Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH:9]1([C:14]#[CH:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:15]#[C:14][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: C#CC1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Brc1cccc(C#CC2CCCC2)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2,6-Dibromo-pyridine (0.544 g, 2.34 mmol), cyclopentylacetylene (0.220 g, 2.34 mmol), copper(I) iodide (0.445 g, 2.34 mmol), triethylamine (0.98 mL, 7.01 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.164 g, 0.023 mmol) were combined in DMF and stirred at room temperature for 2 days. The reaction was purified via silica gel chromatography to afford the title compound.
Reaction SMILES: COC[O:4][CH:5]([CH2:26][N:27]1[C:32](=[O:33])[CH:31]=[N:30][C:29]2[CH:34]=[CH:35][C:36]([O:38][CH3:39])=[N:37][C:28]1=2)[CH2:6][NH:7][CH2:8][C@@H:9]1[CH2:13][N:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:18][CH2:19][C:20](=[O:24])[NH:21][C:22]=3[N:23]=2)[C:11](=[O:25])[CH2:10]1.Cl>CO.O1CCCC1>[OH:4][CH:5]([CH2:26][N:27]1[C:32](=[O:33])[CH:31]=[N:30][C:29]2[CH:34]=[CH:35][C:36]([O:38][CH3:39])=[N:37][C:28]1=2)[CH2:6][NH:7][CH2:8][C@@H:9]1[CH2:13][N:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:18][CH2:19][C:20](=[O:24])[NH:21][C:22]=3[N:23]=2)[C:11](=[O:25])[CH2:10]1
Reactant: COCOC(CNC[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1)Cn1c(=O)cnc2ccc(OC)nc21
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2ncc(=O)n(CC(O)CNC[C@H]3CC(=O)N(c4ccc5c(n4)NC(=O)CO5)C3)c2n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 18.3 %

Procedure:
In a mixed solution (2 ml) of methanol/tetrahydrofuran (1:1) was dissolved 6-[(4R)-4-({[2-(Methoxymethoxy)-3-(6-methoxy-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl)propyl]amino}methyl)-2-oxopyrrolidin-1-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (41.3 mg, 0.077 mmol). To this solution was added a 4N hydrochloric acid aqueous solution (1 ml) under cooling on ice and the mixture was stirred at 60° C. for 4 hours. The reaction solution was cooled in the air, and the solvent was then removed under reduced pressure. The residue was dissolved in a lower layer solvent of the chloroform/methanol/water (7:3:1) and alkalized by adding saturated sodium bicarbonate water under cooling on ice. The mixture was extracted with a lower layer solvent of chloroform/methanol/water (7:3:1), the extract was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by preparative layer chromatography (chloroform/methanol) to yield 7 mg (18%) of the title compound in the form of an orangish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:21]=[CH:20][C:19]4[C:15](=[CH:16][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[N:18]=4)[CH:14]=3)[OH:12])=[CH:9][N:10]=2)[N:7]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:21]=[CH:20][C:19]4[C:15](=[CH:16][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[N:18]=4)[CH:14]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc2cc(C(O)c3cnc4ccc(Cl)nn34)ccc2n1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CC(C)=O
Product: C[Si](C)(C)CCOCn1cc2cc(C(=O)c3cnc4ccc(Cl)nn34)ccc2n1
Temperature: 25 °C

Procedure:
(rac)-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-[2-(2-trimethylsilanyl-ethoxymethyl)-2H-indazol-5-yl]-methanol (Stage 195.4, 580 mg, 1.349 mmol) was dissolved in acetone (40 mL) and heated 1 h to reflux together with 2-iodoxybenzoic acid (1.133 g, 4.05 mmol). The RM was cooled down to rt and the acetone was removed under reduced pressure. The residue was mixed with 2 M NaOH solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and the solvent was evaporated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, n-hexane/EtOAc=50:50->0: 100) to afford the title compound as a light brown foam (tR 7.11 min (conditions 3), MH+=428).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:22]([C:25]#[N:26])([CH3:24])[CH3:23])[C:8]([O:20][CH3:21])=[C:9]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:27][C@@H:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C@@H:29]1[OH:37].C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.C(N(CC)C(C)C)(C)C>C(#N)C>[C:1]([C:5]1[CH:6]=[C:7]([C:22]([C:25]#[N:26])([CH3:23])[CH3:24])[C:8]([O:20][CH3:21])=[C:9]([NH:11][C:12]([NH:27][C@@H:28]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C@@H:29]2[OH:37])=[O:19])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(NC(=O)OCC(Cl)(Cl)Cl)cc(C(C)(C)C)cc1C(C)(C)C#N
Reactant: N[C@@H]1Cc2ccccc2[C@@H]1O
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1c(NC(=O)N[C@@H]2Cc3ccccc3[C@@H]2O)cc(C(C)(C)C)cc1C(C)(C)C#N
Temperature: 110 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a solution of 2,2,2-trichloroethyl 5-tert-butyl-3-(2-cyanopropan-2-yl)-2-methoxyphenylcarbamate (0.086 g, 0.203 mmol) and (1S,2R)-2-amino-2,3-dihydro-1H-indene-1-ol.L-tartaric acid salt (0.067 g, 0.223 mmol) in acetonitrile (0.8 mL), N,N-diisopropylethylamine (0.058 mL, 0.333 mmol) was added, the mixture was stirred overnight at 110° C. The reaction mixture was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=10/90-60/40) to obtain 0.044 g of the captioned compound (51% yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][N:5]2[C:11]=1[C:12]1[S:13][C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)=[CH:15][C:16]=1[CH3:17].[CH2:25]1C[O:28][CH2:27][CH2:26]1.[Li+].CC([N-]C(C)C)C.CON(C)C(=O)CC>CCOC(C)=O>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([C:27](=[O:28])[CH2:26][CH3:25])=[CH:8][C:7]([CH3:10])=[N:6][N:5]2[C:11]=1[C:12]1[S:13][C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)=[CH:15][C:16]=1[CH3:17]
Reactant: Cc1cccc(-c2cc(C)c(-c3c(C)nc4ccc(C)nn34)s2)n1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: CCC(=O)N(C)OC
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CCC(=O)c1cc(C)nn2c(-c3sc(-c4cccc(C)n4)cc3C)c(C)nc12
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 25 %

Procedure:
To a −78° C. solution of 2,6-dimethyl-3-[3-methyl-5-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine (0.34 g, 1.02 mmol) and THF (9 mL) is added 2.0 M LDA (0.61 mL, 1.22 mmol). After 3 minutes, N-methoxy-N-methyl-propionamide (Wolberg et. el. Chem. Eur. J., 2001, 7, 4562) (1.17 g, 1.42 mmol) is added and the solution stirred for 20 minutes, warmed to ambient temperature and stirred for 30 minutes. The solution is diluted with EtOAc (50 mL) washed with sat. NH4Cl (30 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (20%-30% EtOAc/hexane gradient) furnish the title compound (0.10 g, 0.26 mmol, 25%). 1H NMR (CDCl3), δ 1.28 (t, J=7.0 Hz, 3H), 2.13 (s, 3H), 2.54 (s, 3H), 2.58 (s, 6H), 3.59 (q, J=7.0 Hz, 2H), 7.03 (d, J=7.5 Hz, 1H), 7.33 (s, 1H), 7.47 (d, J=7.9 Hz, 1H), 7.55 (bs, 1H), 7.58 (dd, J=7.9, 7.5 Hz, 1H). LC/MS (m/z): calcd. for C22H22N4OS (M+H)+: 391.2; found: 391.2.
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]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH:30]1[CH:34]=[N:33][C:32]([C:35](O)=[O:36])=[N:31]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:35]([C:32]4[N:33]=[CH:34][NH:30][N:31]=4)=[O:36])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc[nH]n1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2nc[nH]n2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 1H-1,2,4-triazole-3-carboxylic acid (17 mg, 0.15 mmol).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[C:9]1(=O)[O:13][CH2:12][CH2:11][CH2:10]1>>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:9][CH2:10][CH2:11][C:12]1=[O:13]
Reactant: NCCCCCCN
Reactant: O=C1CCCO1
Product: NCCCCCCN1CCCC1=O
Temperature: 25 °C

Procedure:
Hexamethylenediamine (100 g, 0.86 mole) was heated with γ-butyrolactone (23.36 ml, 0.31 mole) at 210° C. under nitrogen for 24 hours in a three-neck reaction flask equipped with air reflux condenser. After the reaction, most of the unreacted diamine was crystallized upon cooling to room temperature; therefore, most of the excess diamine was filtered off. The remaining unreacted diamine in solution was vacuum distilled, then N-(6-aminohexyl)-2-pyrrolidone was obtained at 140° C. (0.9 torr) as a colorless liquid. Yield: 35 g (62%). Mass Spectra: m/e (relative intensity) 185(M+1+, 16.97).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:40])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[CH:38]=[CH:37][CH:36]=[N:35]2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:14]1([C:12]2[C:11]([C:20]([F:22])([F:21])[F:23])=[CH:10][C:9]3[NH:24][C:25](=[O:40])[CH2:26][C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([N:34]5[CH:38]=[CH:37][CH:36]=[N:35]5)[CH:29]=4)=[N:7][C:8]=3[CH:13]=2)[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2cccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3cccn3)c2)=Nc2cc(N3CCOCC3)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {5-morpholin-4-yl-2-[3-oxo-3-(3-pyrazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M32) (322 mg, 0.56 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (146 mg).
Reaction SMILES: CC([O-])(C)C.[Na+].Cl[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COCCOC>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:9][CH:10]=1)#[N:13]
Reactant: C1COCCN1
Reactant: N#Cc1ccc(Cl)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: N#Cc1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 26 h
Yield: 96.7 %

Procedure:
An oven-dried resealable Schlenk tube was purged with argon and charged with Pd2(dba)3 (11.5 mg, 0.025 mmol, 5 mol % Pd), 2 [Example 1] (14.8 mg, 0.075 mmol, 7.5 mol %), NaOt-Bu (68 mg, 0.71 mmol) and 4-chlorobenzonitrile (69 mg, 0.50 mmol). The tube was purged with argon then DME (0.5 mL) and morpholine (53 ILL, 0.61 mmol) were added through a rubber septum. The septum was removed, the tube was sealed with a teflon screw cap and the mixture was stirred at room temperature for 26 h. The reaction was then diluted with EtOAc (20 mL), filtered through celite and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 91 mg (96%) of a tan solid.
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25]>>[OH:25][CH2:24][C:23]([NH:22][C:18]([C:14]1[S:13][C:12](/[CH:11]=[CH:10]/[C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:21])=[N:16][C:15]=1[CH3:17])=[O:20])([CH3:27])[CH3:26]
Reactant: CC(C)(N)CO
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NC(C)(C)CO)s1
Yield: 46 %

Procedure:
As described for example 104, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (153 mg, 0.5 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of rac-2-amino-1-butanol, to the title compound (87 mg, 46%) which was obtained as a colourless gum after purification by chromatography (silica, 0 to 100% ethyl acetate in heptane). MS: m/e=378.3 [M+H]+.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Sn](Cl)(Cl)CCCC)CCC.[CH:27]([C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1)=O.C1([SiH3])C=CC=CC=1>C1COCC1>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:27][C:29]3[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: C1=Cc2ccccc2Nc2ccccc21
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN2c3ccccc3C=Cc3ccccc32)cc1
Reaction time: 72 h
Yield: 82.8 %

Procedure:
(Z)-5H-Dibenzo[b,f]azepine (100 mg, 0.52 mmol), dibutyltin dichloride (54 mg, 0.16 mmol) and methyl 4-formylbenzoate (260 mg, 1.60 mmol) were stirred in THF (2 mL) for 30 minutes. Phenylsilane was added and the reaction mixture was stirred for 3 days. The solvent was evaporated and the residue was purified by flash chromatography (0% to 40% EtOAc in hexanes). The fractions containing some product were washed with Na2S2O4. The layers were split and the organic layer was evaporated to afford title compound 350 (147 mg, 83%) as a yellow solid.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[CH3:17]COCC>CO>[ClH:1].[CH3:17][O:15][C:14](=[O:16])[C@H:3]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[NH2:2]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CCOCC
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Temperature: 20 °C
Reaction time: 120 h

Procedure:
A 1.2 M solution of HCl in MeOH (440 mL; 0.528 mol) was added to a suspension of L-tryptophan (commercial product) (30.6 g; 150 mmol) in MeOH (70 mL). The resulting clear solution was stirred for 5 days at 20° C. The solution was concentrated (35° C.; 1.3 kPa) to yield a solid which was dissolved in MeOH (10 mL). Et2O (300 mL) was added to the solution and the mixture was vigorously stirred for 1 h. The mixture was filtered and the solid was washed with Et2O (70 mL). The combined solutions were concentrated (35° C.; 1.3 kPa) to a volume of 100 mL and filtered. The solid materials were combined and dried (40° C.; P205; 1.3 kPa) to give as a white solid the desired product (38.5 g; 149.5 mmol). Quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH2:7][C:8](=O)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CS(O)(=O)=O.[OH-].[Na+].C(OC)(C)(C)C>C(Cl)Cl>[C:11]1([CH2:10][CH2:9][C:8]2[C:18]3[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[O:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc(OCC(=O)CCc2ccccc2)c1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: COc1ccc2c(CCc3ccccc3)coc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The product from Step A (2.368 grams), dissolved in dry CH2Cl2 (25 mL) was added dropwise to a −10° C. CH2Cl2 solution (10 mL) of methanesulfonic acid (5.68 mL). The reaction was warmed to ambient temperature and stirred for 30 minutes. The reaction was rapidly poured into a vigorously stirred cold mixture of excess 5N NaOH and methyl tert-butyl ether. The organic was dried over magnesium sulfate and filtered. Concentration and chromatography over silica gel (step gradient; 4:1 hex/CH2Cl2 to 1:1 hex/CH2Cl2) gave the title compound as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:22]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: Cc1ccccc1C(=O)Cl
Product: Cc1ccccc1C(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 94.2 %

Procedure:
Beginning with 10 mg (0.0437 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 6.0 μL (0.0458 mMol) 2-methylbenzoyl chloride, 14.3 mg (95%) of the title compound were recovered.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].C([O-])([O-])=O.[K+].[K+]>CC#N>[OH:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][N:4]([CH2:11][CH2:12][N:13]2[C:14](=[O:23])[C:15]3[C:16](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:18])[CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: OCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(CCO)CC1
Temperature: 25 °C

Procedure:
2-piperazin 1-yl-ethanol (510 mg, 3.9 mmol) is dissolved in CH3CN (5 mL). N-(2-Bromoethyl)-phthalimid (995 mg, 3.9 mmol) and anhydrous K2CO3 (1.1 g, 7.8 mmol) are added at RT and then the reaction mixture is refluxed for 5 h. The reaction mixture is allowed to cool to RT again and the precipitated crude product is isolated by filtration. It is then purified by flash chromatography (SiO2; DCM/MeOH, gradient 1-5% MeOH) to give the title compound as a white powder.: M+H=304.1; HPLC: CtRet=1.73 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[C:12](O)[CH:13]=[CH:14][CH:15]=3)[C:10]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)=[C:9]2[C:27]([O:29]CC)=[O:28])=[CH:4][CH:3]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:9]2[C:27]([OH:29])=[O:28])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2c(O)cccc2C1c1ccc(F)cc1
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)C1C(c2ccc(F)cc2)c2ccccc2C1c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
Ethyl (RS)-1-(4-Fluorophenyl)-3-(3,4-methylene-dioxyphenyl)indene-2-carboxylate. To a solution of ethyl (1RS)-1-(4-fluorophenyl)-hydroxy-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate (45 mg, 0.11 mmol) in CH2Cl2 (3 ml) at 0° C. was added triethylsilane (38 μl, 0.24 mmol), followed by boron trifluoride etherate (121 μl, 0.98 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 15 min, at which time was added slowly 3M HCl. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl. The solvent was removed in vacuo to provide the title compound (40 mg, 90%) as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([C:5]1[C:6]([F:12])=[N:7][CH:8]=[CH:9][C:10]=1[I:11])[OH:4]>C1(C)C=CC=CC=1.[O-2].[Mn+4].[O-2]>[F:14][C:2]([F:1])([F:13])[C:3]([C:5]1[C:6]([F:12])=[N:7][CH:8]=[CH:9][C:10]=1[I:11])=[O:4]
Reactant: OC(c1c(I)ccnc1F)C(F)(F)F
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: O=C(c1c(I)ccnc1F)C(F)(F)F
Yield: 89.4 %

Procedure:
2,2,2-trifluoro-1-(2-fluoro-4-iodo-3-pyridyl)ethanol (45 g, 140.2 mmol) was dissolved in anhydrous toluene (1 L). Manganese (IV) oxide (143.4 g, 1.402 mol) was added portionwise with rapid stirring. The mixture was heated to reflux for 3 hours and then allowed to cool and filtered through a plug of celite. The solid residues were washed with EtOAc and the filtrate was concentrated to a deep red oil which was slurried in petrol and then filtered to give a white solid impurity. The filtrate was concentrated to give the product as a red oil (40 g, 89% Yield).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH:10]([CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[CH3:23][Mg]I.[Cl-].[NH4+]>C(OCC)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([CH3:23])([OH:15])[CH:10]([CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:9][CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)CCC(CN1CCCCC1)C2=O
Reactant: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(C)c1ccc2c(c1)CCC(CN1CCCCC1)C2(C)O
Yield: 82.4 %

Procedure:
6-Tert-butyl-2-piperidinomethyl-1,2,3,4-tetrahydronaphthalen-1-one (4.4 g, 0.015 mol) in diethyl ether (40 ml) was added to an ethereal solution of methylmagnesium iodide [prepared from methyl iodide (1.9 ml, 0.03 mol) and magnesium (0.72 g, 0.03 mol)] at such a rate as to maintain reflux. It was refluxed for 1 hour, cooled and treated with saturated ammonium chloride solution (100 ml) and refluxed for 30 minutes. The ether was separated and the aqueous extracted with further ether, the combined extracts were dried over magnesium sulphate and evaporated to give a solid residue. Purification by column chromatography using silica gel with ethyl acetate: petroleum 60°-80°, 3:7 gave 6-tert-butyl-1-methyl-2-piperidinomethyl-1,2,3,4-tetrahydronaphthalen-1-ol (3.9 g, 82% yield) a white solid melting at 113°-4°. 6-tert-butyl-1-methyl-2-piperidinomethyl-1,2,3,4-tetrahydronaphthalen-1-ol (3.7 g, 0.012 mol) was refluxed in dilute sulphuric acid (50 ml, 10%) for 45 minutes. After cooling it was neutralized with sodium hydroxide, extracted with ether, dried over magnesium sulphate and evaporated under reduced pressure to give the title compound (3.5 g, 98% yield) as a clear oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([O:14]C(N(C)C)N(C)C)(C)(C)C.I([O-])(=O)(=O)=O.[Na+]>CN(C)C=O.O1CCCC1.O.ClCCl>[Br:1][C:2]1[C:3]([CH:9]=[O:14])=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1cc(Cl)ncc1Br
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Cl)ncc1Br
Temperature: 120 °C
Yield: 91.4 %

Procedure:
To a solution of 5-bromo-2-chloro-4-methylpyridine (5.0 g, 20 mmol) in N,N-dimethylformamide (38 mL) was added tert-butoxybis(dimethylamino)methane (7.0 mL, 33.9 mmol). The reaction mixture was heated at 120° C. for 2 hours. The cooled reaction mixture was concentrated in vacuo to afford a thick orange oil, which was redissolved in tetrahydrofuran (40 mL) and slowly poured into a separate flask containing slurry of sodium periodate in water (150 mL) at 0° C. The reaction flask was equipped with an overhead stirrer and allowed to warm to room temperature. The reaction mixture was mixed vigorously for three hours, and then diluted with dichloromethane (150 mL) and filtered. The collected solids were washed with dichloromethane (2 ×150 mL), and the organic layer was separated from the filtrate and washed with saturated sodium bicarbonate solution (50 mL). The aqueous layer was neutralized via addition of solid sodium bicarbonate, and then back-extracted with dichloromethane (100 mL). The organic portions were combined, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 120 g, ISCO, 0-40% ethyl acetate in heptane) to afford the title compound as an off-white solid (4.03 g, 80%). 1H NMR (500 MHz, d6-DMSO) δ 10.10 (s, 1H), 8.85 (s, 1H), 7.81 (s, 1H).