Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@:2]12[C@@H:15]3[NH:16][CH2:17][CH2:18][C@:7]1([C:8]1[CH:9]=[C:10]([O:19][CH3:20])[CH:11]=[CH:12][C:13]=1[CH2:14]3)[CH2:6][CH2:5][CH2:4][CH2:3]2.C(N(CC)CC)C.C(O)C.[CH2:31](Br)[CH:32]=[CH2:33]>CCOCC>[CH2:33]([N:16]1[CH2:17][CH2:18][C@@:7]23[C:8]4[CH:9]=[C:10]([O:19][CH3:20])[CH:11]=[CH:12][C:13]=4[CH2:14][C@@H:15]1[C@:2]2([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:32]=[CH2:31]
Reactant: COc1ccc2c(c1)[C@@]13CCCC[C@@]1(O)[C@@H](C2)NCC3
Reactant: C=CCBr
Solvent: CCO
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CCN1CC[C@]23CCCC[C@@]2(O)[C@H]1Cc1ccc(OC)cc13

Procedure:
To a stirred mixture of 900 mg. (3.3. mmole) of the aminoalcohol XXI and 1.7 g. (16.5 mmole) of triethylamine in 12 ml. of absolute ethanol was added, at room temperature and under nitrogen, a solution of 0.605 g. (5 mmole) of allyl bromide. After the addition had been completed, the reaction mixture was refluxed for eighteen hours and then evaporated to dryness. The residue was mixed with a 20% aqueous sodium carbonate solution and the resulting mixture extracted with several portions of ether. The combined ether extracts were dried over Na2SO4 and evaporated to yield 940 mg. of an oil which was dissolved in ether. The resulting solution was filtered through a celite-charcoal mixture and the filtrate concentrated at reduced pressure. The remaining oil was converted, in ether, into the hydrochloride salt. Recrystallization from a methanol-ether mixture yielded 600 mg. of a white solid melting at 244°-46° C. (dec.). Yield, 51.9%. The IR and NMR spectra were consistent with the structure.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1([C:17]2[C:18]([O:23][CH2:24][CH3:25])=[N:19][CH:20]=[CH:21][CH:22]=2)[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([C:13]#[N:14])[CH:11]=2)[NH:6][C:5]1=[O:16].[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[S:36](Cl)(=[O:38])=[O:37]>CN(C)C=O>[NH2:3][C:4]1([C:17]2[C:18]([O:23][CH2:24][CH3:25])=[N:19][CH:20]=[CH:21][CH:22]=2)[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([C:13]#[N:14])[CH:11]=2)[N:6]([S:36]([C:29]2[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:28]=2[O:27][CH3:26])(=[O:38])=[O:37])[C:5]1=[O:16]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: CCOc1ncccc1C1(N)C(=O)Nc2cc(F)c(C#N)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ncccc1C1(N)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2cc(F)c(C#N)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 41.1 %

Procedure:
80 mg (1.68 mmol) of sodium hydride (60% dispersion in mineral oil) were added in portions to a solution of 350 mg (1.12 mmol) of 3-amino-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile in 15 ml of anhydrous dimethylformamide under a nitrogen atmosphere and while cooling in an ice bath. The mixture was stirred at 0° C. for 10 min and then 398 mg (1.68 mmol) of 2,4-dimethoxy-phenylsulfonyl chloride were added, and the mixture was stirred at room temperature for 15 min. The reaction mixture was poured into ice-water and then extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by chromatography on silica gel (Redisep cartridge, mobile phase gradient from 0 to 3% methanol in ethyl acetate). 236 mg of the title compound were obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[OH:11].CI.[C:14](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[O:11][CH3:14]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cccc(F)c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(F)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 101 %

Procedure:
A solution of 2-fluoro-6-nitrophenol (10.0 g, 63.6 mmol) in DMF (25.0 mL) was charged with methyl iodide (5.94 mL, 95.5 mmol) and potassium carbonate (13.2 g, 95.5 mmol). The reaction mixture was stirred at rt for 16 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (30 mL). The organic layer was washed with water (25 mL), washed with Brine (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield a brown oil, 11.0 g (101% yield). 1H NMR (CDCl3, 400 MHz): δ=4.08 (d, J=2.02 Hz, 3H), 7.14 (td, J=8.34, 4.80 Hz, 1H), 7.35 (ddd, J=10.74, 8.34, 1.64 Hz, 1H), 7.58 (dt, J=8.27, 1.55 Hz, 1H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd]>[CH:1]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccccc1
Agent: [Pd]
Product: c1ccc(C2CCCCC2)cc1

Procedure:
A 41 wt % EMM-12 calcined of Example 3 and 59 wt % palladium-containing alumina catalyst of Example 4 was prepared. This catalyst was tested for benzene hydroalkylation to form cyclohexylbenzene.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[C:17](=[O:18])[C:16]2[CH:19]=[C:20]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][C:15]=2[O:14][CH:13]=1.C(OC(C)C)(C)C>C(Cl)Cl>[CH:1]([NH:11][C:12]1[C:17](=[O:18])[C:16]2[CH:19]=[C:20]([O:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:21]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])=[CH:22][C:15]=2[O:14][CH:13]=1)=[O:2]
Reactant: O=CO
Reactant: CS(=O)(=O)Nc1cc2occ(N)c(=O)c2cc1Oc1ccccc1
Solvent: CC(C)OC(C)C
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc2occ(NC=O)c(=O)c2cc1Oc1ccccc1
Reaction time: 1.5 h
Yield: 73 %

Procedure:
27.6 g of formic acid was added to 30.6 g of acetic anhydride. The mixture was stirred for 1.5 hours at 40°-45° C. The reaction mixture was dropwise added to a solution of 34.6 g of 3-amino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one dissolved in 400 ml of methylene chloride. The mixture was stirred for 1 hour at 20°-25° C. 400 ml of diisopropyl ether was added thereto. The resulting crystal was collected by filtration and recrystallized from acetonitrile to obtain 27.3 g (yield: 73%) of 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one having a melting point of 236°-238° C.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=C[CH:15]=[CH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1.COC(C1C=NC=CN=1)=[NH:40]>>[F:1][C:2]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=[N:40][CH:15]=[CH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1
Reactant: COC(=N)c1cnccn1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2cc(F)ccc2F)cn1
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2Oc2cc(F)ccc2F)cn1

Procedure:
The entitled compound was obtained as a white solid in the same method as in Example 205 or in accordance with the method or by combining it with an ordinary method but using 4-(2,5-difluoro-phenoxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 232 and methylpyrazin-2-imidate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]2[CH:12]=[CH:13][NH:14][C:9]2=[CH:8][C:7]=1[Cl:15])=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[F:22][CH:23]([F:26])[CH2:24]I.[NH4+].[Cl-]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]2[CH:12]=[CH:13][N:14]([CH2:24][CH:23]([F:26])[F:22])[C:9]2=[CH:8][C:7]=1[Cl:15])=[O:5])[CH3:2]
Reactant: FC(F)CI
Reactant: CCOC(=O)c1nc2cc[nH]c2cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2ccn(CC(F)F)c2cc1Cl
Reaction time: 48 h

Procedure:
To a solution of 6-chloro-1H-pyrrolo[3,2-b]pyridine-5-carboxylic acid ethyl ester (210 mg, 0.935 mmol) in DMF (10 ml) was added cesium carbonate (457 mg, 1.402 mmol), after 15 min stirring at room temperature 1,1-difluoro-2-iodoethane (538 mg, 2.8 mmol) was added and stirring was continued over night. Tetrabutylammonium iodide (34.5 mg, 0.093 mmol) was added and stirring was continued for another 48 h. To the reaction mixture was added saturated aq. NH4Cl and the mixture was extracted with MTBE (2×). The combined organic layers were washed with half-saturated aq. NaCl, dried with Na2SO4 and evaporated. The residue was purified by chromatography on silica gel (cyclohexane to cyclohexane/EtOAc 20:80) to provide the title compound as yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[C:24](OC)=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+].[BH4-].[Na+].C(O)C>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]1[CH2:24][OH:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
To a solution of 5.32 g of methyl 1-(benzyloxycarbonyl)-4-(tert-butyloxycarbonyl)piperazine-2-carboxylate in 30 mL of THF was added 834 mg of lithium chloride, 744 mg of sodium borohydride, and 30 mL of ethanol. The mixture was stirred overnight at room temperature, concentrated, and redissolved in 200 mL of CH2Cl2. This CH2Cl2 solution was washed with 100 mL of water and 100 mL of brine, dried over MgSO4, and concentrated. The residue was purified by flash chromatography, eluting with a gradient system of 2:1 hexanes-EtOAc to 1:1 hexanes-EtOAc, to yield 2.65 g of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CCCCCC>[Cl:19][C:18]([Cl:21])([Cl:20])[CH2:17][O:16][C:14]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:15]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC(Cl)(Cl)Cl

Procedure:
L-phenylalanine was reacted with 2,2,2-trichloroethyl chloroformate in a 2N sodium bicarbonate solution, and after the usual working-up there was obtained the desired acid as crystals, melting point 126° (from methylene chloride/hexane).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[NH:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:2]1.[CH3:18][CH2:19][O-:20].[Na+]>C(O)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[NH:15][C:14](=[O:16])[N:13]([CH2:4][CH2:3][CH2:2][N:1]3[CH2:9][CH2:8][O:20][CH2:19][CH2:18]3)[C:12]2=[O:17])=[CH:2]1
Reactant: CC[O-]
Reactant: O=C1NC(=O)C(Cc2c[nH]c3ccccc23)N1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1NC(Cc2c[nH]c3ccccc23)C(=O)N1CCCN1CCOCC1

Procedure:
5-[(Indol-3-yl)methyl]hydantoin (5 g; 0.022 mole) was added to NaOC2H5 (0.022 mole) in 300 ml of anhydrous C2H5OH. The first mixture was heated to reflux, and 1-(3-chloropropyl)-morpholine (3.5 g, 0.022 mole) was added. The mixture was heated for 6 hours and then diluted with H2O. The solid was collected and recrystallized from 2-propanol-petroleum ether, yield 3 g, mp 158°-60°.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:14][CH:15]([F:18])[CH2:16][OH:17].CC([O-])(C)C.[K+].C(Cl)Cl.CCO>C1COCC1>[F:14][CH:15]([F:18])[CH2:16][O:17][C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: OCC(F)F
Reactant: O=C(O)c1cc([N+](=O)[O-])cnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: ClCCl
Product: O=C(O)c1cc([N+](=O)[O-])cnc1OCC(F)F

Procedure:
Prepared analogously to Example 5a from 2 chloro-5-nitro nicotinic acid and 2,2-difluoroethanol with KOtBu in THF. Yield: (25%). MS [M−H]−=247; TLC: Rf=0.13 (silica gel, DCM:EtOH 9:1).
Reaction SMILES: [OH:1][C@H:2]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:3][N:4]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([NH:28][S:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])(=[O:31])=[O:30])=[O:27])=[C:22]([O:37][CH:38]([CH3:40])[CH3:39])[CH:21]=2)=[CH:16][CH:15]=1)C(=O)OC(C)(C)C.C(OC(=O)C)C.[ClH:53]>C(OCC)(=O)C>[ClH:53].[OH:1][C@H:2]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH2:3][NH:4][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([NH:28][S:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])(=[O:31])=[O:30])=[O:27])=[C:22]([O:37][CH:38]([CH3:39])[CH3:40])[CH:21]=2)=[CH:18][CH:19]=1
Reactant: CCCCCS(=O)(=O)NC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3ccccc3)C(=O)OC(C)(C)C)cc2)cc1OC(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCCS(=O)(=O)NC(=O)c1ccc(-c2ccc(CCNC[C@H](O)c3ccccc3)cc2)cc1OC(C)C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl [(2R)-2-hydroxy-2-phenylethyl][2-[3′-isopropoxy-4′-[[(pentylsulfonyl)amino]-carbonyl]-4-biphenylyl]ethyl]carbamate (170 mg) in ethyl acetate (2 ml) was added hydrochloric acid ethyl acetate solution (4N, 4 ml) at room temperature and the mixture was stirred at the same temperature overnight. The mixture was filtered to collect the precipitate and the precipitate was washed with ethyl acetate. The precipitate was dried under reduced pressure to give 4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-isopropoxy-N-(pentylsulfonyl)-4-biphenylcarboxamide hydrochloride (106 mg).
Reaction SMILES: [OH:1][CH:2]([N:15]1[C@H:18]([SH:19])[C@H:17]([NH:20][C:21](=[O:29])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]1=[O:30])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4].Br[CH2:32][C:33]([CH:35]1[CH2:39][CH2:38][CH2:37][O:36]1)=[O:34].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[OH:1][CH:2]([N:15]1[C@H:18]([S:19][CH2:32][C:33]([CH:35]2[CH2:39][CH2:38][CH2:37][O:36]2)=[O:34])[C@H:17]([NH:20][C:21](=[O:29])[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:16]1=[O:30])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4]
Reactant: O=C(CBr)C1CCCO1
Reactant: COc1ccc(COC(=O)C(O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C(O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SCC(=O)C2CCCO2)cc1
Reaction time: 0.17 h

Procedure:
The crude thiol was dissolved in acetone (35ml) and treated with a solution of (RS)-2-bromoacetyltetrahydrofuran (3.48g, 18.0mmol) in acetone (5ml). After 10 min, potassium carbonate (1.24g, 8.9mmol) was added, and the mixture stirred for a further 30 min. The reaction mixture was diluted with ethyl acetate, washed successively with water (x2) and brine, dried and concentrated. The residue was flash chromatographed on silica gel eluting with 50, 70 and 80% ethyl acetate in hexane yielding the title compound as a colourless foam (5.40g, 55%); vmax (CH2Cl2) 3409, 1781, 1745, 1684, 1613, 1516cm-1. [Mass spectrum +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (565)].
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>CO.O.[Fe]>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CC(C)(C)N1CCN(c2ccc(N)cc2)CC1
Reaction time: 7 h
Yield: 89.6 %

Procedure:
To a solution of 840 mg (3.189 mmol) of 1-tert-butyl-4-(4-nitrophenyl)piperazine in 24 mL of methanol, 904 mg (16.9 mmol) of ammonium chloride dissolved in 6 mL of water and 552 mg (9.886 mmol) of iron were added. After 7 hours, the suspension was cooled and filtered. pH was adjusted to 10 through portionwise addition of Na2CO3 to the aqueous phase. Extraction with dichloromethane yielded 667 mg of the title amine.
Reaction SMILES: [CH:1]1([C:6]([OH:19])([C:17]#[CH:18])[CH2:7][C:8]2[O:13][C:12]([CH3:15])([CH3:14])[O:11][C:10](=[O:16])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1.C(NC(C)C)(C)C>C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.[Cu]I.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.O1CCOCC1>[CH:1]1([C:6]([OH:19])([C:17]#[C:18][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:7][C:8]2[O:13][C:12]([CH3:15])([CH3:14])[O:11][C:10](=[O:16])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#CC(O)(CC1=CC(=O)OC(C)(C)O1)C1CCCC1
Reactant: COc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: N#Cc1ccccc1
Solvent: C1COCCO1
Solvent: CC(C)NC(C)C
Product: COc1ccc(C#CC(O)(CC2=CC(=O)OC(C)(C)O2)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 66.9 %

Procedure:
To a solution of 6-(2-cyclopentyl-2-hydroxy-but-3-ynyl)-2,2-dimethyl-[1,3]dioxin-4-one (66 mg, 0.25 mmol), 4-bromoanisole (34.4 μL, 0.275 mmol), diisopropylamine(42.4 μL, 0.30 mmol), P(t-Bu)3 (30 μL of 10% by weight solution in hexanes, 0.015 mmol), and anhydrous dioxane (220 μL), under argon, was added Pd(PhCN)2Cl2 (2.87 mg, 0.0075 mmol), and CuI (0.95 mg, 0.005 mmol), at room temperature. The reaction was vacuum-flushed with argon (3×), then stirred at room temperature for 2.5 hours. HPLC at this time indicated −60% conversion. The reaction was then placed in a 35° C. oil bath for an additional 2 hours, at which time all starting material had been consumed. The reaction was concentrated and purified by silica gel chromatography-eluted with 30% ethytacetate/hexanes, which gave 62 mg of the product (67% yield). 1H NMR (CDCl3): δ 1.63 (m, 4H), 1.72 (s, 3H), 1.73 (s, 3H), 2.23 (pentet, 1H, J=8.0 Hz), 2.54(s, 1H), 2.65 (s, 2H), 3.81 (s, 3H), 5.47 (s, 1H), 6.83 (d, 2H, J=8.7 Hz), 7.31 (d, 2H, J=8.1 Hz); ESIMS (M+Na+): 393.2.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].COC.O=[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:13][CH2:12]1>O1CCCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]=[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:13][CH2:12]1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)NN1CCC(=O)c2ccccc21
Agent: COC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCN(NC(=O)OC(C)(C)C)c2ccccc21

Procedure:
3.96 ml of a 1N solution of potassium tert-butoxide in tetrahydrofuran, 1.45 g of methyltriphenylphosphonium bromide and 30 ml of dimethyl ether are placed in a 150 ml three-necked flask equipped with a magnetic stirrer and placed under an inert atmosphere. The reaction mixture is heated at reflux for 1 h. After returning to ambient temperature, 0.7 g of tert-butyl 4-oxo-3,4-dihydro-2H-quinoline-1-carbamate is added and the reaction mixture is heated at reflux for 1.5 h and then concentrated under reduced pressure. Water and ethyl acetate are added. The organic phase is washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel eluted with dichloromethane. 0.556 g of tert-butyl 4-methylene-3,4-dihydro-2H-quinoline-1-carbamate is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:18]([NH2:20])=[O:19])[C:5]2[NH:6][C:7]3[CH:8]=[C:9]([N:15]([CH3:17])[CH3:16])[CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].C([O-])([O-])=O.[Na+].[Na+].N>CN(C=O)C.O.CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.C(#N)C.COCCOC>[Cl:21][C:22]1[CH:23]=[C:24]([C:2]2[CH:3]=[C:4]([C:18]([NH2:20])=[O:19])[C:5]3[NH:6][C:7]4[CH:8]=[C:9]([N:15]([CH3:17])[CH3:16])[CH:10]=[CH:11][C:12]=4[C:13]=3[N:14]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: CN(C)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Br)nc12
Reactant: COc1ccc(B(O)O)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(-c2cc(C(N)=O)c3[nH]c4cc(N(C)C)ccc4c3n2)cc1Cl
Temperature: 100 °C
Yield: 80 %

Procedure:
A microwave vial containing a mixture of 2-bromo-7-(dimethylamino)-5H-pyrido[3,2-b]indole-4-carboxamide (30 mg, 0.090 mmol), 3-chloro-4-methoxyphenylboronic acid (34 mg, 0.18 mmol), PdCl2(dppf)-CH2Cl2 adduct (7.4 mg, 9.0 μmol) was flushed with nitrogen. DME (1.5 mL) and Na2CO3 (0.23 mL, 0.45 mmol, 2.0 M aq. solution) were added and the vial was sealed and heated at 100° C. in an oil bath for 2 hrs. This was diluted with DMF and preparative HPLC (PHENOMENEX® Luna C18 30×100 10u Column, Solvent A=10 mM NH4OAc in 95% water:5% acetonitrile; B=10 mM NH4OAc in 5% water:95% acetonitrile, 30 to 100% B over 20 min at 30 mL/min) followed by SCX capture and release with 2 N solution NH3 in MeOH afforded 2-(3-chloro-4-methoxyphenyl)-7-(dimethylamino)-5H-pyrido[3,2-b]indole-4-carboxamide (30 mg, 0.072 mmol, 80% yield) as a yellow solid. MS (ESI) m/z 395.12 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.10 (1H, s), 8.49 (1H, s), 8.33 (1H, d, J=2.14 Hz), 8.16-8.27 (2H, m), 8.02 (1H, d, J=8.55 Hz), 7.78 (1H, s), 7.31 (1H, d, J=8.55 Hz), 6.99 (1H, d, J=2.14 Hz), 6.79 (1H, dd, J=8.85, 2.14 Hz), 3.95 (3H, s), 3.04 (6H, s).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.C1COCC1.[CH3:16][C:17]([CH3:20])([O-:19])[CH3:18].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[C:17]([O:19][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)([CH3:20])([CH3:18])[CH3:16]
Reactant: CC(C)(C)[O-]
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)Oc1ccc(C(=O)O)cn1
Yield: 58.1 %

Procedure:
To a mixture of 3.0 g of 6-chloronicotinic acid and 111 ml of THF was added 6.4 g of potassium tert-butoxide, followed by heating under reflux for 1 day. The reaction solution was poured into water, neutralized with citric acid, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 2.16 g of 6-tert-butoxynicotinic acid.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si](C(C)(C)C)(C)C)[CH:12]=[CH:11][C:10]=1[C@H:23]1[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:32])[CH3:31])[CH2:25][CH2:24]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)(O)[O-].[Na+]>O1CCCC1>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[C@H:23]1[CH2:24][CH2:25][C@H:26]([NH:29][C:30](=[O:32])[CH3:31])[CH2:27][CH2:28]1
Reactant: CC(=O)N[C@H]1CC[C@H](c2ccc(O[Si](C)(C)C(C)(C)C)cc2O[Si](C)(C)C(C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)N[C@H]1CC[C@H](c2ccc(O)cc2O)CC1
Reaction time: 3 h

Procedure:
To a round bottomed flask equipped with magnetic stirrer was added cis/trans-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]acetamide (15 mg, 31 μmol), tetrahydrofuran (3 ml) and tetra-n-butylammonium fluoride (93 μl, 93 μmol, 1.0M solution in tetrahydrofuran). The resulting solution was stirred for 3 hr. Tetra-n-butylammonium fluoride (90 μl, 90 μmol, 1.0M solution in tetrahydrofuran) was added and the solution stirred for a further 64 hr. Saturated aqueous sodium bicarbonate solution (3 ml) was added and the solvents removed in vacuo. The residue was partitioned between ethyl acetate (20 ml) and water (5 ml) and the aqueous layer extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via flash column chromatography (SiO2, methanol/dichloromethane, 1:9, v/v) afforded an oily solid (6 mg) which was a mixture of isomers by NMR. Further purification via HPLC afforded the title compound (0.5 mg, 6%) as a mixture of diastereoisomers and a colourless oil. m/z (ES−) 308 (M−1+60{acetate}); δH(CD3OD) 1.41 (1H, m), 1.57 (1H, m), 1.70 (2H, m), 1.83 (1H, m), 1.87 (1H, m), 1.93 (1H, m), 1.96 (1.5H, m), 2.04 (1.5H, m), 2.05 (1H, m), 2.82 (1H, m), 3.72 (0.5H, m), 4.14 (0.5H, m), 6.28 (2H, m), 6.92 (0.5H, dd), 6.97 (0.5H, dd).