzylmethylaminoindan-1-one is added and the mixture is refluxed for 2 hours. The reactants are allowed to stand overnight and then poured onto ice-cold ammonium chloride solution. Tetrahydrofuran is added and the two layers formed are allowed to separate. The solvent layer is decanted off and the aqueous layer is extracted twice with 10 milliliters of tetrahydrofuran which are decanted off and combined with the remaining solvent layer. The organic phase is dried over anhydrous magnesium sulphate, filtered and evaporated to dryness to yield 3-benzylmethylamino-1-methylindan-1-ol as a yellow oil.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]2[O:9][C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:11][C:7]=2[CH:6]=1)=[O:4].[CH2:26]([Li])CCC.CI.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:1][NH:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]2[O:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[O:11][C:7]=2[C:6]=1[CH3:26])=[O:4]
Reactant: [Li]CCCC
Reactant: CNC(=O)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CNC(=O)c1ccc2c(c1C)OC(c1ccccc1)(c1ccccc1)O2
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of 3.30 g of N-methyl-2,2-diphenyl-1,3-benzodioxole-5-carboxamide in 20 ml of tetrahydrofuran, cooled to -78° C., were added 12.5 ml of a 1.6M solution of n-butyllithium in hexane. The solution was stirred for 1 hour, the temperature being allowed to warm up to 20° C. Then, 1.37 g of methyl iodide were added, and stirring was continued for 1 hour. After the addition of 20 ml saturated ammonium chloride solution, the mixture was extracted with ethyl acetate. The organic layer was washed successively with 2N potassium hydrogensulfate solution, saturated potassium bicarbonate solution and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the solid residue was crystallized from ethanol to give 15.6 g of N, 4-dimethyl-2,2-diphenyl-1,3-benzodioxole-5-carboxamide, m.p. 178°-180° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([N:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:32]>O1CCOCC1>[ClH:32].[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(c1ccccc1)n1ccc2c(N3CCNCC3)cccc21
Yield: 99 %

Procedure:
A portion of the t-butyl 4-(1-benzenesulfonyl-1H-indol-4-yl)piperazine-1-carboxylate (0.85 g) is stirred in a mixture of 4N HCl and dioxane at room temperature for 2 hrs and filtered. The filtercake is dried to give the title product as a while solid, 0.64 g (99% yield) mp 60° C. identified by mass spectral and NMR analyses.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH2:12][C@@H:11]1[OH:37].C(=O)([O-])[O-].[Ca+2].[C:44]1([Se:50]Br)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.BrBr.C1([SeH-](C2C=CC=CC=2)=[Se])C=CC=CC=1.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3](=[O:38])[CH2:4][CH2:5][CH2:6][CH:7]([Se:50][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH:8]1[O:37][C@H:11]2[CH2:12][C@@H:13]([O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[C@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:10]2[CH2:9]1
Reactant: Br[Se]c1ccccc1
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Product: CCCCC[C@@H](/C=C/[C@@H]1[C@H]2CC(C(CCCC(=O)OC)[Se]c3ccccc3)O[C@H]2C[C@H]1OC1CCCCO1)OC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3.3 g of (5Z,13E)-(9α,11α,15S)-9-hydroxy-11,15-bis(tetrahydropyran-2-yloxy)prosta-5,13-dienoic acid methyl ester in 60 ml of tetrahydrofuran was added 610 mg of calcium carbonate at -20° C., and then 6 ml of a solution of benzeneselenenyl bromide in tetrahydrofuran (prepared by adding 0.19 ml of bromine to a solution of 1.25 g of diphenyldiselenide in 6 ml of tetrahydrofuran and stirring the mixture at room temperature for one hour) was added and the reaction mixture was stirred at the same temperature for 10 minutes and further stirred for one hour at 0° C., and then an aqueous solution of ammonium chloride was added. The reaction mixture was extracted with ethyl acetate. The extract was washed with water and an aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (7:1) as eluent to give 1.62 g of the title compound having the same physical characteristics as hereinbefore described.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[NH:26]([C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C@H:27]([C:31]([OH:33])=O)[CH:28]([CH3:30])[CH3:29].[NH2:44][C@H:45]([C:54]([OH:56])=[O:55])[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([OH:53])=[CH:49][CH:48]=1.[N:57]1([NH-:63])[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>C(Cl)Cl>[NH:26]([C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C@H:27]([C:31]([NH:44][C@H:45]([C:54]([OH:56])=[O:55])[CH2:46][C:47]1[CH:48]=[CH:49][C:50]([OH:53])=[CH:51][CH:52]=1)=[O:33])[CH:28]([CH3:29])[CH3:30].[N:57]1([NH-:63])[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [NH-]N1CCOCC1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reaction time: 0.33 h

Procedure:
At 0° C., 5.18 g (25 mmol) of DCC and 3.73 g (27.5 mmol) of HOBT are added to a solution of 6.3 g (25 mmol) of Z-(L)-Val-OH in 400 ml of methylene chloride and the mixture is then stirred for 20 min. A solution of 6.27 g (25 mmol) of H-(L)-Tyr-morpholin-4-ylamide in 600 ml of methylene chloride is subsequently added. After the mixture has been stirred for 18 h at RT, working up is carried out as described in Example 41 A) a): TLC Rf (B)=0.50.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14](=O)[CH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=1[O:25][CH3:26])C.Cl>O1CCCC1>[CH3:26][O:25][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([N+:22]([O-:24])=[O:23])[C:16]=1[CH2:15][CH2:14][OH:13]
Reactant: CCOC(=O)Cc1c(OC)cccc1[N+](=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: COc1cccc([N+](=O)[O-])c1CCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
Diisobutylaluminium hydride (20 wt % in toluene; 2.38 g, 16.8 mmol) was added to a solution of (2-methoxy-6-nitro-phenyl)-acetic acid ethyl ester (1.0 g, 4.18 mmol) in tetrahydrofuran (8 mL) at −5° C. The reaction mixture was stirred for 1 h at 0° C. and then poured into 1N hydrochloric acid solution. The mixture was extracted with ethyl acetate (30 mL) then the separated organic phase was washed with water (2×30 mL), brine (25 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(2-methoxy-6-nitro-phenyl)-ethanol (780 mg, 94%).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:9]=3[N:8]=2)=[CH:3][CH:2]=1.[C:18](Cl)(=[O:22])[CH2:19][CH2:20][CH3:21].C(OCC)(=O)C>N1C=CC=CC=1>[C:1]1([CH3:17])[CH:2]=[CH:3][C:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([NH:16][C:18](=[O:22])[CH2:19][CH2:20][CH3:21])=[CH:15][C:9]=3[N:8]=2)=[CH:5][CH:6]=1
Reactant: CCCC(=O)Cl
Reactant: Cc1ccc(-c2nc3cc(N)ccc3[nH]2)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1ccc2[nH]c(-c3ccc(C)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.5 %

Procedure:
To a solution of 2-p-tolyl-1H-benzo[d]imidazol-5-amine (150 mg, 0.67 mmol) in pyridine (10 mL) at room temperature was added butyryl chloride (77 μL, 0.74 mmol). The resulting mixture was stirred at room temperature for 16 h. Ethyl acetate was added and the organic layer was washed twice with saturated aqueous copper sulfate, followed by sodium bicarbonate and brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 50:50 v/v to afford 56 mg (28%) of the title compound (LCMS RT=6.96 min, MH+ 294.0)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]=[C:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[C:22]#[N:23])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]>CCO.CCOC(C)=O.CO.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[C:22]#[N:23])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc2[nH]cc(C#N)c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CO
Product: CCOC(=O)CC(c1ccccc1)c1ccc2[nH]cc(C#N)c2c1
Reaction time: 19 h

Procedure:
To a solution of 3-(3-cyano-1H-Indol-5-yl)-3-phenyl-acrylic acid ethyl ester LXIII (1.81 g, 5.71 mmol) in EtOH/EtOAc/MeOH (1/1/1, 60 ml) was added a catalytic amount of Pd/C (5%). The mixture was hydrogenated in a Parr apparatus at 60 psi of H2 for 19 hours, filtered through celite, and the filter cake was washed with MeOH and EtOAc. The filtrate was concentrated to afford 3-(3-Cyano-1H-Indol-5-yl)-3-phenyl-propionic acid ethyl ester LXIV as a white foamy solid in quantitative yield (1.86 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[C@H:10]([CH3:11])[O:9]1.[N:18]1([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:33]=[CH:32][NH:31][C:30]3=[O:34])=[CH:25][CH:24]=2)[CH:22]=[N:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:9])([CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[C@H:10]([N:31]1[CH:32]=[CH:33][N:29]([C:26]2[CH:25]=[CH:24][C:23]([N:18]3[CH:22]=[N:21][CH:20]=[N:19]3)=[CH:28][CH:27]=2)[C:30]1=[O:34])[CH3:11]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccccc1F
Reactant: O=c1[nH]ccn1-c1ccc(-n2cncn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C[C@@H](n1ccn(-c2ccc(-n3cncn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccccc1F
Temperature: 100 °C
Reaction time: 17 h
Yield: 10.2 %

Procedure:
(2R,3S)-2-(2-fluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (2.24 g), 1-[4-(1H-1,2,4-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone (2.17 g) and cesium carbonate (powder: 7.76 g) were added to dimethylsulfoxide (100 ml), and the mixture was heated with stirring at 100° C. for 17 hours. After being cooled, the reaction solution was diluted with ethyl acetate (200 ml). Ice water (200 ml) was added thereto to separate the ethyl acetate layer. The aqueous layer was extracted with ethyl acetate (100 ml). The ethyl acetate layers were combined and washed with 0.5N-sodium hydroxide (100 ml), 1N-hydrochloric acid (100 ml×2) and a saturated aqueous solution of sodium chloride (100 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent: ethyl acetate/acetone=4/1) to give 1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-[1H-1,2,4-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone (Compound 38; 0.45 g).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][CH2:25][C:24]1=[O:43])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:44]([N-]C(C)C)(C)[CH3:45].[Li+].ICC>C1COCC1>[Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][CH:25]([CH2:44][CH3:45])[C:24]1=[O:43])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [Li+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCC1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a −78° C. solution of (5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (764 mg, 1.211 mmol; Example 185, Step C) in THF (6 mL) under argon was added 1.0M lithium diisopropyl amide solution in THF (1.211 mL, 1.211 mmol). The mixture was warmed to 0° C. for 30 minutes. The mixture was cooled to −78° C. and iodoethane (0.117 mL, 1.454 mmol) was added. The resulting solution stirred at 0° C. for 1 hour. The mixture was quenched with sat. aq. NH4Cl solution. The mixture was extracted with ethyl acetate. The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel (eluent: 5 to 25% ethyl acetate/hexanes) to afford the title compound as a mixture of diastereomers.
Reaction SMILES: CN(C(O[N:9]1[N:17]=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:23][C:24]1[C:25]([CH3:33])=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](O)=[O:28].CCN(C(C)C)C(C)C.NN.C1COCC1>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[C:25]([CH3:33])=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH:9][NH2:17])=[O:28]
Reactant: Cc1c(Cl)cccc1C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1C(=O)NN
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
TBTU (678 mg, 2.11 mmol) was added to a rt solution of 3-chloro-2-methylbenzoic acid (300 mg, 1.76 mmol) and DIPEA (0.9 mL, 5.28 mmol) in DMF (5.0 mL) and the resulting solution was stirred at rt for 15 min. The mixture was cooled to 0° C. and 1M hydrazine in THF (10.6 mL, 10.6 mmol) was added and the yellow solution was stirred at rt overnight. The rxn mixture was diluted with DCM and washed with sat. aq. NaHCO3. The aq. layer was re-extracted with DCM (1×) and the combined org. layers were concentrated in vacuo to give the title compound D-1-2 as a light orange solid that was used further without purification. LC-MS A: tR=0.50 min; [M(35Cl)+H]+=185.24.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[C:16]4[CH2:17][C:18]5[S:19][CH:20]=[CH:21][C:22]=5[C:15]=4[N:14](COCC[Si](C)(C)C)[N:13]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>CO>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[C:16]4[CH2:17][C:18]5[S:19][CH:20]=[CH:21][C:22]=5[C:15]=4[NH:14][N:13]=3)=[CH:10][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(N3CCCC3)cc2)c2c1-c1ccsc1C2
Agent: Cl
Solvent: CO
Product: c1cc2c(s1)Cc1c(-c3ccc(N4CCCC4)cc3)n[nH]c1-2
Temperature: 100 °C
Yield: 78.9 %

Procedure:
6-(4-Pyrrolidin-1-yl-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (1.7 g, 0.38 mmol) was dissolved in MeOH and treated with concentrated HCl (0.12 mL, 3.8 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding 6-(4-Pyrrolidin-1-yl-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.1 g, 0.3 mmol) as brown solid in 85% yield.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([NH:20][C:21]([C@H:23]2[C:32]3[C:27](=[CH:28][C:29]([O:33][CH3:34])=[CH:30][CH:31]=3)[CH2:26][CH2:25][N:24]2C(OC(C)(C)C)=O)=[O:22])[CH:12]=[C:13]([F:19])[C:14]=1[Si:15]([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[K+].[K+]>>[F:8][C:9]1[CH:10]=[C:11]([NH:20][C:21]([C@H:23]2[C:32]3[C:27](=[CH:28][C:29]([O:33][CH3:34])=[CH:30][CH:31]=3)[CH2:26][CH2:25][NH:24]2)=[O:22])[CH:12]=[C:13]([F:19])[C:14]=1[Si:15]([CH3:17])([CH3:16])[CH3:18]
Reactant: COc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)CCN[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 70.8 %

Procedure:
Cooled TFA (4.5 mL) was added to tert-butyl (R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (439 mg, 0.89 mmol) at room temperature, and the mixture was stirred at room temperature for 2 min. The reaction mixture was poured into ice and aqueous sodium hydrogencarbonate solution, the pH of mixture was adjusted to 8 with potassium carbonate, and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The precipitate was washed with IPE/hexane to give (R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (246 mg, 0.630 mmol, 70.4%) as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[C:5]([CH3:17])([CH3:16])[C:4]=2[CH:3]=1.B(OC(C)C)(OC(C)C)[O:19]C(C)C.C([Li])CCC.Cl>C1COCC1.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:11]3[CH:10]=[CH:9][C:8]([OH:19])=[CH:7][C:6]=3[C:5]2([CH3:17])[CH3:16])=[CH:13][CH:14]=1
Reactant: CC1(C)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)c2cc(O)ccc2-c2ccc(Br)cc21
Reaction time: 2 h

Procedure:
21.2 g (58.6 mmol) of 2,7-dibromo-9,9-dimethyl-9H-fluorene (CAS No. 28320-32-3) and 19.0 ml (82.8 mmol) of triisopropyl borate are dissolved in 500 ml of THF, and 56 ml (89 mmol) of a 15 percent solution of n-butyllithium in n-hexane are added at −70° C. After 2 h, 200 ml of 2 M hydrochloric acid are added, and the batch is allowed to thaw at room temp. and extracted three times with MTB ether. The combined org. phases are dried over sodium sulfate, the solvent is removed in vacuo, and the residue is taken up in 400 ml of toluene. After addition of 85 ml of 2 M sodium hydroxide solution, 15.5 ml of 30 percent hydrogen peroxide are added with vigorous stirring at such a rate that the temp. does not exceed 40° C. When the addition is complete, the batch is stirred for a further 30 min, added to 500 ml of water and acidified using 2 M hydrochloric acid. The aqueous phase is separated off and extracted three times with ethyl acetate. The combined org. phases are washed with dil. ammonium iron(II) sulfate soln. and water, dried over sodium sulfate and evaporated. Filtration of the crude product through silica gel with toluene/ethyl acetate (9:1) gives 7-bromo-9,9-dimethyl-9H-fluoren-2-ol as colourless solid.
Reaction SMILES: [N:1]1([C:6](=[CH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+]>CO>[N:1]1([C:6](=[CH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:7]([OH:12])[C:8]([CH3:10])([CH3:11])[CH3:9])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(C)C(=O)C=C(C(=O)C(C)(C)C)n1cncn1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)C(=O)C=C(C(O)C(C)(C)C)n1cncn1

Procedure:
The product (1.8 g) of Stage 2 was dissolved in dry methanol (20 ml) and sodium hydride (100 mgs) added portionwise to this solution at 0°. After stirring at 0° for 1 hour the methanol was removedin vacuo and the residue washed several times with water to give a white crystalline solid which recrystallised from petroleum ether/ethanol to give the title compound, m.p. 142°-5°.
Reaction SMILES: [NH2:1][C@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[C:19]([C:22]1[CH:26]=[C:25]([C:27](O)=[O:28])[NH:24][N:23]=1)(=[O:21])[CH3:20].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:19]([C:22]1[CH:26]=[C:25]([C:27]([NH:1][C@H:2]([CH3:18])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=3)=[N:5]2)=[O:28])[NH:24][N:23]=1)(=[O:21])[CH3:20]
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1cc(C(=O)N[C@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.8 %

Procedure:
The title compound was prepared using the method of Example 34(d). (R)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (1.00 g, 3.84 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (0.591 g; 3.84 mmol), 1.0 ml of DIPEA were dissolved in 3 ml of dry DCM under nitrogen. HOBt (0.777 g; 5.75 mmol) and EDCI (1.103 g; 5.75 mmol) were added and the reaction stirred at RT overnight. The crude product (576 mg) was crystallized from 4 ml of EtOH to obtain 164 mg (11%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.16 (d, 3H), 2.49 (s, 3H), 4.34-4.38 (m, 2H), 4.40-4.53 (m, 1H), 6.93 (d, 1H), 7.31 (m, 1H), 7.81 (d, 1H), 7.85-8.09 (m, 3H), 8.48 (broad s, 1H), 14.15 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:28]\[OH:29])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1[C@H](C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 5-[(R)-3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=425.1 [M+H]+.