Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][C@H:14]([OH:17])[CH2:15][OH:16].[OH-].[Na+]>Br.CO.O>[O:17]1[C:2]2[C:3](=[CH:4][CH:5]=[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]3=2)[CH2:12][CH2:13][C@@H:14]1[CH2:15][OH:16]
Reactant: OC[C@@H](O)CCc1ccc2ccccc2c1O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OC[C@H]1CCc2ccc3ccccc3c2O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 166.3 %

Procedure:
(2S)-4-(1-hydroxy-2-naphthyl)-1,2-butanediol (3.50 g, 15.1 mmol) is dissolved in hydrogen bromide (30 wt. % in acetic acid, 100 mL) and the reaction mixture is stirred at 0° C. for 2 h. The reaction mixture is quenched by the addition of water (500 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts are washed with water (3×200 mL), aqueous sodium chloride (300 mL), dried (magnesium sulfate), and the solvent is removed in vacuo to provide a crude oil. The residue is dissolved in methanol (100 mL) and the resulting solution is slowly added to a solution of aqueous sodium hydroxide (2.5 M, 150 mL) in water (350 mL) and the reaction mixture is allowed to stir at 0° C. for 30 min. The reaction mixture is quenched by the addition of aqueous hydrogen chloride (1.0 M, 500 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts are washed with water (2×200 mL), aqueous sodium chloride (300 mL), dried (magnesium sulfate), and the solvent is removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:1) provides 5.38 g (70%, 50% ee) of (2R)-3,4-dihydro-2H-benzo[h]chromen-2-ylmethanol as a colorless oil. [α]D25=−51.23 (c 11.58 in chloroform, 50% ee); Rf=0.52 (silica, ethyl acetate:hexanes 1:1); Anal. Calcd. for C14H14O2.0.25H2O: C, 76.86; H, 6.68. Found: C, 76.47; H, 6.38.
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[F:25][C:26]([F:36])([F:35])C1C=CC(CN)=NC=1>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:26]([F:36])([F:35])[F:25])=[CH:21][N:20]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: NCc1ccc(C(F)(F)F)cn1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Agent: Cl
Product: Cc1nc(NCc2ccc(C(F)(F)F)cn2)nc(NC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using {[5-(trifluoromethyl)pyridin-2-yl]methyl}amine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-grey solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04-1.16 (m, 3H), 1.16-1.19 (m, 2H), 1.38 (d, J=10.21 Hz, 2H), 1.55 (s, 3H), 1.86 (s, 3H), 2.26 (bs, 3H) 3.53 (d, J=5.37 Hz, 1H), 4.73 (s, 2H), 7.53 (d, J=7.52 Hz, 2H), 8.15 (d, J=7.79 Hz, 2H), 8.89 (s, 1H), 12.98 (bs, 1H); MS (ESI) m/z 380.0 (M+1)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([NH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]([CH2:19][CH2:20][CH2:21][CH3:22])[O:14][C:15]2=[O:16])=[CH:11][CH:10]=1)(=[O:7])[CH3:6]>>[C:5]([NH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]([CH2:19][CH2:20][CH2:21][CH3:22])[O:14][C:15]2=[O:16])=[CH:11][C:10]=1[N+:1]([O-:4])=[O:2])(=[O:7])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CCCCC1OC(=O)c2cc(NC(C)=O)ccc21
Product: CCCCC1OC(=O)c2cc(NC(C)=O)c([N+](=O)[O-])cc21
Reaction time: 8 h

Procedure:
To 100 ml of stirred and ice-cold turning nitric acid (sp. gr. 1.50) there are added, in portions, 59 g (0.288 mol) of compound obtained in Example 7 with the temperature below 10° C. The resulting clear solution is put aside at room temperature overnight. The reaction material is poured into crushed ice, and the solid is filtered, washed with water, dried and crystallised from ethanol, giving the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[C:8]([NH:13][C:14](=[O:23])[C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>C(COC)OC>[Cl:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:15]=1[C:14]([NH:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[N:6]=[CH:5][C:4]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:3]2[CH2:2][N:29]1[CH:33]=[CH:32][N:31]=[CH:30]1)=[O:23]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CBr
Solvent: COCCOC
Product: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1Cn1ccnc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
A mixture of 4-bromomethyl-8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonylquinoline (150 mg) and imidazole (106 mg) in dimethoxyethane was stirred for 1 hour at 70° C. The mixture was evaporated in vacuo, and the residue was purified by preparative thin layer chromatography (methanoldichloromethane) to give 8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonyl-4-(imidazol-1-ylmethyl)quinoline (110 mg).
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:30])[C@@H:18]([NH:19][C:20](=[O:29])[C@H:21]([NH2:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:15]3[S:14][C@:13]2([CH2:32][O:33][C:34](=[O:39])[NH:35][C:36](=[O:38])[CH3:37])[CH3:31])=[O:11])=CC=1)([O-])=O.[H][H]>[Pd].O>[C:36]([NH:35][C:34]([O:33][CH2:32][C@@:13]1([CH3:31])[C@H:12]([C:10]([OH:11])=[O:9])[N:16]2[C:17](=[O:30])[C@@H:18]([NH:19][C:20](=[O:29])[C@H:21]([NH2:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:15]2[S:14]1)=[O:39])(=[O:38])[CH3:37]
Reactant: [H][H]
Reactant: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: O
Product: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Yield: 62.8 %

Procedure:
To a prehydrogenated suspension of 10% palladium on carbon (0.59 gm), water-washed ethyl acetate (6.0 ml) and water (3.0 ml) was added (2R,3S,5R,6R) 2-(N-acetyl)carbamoyloxymethyl-6-[(R)-2-amino-2-phenylacetamido]-2-methylpenam-3-carboxylic acid p-nitrobenzyl ester (0.59 gm. 1.06 mmol). The mixture was shaken at 50 psi hydrogen pressure for 3 hours at 25° C. and then filtered through Dicalite-coated paper. The aqueous phase was separated, concentrated at reduced pressure to remove volatile solvent and gases, frozen and lyophilized. There was obtained 0.30 gm of the title compound as an amorphous solid. The purity was estimated from its nmr spectrum to be 60-70%.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([NH:14][CH2:15][CH2:16][NH2:17])[CH3:13]>N1C=CC=CC=1>[CH2:12]([NH:14][CH2:15][CH2:16][NH:17][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH3:13]
Reactant: CCNCCN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCNCCNS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C

Procedure:
A solution of 95 grams of p-toluenesulfonyl chloride in 175 ml. of pyridine was added dropwise to a stirred solution of 135 grams of N-ethyl ethylenediamine in 250 ml. of pyridine cooled in an ice bath. After addition was completed, the mixture was stirred one-half hour at room temperature then heated in a steam bath for one-half hour. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate and extracted with sodium carbonate solution and water. After drying the ethyl acetate portion over magnesium sulfate, the solvent was removed in vacuo to obtain N-[2-(ethylamino)ethyl]-p-toluenesulfonamide as a viscous oil which crystallized on standing. Analytical sample prepared from ether-hexane melted at 50°-53°C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][N:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:47]([O:50][CH2:51][CH2:52][NH:53][CH2:54][CH2:55][O:56][CH:57]([CH3:59])[CH3:58])([CH3:49])[CH3:48]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][N:37]([CH2:40][C:41]([N:53]([CH2:52][CH2:51][O:50][CH:47]([CH3:49])[CH3:48])[CH2:54][CH2:55][O:56][CH:57]([CH3:58])[CH3:59])=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)OCCNCCOC(C)C
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(CCOC(C)C)CCOC(C)C)CC1

Procedure:
In a manner analogous to the method described in example 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid was coupled with bis-(isopropoxy-ethyl)-amine (TCI-US) to give the title compound. HR-MS (ES, m/z) calculated for C45H62Cl2N6O5 [(M+H)+] 837.4232, observed 837.4231.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:4][N:5]2[C:10](Cl)=[C:9]([CH:12]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:13]([O:15][CH3:16])=[O:14])[C:8]([CH3:22])=[N:7][C:6]=12.[F:29][C:30]1[CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[C:33]([CH3:40])=[C:34]2[C:39]=1[O:38][CH2:37][CH2:36][CH2:35]2.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[Br:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:4][N:5]2[C:10]([C:32]3[C:33]([CH3:40])=[C:34]4[C:39](=[C:30]([F:29])[CH:31]=3)[O:38][CH2:37][CH2:36][CH2:35]4)=[C:9]([CH:12]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:13]([O:15][CH3:16])=[O:14])[C:8]([CH3:22])=[N:7][C:6]=12
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2c(Br)c(-c3ccccc3)nn2c1Cl
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cc(F)c2c1CCCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2c(Br)c(-c3ccccc3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Temperature: 110 °C
Yield: 9.4 %

Procedure:
To a 2-5 ml microwave tube was added methyl 2-(3-bromo-7-chloro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (290 mg, 0.621 mmol), tetrakis(triphenylphosphine)palladium(0) (71.8 mg, 0.062 mmol), 2-(8-fluoro-5-methylchroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200 mg, 0.683 mmol), DMF (2 mL) followed by 2M K2CO3 solution (200 μl). The reaction mixture was heated in a microwave reactor at 110° C. for 40 min. The reaction mixture was filtered and the filtrate was purified by silica gel chromatography to afford (35 mg, 9.4%) of the title compound. 1H NMR (500 MHz, CHLOROFORM-d) δ 7.90 (dd, J=8.1, 1.4 Hz, 2H), 7.53-7.32 (m, 3H), 6.86 (d, J=10.7 Hz, 1H), 5.02 (s, 1H), 4.48-4.18 (m, 2H), 3.64 (s, 3H), 2.82 (s, 3H), 2.75 (t, J=6.4 Hz, 2H), 2.20-2.12 (m, 2H), 1.84 (s, 3H), 1.16 (s, 9H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[SH:13].[Cl:14][CH2:15][C:16](OCC)(OCC)OCC>C(O)C>[Cl:14][CH2:15][C:16]1[S:13][C:4]2[CH:5]=[CH:6][C:7]([C:9]([F:10])([F:11])[F:12])=[CH:8][C:3]=2[N:2]=1
Reactant: Nc1cc(C(F)(F)F)ccc1S
Reactant: CCOC(CCl)(OCC)OCC
Agent: Cl
Solvent: CCO
Product: FC(F)(F)c1ccc2sc(CCl)nc2c1
Temperature: 60 °C

Procedure:
To a solution of 2-amino-4-trifluoromethylthiophenol hydrochloride (30.0 g) in ethanol (125 ml) was added 2-chloro-1,1,1-triethoxyethane (31.0 g). The mixture was heated for 1 hour at 60° C. The solution was concentrated to remove excess ethanol and the resulting material was extracted with ether (500 ml). The organic extract was washed successively with 10% HCl (20 ml), water (100 ml), 10% sodium bicarbonate solution and water (100 ml), and then evaporated to obtain an amber colored oil, which crystallized upon standing at room temperature (28.9 g; m.p. 52° C).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[CH2:23]O>>[F:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[CH2:23][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(CO)c(F)c1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: Cc1ccc(COc2ccnn2-c2cc(C#N)ccn2)c(F)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2-fluoro-4-methylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.36 (3H, s), 5.26 (2H, s), 5.80 (1H, d, J=2.0 Hz), 6.93 (1H, d, J=11.2 Hz), 6.98 (1H, d, J=8.0 Hz), 7.31-7.35 (1H, m), 7.38 (1H, dd, J=1.2 Hz, 4.8 Hz), 7.57 (1H, d, J=1.6 Hz), 8.01 (1H, s), 8.69 (1H, d, J=4.8 Hz). [M+H] Calc'd for C17H13FN4O, 309. Found, 309.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>>[C:8]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Oc1ccccc1
Agent: Cl
Product: O=C(Oc1ccccc1)c1ccccc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A mixture of 9.4 g (0.1 mole) of phenol, 11.6 g (0.1 mole) of benzoyl chloride and 0.176 g (0.5 millimole) of MoTe2 having a surface area of 1.5 to 2 square meters per cubic centimeter, a mean diameter of 4.1 to 4.8 microns and a particle size distribution of 0.6 to 7.5 microns, was warmed at 30° C. There was a vigorous evolution of HCl. After 1 hour the entire mixture had solidified. It was heated at 60° C. for 2 hours, the solid was broken up, washed with water, dissolved in acetone, filtered from MoTe2, and evaporated to give 17.6 g (89 mole percent) of white crystalline phenyl benzoate, Mp and mixed mp 70° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[C:3]=1[Cl:13].[Cu](C#N)[C:15]#[N:16].O>CN(C=O)C>[Cl:13][C:3]1[C:4]([CH3:12])=[C:5]([NH:8][C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][C:2]=1[C:15]#[N:16]
Reactant: CC(=O)Nc1ccc(Br)c(Cl)c1C
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(C#N)c(Cl)c1C
Temperature: 150 °C
Yield: 70.5 %

Procedure:
A suspension of N-(4-bromo-3-chloro-2-methylphenyl)acetamide (45 g, 0.17 mol) and copper cyanide (34 g, 0.34 mol) in DMF (450 mL) was heated to 150° C. for 24 h. The suspension was cooled, poured into water with stirring. The solid was filtered and dried to give 25 g (70%) of the title compound which was used for the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:10]=[O:11])=[C:7]([OH:9])[CH:8]=1)[CH3:2].CS(O[CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][O:19]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:10]=[O:11])=[C:7]([O:9][CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][O:19]2)[CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C=O)c(O)c1
Reactant: CS(=O)(=O)OCC1CCOCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(C=O)c(OCC2CCOCO2)c1
Temperature: 80 °C
Yield: 55.3 %

Procedure:
A stirred solution of 3.8 grams (0.026 mole) of 5-ethyl-2-formylphenol, 5.0 grams (0.026 mole) of 4-methylsulfonyloxymethyl-1,3-dioxane, and 7.0 grams (0.051 mole) of potassium carbonate in 150 mL of N,N-dimethylformamide was heated at 80° C. for about 18 hours. Analysis by thin layer chromatography (TLC) indicated the reaction was not complete. An additional 2.5 grams (0.013 mole) of 4-methylsulfonyloxymethyl-1,3-dioxane was added, and the reaction mixture was heated at 80° C. for an additional five hours. After this time the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with aqueous 10% lithium chloride, dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel, yielding 3.6 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[CH:15]=[C:14](I)[CH:13]=[C:12]([CH3:17])[C:11]=2[NH:18][C:19]([C:21]2[N:22]([C:30]3[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][N:31]=3)[N:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=2)=[O:20])=[O:9])([CH:4]2[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[C:37]([Cu])#[N:38]>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]1([NH:7][C:8]([C:10]2[CH:15]=[C:14]([C:37]#[N:38])[CH:13]=[C:12]([CH3:17])[C:11]=2[NH:18][C:19]([C:21]2[N:22]([C:30]3[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][N:31]=3)[N:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=2)=[O:20])=[O:9])([CH:4]2[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: N#C[Cu]
Reactant: Cc1cc(I)cc(C(=O)NC2(C3CC3)CC2)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(C(=O)NC2(C3CC3)CC2)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 101.2 %

Procedure:
To a solution of 3.29 g (5.23 mmol) 2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid [2-(bicyclopropyl-1 -ylcarbamoyl)-4-iodo-6-methyl-phenyl]-amide in 50 ml tetrahydrofuran is added 1.19 g (6.25 mmol) Cul, 0.30 g tetrakis(triphenylphosphine) palladium and 2.78 g (31.0 mmol) CuCN. The mixture is heated 1 h at 80° C. and turns dark green. After cooling down, the mixture is filtered on Hyflo and evaporated. The residue is dissolved in 15 ml DMF and poured into 100 ml water containing 5 g NaHCO3. After 30 min stirring, the crystals are filtered, washed with water and a mixture of hexane/acetone (1:3) to afford 2.8 g of the title compound.
Reaction SMILES: [CH2:1]([CH:3]([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:4][N:5]1[C:17]2[C:12](=[CH:13][C:14]([N+:22]([O-:24])=[O:23])=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33])=O)[CH:10]=2)[CH3:2].[Cl-].[OH:39][NH3+:40]>N1C=CC=CC=1>[CH2:1]([CH:3]([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:4][N:5]1[C:17]2[C:12](=[CH:13][C:14]([N+:22]([O-:24])=[O:23])=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33])=[N:40][OH:39])[CH:10]=2)[CH3:2]
Reactant: CCCCC(CC)Cn1c2ccc(C(=O)c3ccccc3C)cc2c2cc([N+](=O)[O-])c3ccccc3c21
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: c1ccncc1
Product: CCCCC(CC)Cn1c2ccc(C(=NO)c3ccccc3C)cc2c2cc([N+](=O)[O-])c3ccccc3c21
Temperature: 0 °C
Reaction time: 16 h
Yield: 75.6 %

Procedure:
To [11-(2-ethyl-hexyl)-5-nitro-11H-benzo[a]carbazole-8-yl]-o-tolyl-methanone (0.36 g, 0.73 mmol) in pyridine (6 ml) is added hydroxylammonium chloride (0.10 g, 1.45 mmol) at 120° C. After stirring for 16 hours, the reaction mixture is poured into ice-water. The crude is extracted with AcOEt, and washed with water and brine. After drying over MgSO4 and concentration, the crude is purified by column chromatography on silica gel eluting with CH2Cl2 to obtain a yellow resin (0.28 g, 76%). The structure is confirmed by 1H-NMR spectrum (CDCl3). δ [ppm]: 0.79-0.90 (m), 1.13-1.48 (m), 2.21 (m), 2.29 (s), 4.69 (m), 7.25 (d), 7.37-7.47 (m), 7.55 (d), 7.67-7.75 (m), 7.90 (d), 8.04 (s), 8.60 (d), 8.89 (d), 8.92 (s).
Reaction SMILES: Cl.[CH:2]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]#[N:18]>ClC1C=CC=CC=1>[CH:2]1([NH:8][C:17]([NH:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH3:9])=[NH:18])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1ccccc1NC#N
Reactant: NC1CCCCC1
Agent: Cl
Solvent: Clc1ccccc1
Product: Cc1ccccc1NC(=N)NC1CCCCC1
Reaction time: 8 h
Yield: 26.5 %

Procedure:
A suspension of cyclohexylamine hydrochloride (310 mg, 2.28 mmol) and (2-methylphenyl)cyanamide (365 mg, 2.76 mmol) in dry chlorobenzene was heated at 125°-135° for 4 hrs. The solvent was evaporated in vacuo with heating, and the residue partitioned between CH2Cl2 and 20×8 ml 10% HCl. The aqueous extracts were made alkaline to pH 9-9.5, and the white precipitate collected after standing at 4° C. overnight. Two recrystallizations from EtOH/H2O gave 140 mg (22%) of white needles, mp 145°-146°, 1H (CD3OD) 1.149-2.054 (m, 10 H), 2.164 (s, 3 H), 3.50 (m, 1 H), 6.875 (d, 1H, J=7.5 Hz), 6.968 (t, 1H, J=7.5 Hz), 7.118 (t, 1H, J=7.5 Hz), 7.177 (d, 1H, J=7.5 Hz). Anal. Calcd for C14H21N3:C, 72.69; H, 9.15; N, 18.16. Found: C, 72.72; H, 9.24; N, 18.18.
Reaction SMILES: [NH2:1][C:2]1[S:6][CH:5]=[C:4]([CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:8]2)[C:3]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].CCN(C(C)C)C(C)C.[F:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41](Cl)=[O:42]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:26]([O:25][C:23]([C:3]1[C:4]([CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:8]2)=[CH:5][S:6][C:2]=1[NH:1][C:41](=[O:42])[C:40]1[CH:44]=[CH:45][CH:46]=[C:38]([F:37])[CH:39]=1)=[O:24])[CH3:27]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CCOC(=O)c1c(C2CCCN(C(=O)OCc3ccccc3)C2)csc1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(C2CCCN(C(=O)OCc3ccccc3)C2)csc1NC(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 47 %

Procedure:
To a solution of 55 (˜2 mmol) in DCM (10 ml) was added DIEA (0.7 ml, 4 mmol), 3-fluorobenzoyl chloride (0.48 ml, 4 mmol) and catalytic amount of DMAP. The mixture was stirred at rt for 17 hrs, diluted with DCM (50 ml), washed with water, saturated sodium bicarbonate (aq.), water, 1N HCl (aq.) and brine, dried over anhydrous sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under vacuum. The crude product was purified on a silica gel column to give 56 as a yellow oil (0.48 g). LC-MS for C27H27FN2O5S: 510; found: 511.
Reaction SMILES: [Sn](Cl)Cl.[CH3:4][N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[C:19]3[C:14](=[CH:15][C:16]([N+:20]([O-])=O)=[CH:17][CH:18]=3)[N:13]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:12]=2)[CH2:7][CH2:6]1>CO>[CH3:4][N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[C:19]3[C:14](=[CH:15][C:16]([NH2:20])=[CH:17][CH:18]=3)[N:13]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:24])=[O:25])[CH:12]=2)[CH2:9][CH2:10]1
Reactant: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3cc([N+](=O)[O-])ccc23)CC1
Agent: Cl[Sn]Cl
Solvent: CO
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3cc(N)ccc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tin (II) chloride (2 g, 9.35 mmol) was added to a solution of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitro-1-(phenylsulfonyl)-1H-indole (100 mg, 0.25 mmol) in methanol (30 mL). The resulting solution was stirred for 2 hours at reflux temperature After cooling to room temperature, the mixture was concentrated by evaporation to provide 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-1H-indol-6-amine, which was used in the next stage without further purification.