Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:11][C@H:12]([C:14]([N:16]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][CH2:25][CH2:24]2)[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH3:13])(OCC1C=CC=CC=1)=O>[Pd].C(O)C.O>[NH2:11][C@H:12]([C:14]([N:16]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][CH2:25][CH2:24]2)[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH3:13]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=O)O)c1ccc2c(c1)CCC2
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: C[C@H](N)C(=O)N(CC(=O)O)c1ccc2c(c1)CCC2

Procedure:
A solution of N-carbobenzoxy-L-alanyl-N-(5-indanyl)glycine (4.5 g) and 10% palladium on carbon (1.0 g) in 250 ml ethanol was hydrogenated at 25 psi for 2 h and filtered. Concentration of the volatiles in vacuo provided a residue which was dissolved in H2O and filtered over Celite. Lyophilization of the filtrate provided the crystalline (m.p. 119°-120° C.) product.
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([S:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[C:8]2[CH2:33][C:34]([CH3:40])([CH3:39])[C:35]([O:37]C)=[O:36])=[CH:4][CH:3]=1.COC(=O)C(C)(C)CC1N(CC2C=CC(Cl)=CC=2)C2C(C=1SC(C)(C)C)=CC(OC)=CC=2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([S:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[C:8]2[CH2:33][C:34]([CH3:40])([CH3:39])[C:35]([OH:37])=[O:36])=[CH:41][CH:42]=1
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Agent: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OC)ccc2n1Cc1ccc(Cl)cc1
Product: CC(C)(C)Sc1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc12

Procedure:
Using the hydrolytic procedure of Step B but substituting the ether of Step D for the ester of Step A provided the title compound, which was recrystallized from 1:1 EtOAc/hexane. m.p. 208° C.
Reaction SMILES: CS([C:5]1[N:6]=[C:7]([CH3:16])[C:8]2[CH:14]=[CH:13][C:12](=[O:15])[NH:11][C:9]=2[N:10]=1)(=O)=O.[C:17]1([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][CH2:36][OH:37])[CH2:29][CH2:28]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.CC(C)([O-])C.[Na+]>O1CCOCC1>[CH3:16][C:7]1[C:8]2[CH:14]=[CH:13][C:12](=[O:15])[NH:11][C:9]=2[N:10]=[C:5]([O:37][CH2:36][CH2:35][CH2:34][CH2:33][N:30]2[CH2:31][CH2:32][N:27]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[CH2:28][CH2:29]2)[N:6]=1
Reactant: OCCCCN1CCN(c2cccc3ccccc23)CC1
Reactant: Cc1nc(S(C)(=O)=O)nc2[nH]c(=O)ccc12
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nc(OCCCCN2CCN(c3cccc4ccccc34)CC2)nc2[nH]c(=O)ccc12
Reaction time: 1 h
Yield: 38 %

Procedure:
2-Methanesulfonyl-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (300 mg, 1.245 mmol, U.S. Pat. No. 6,498,163), 4-(4-naphthalen-1-yl-piperazin-1-yl)-butan-1-ol (392 mg, 1.379 mmol) and sodium t-butoxide (362 mg, 3.76 mmol) were combined in a vial. Dioxane (10 mL) was added and the solution was stirred for 1 h. The reaction mixture was concentrated and then partitioned between ethyl acetate and water. The organic layer was washed with water, dried over Na2SO4, filtered and concentrated. Purification by liquid chromatography (MPLC, gradient of 100% CH2Cl2 to 100% of 100:8:1 CH2Cl2:EtOH:NH4OH solution) gave the title compound as a solid (220 mg, 0.485 mmol, 38%). MS: APCI: M+1: 444.2 (Exact Mass: 443.23).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[C:7]([O:16]CC)(=[O:15])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C(=O)C(C)C>C(O)(C)(C)C>[CH2:13]([O:12][C:10](=[O:11])[C:9](=[CH:1][CH:2]([CH3:5])[CH3:3])[CH2:8][C:7]([OH:16])=[O:15])[CH3:14]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)CCC(=O)OCC
Agent: CC(C)C=O
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)C(=CC(C)C)CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a solution of 11.2 g (0.1 mol) potassium tert-butoxide in 100 ml tert-butanol was added a mixture of 17.4 g (0.1 mol) diethyl succinate and 7.2 g (0.1 mol) isobutyraldehyde over a period of 30 min. The mixture was allowed to stir at room temperature for one hour and heated to 50° C. for an additional hour. The solvent was removed under reduced pressure, the residue was dissolved in 100 ml water and transferred into a separation funnel. The solution was extracted twice with 50 ml ethyl acetate to remove neutral impurities, acidified with 6M HCl and extracted again twice with 20 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure, to give 13.6 g (68%) of a yellow brown oil. 1H-NMR: 59% E-isomer, 19% Z-isomer, 22% isomerised material.
Reaction SMILES: C(C(CC)(C1C=CC=CC=1OCC1C=CC=CC=1)N)C.[CH:21]1([NH:24][C:25](=[O:53])[C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([N:33]3[CH:38]=[CH:37][N:36]=[C:35]([NH:39][C:40]([CH2:50][CH3:51])([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[OH:49])[CH2:41][CH3:42])[C:34]3=[O:52])[CH:27]=2)[CH2:23][CH2:22]1.C1(O)C=CC=CC=1.Br[CH2:62][CH2:63][Cl:64]>>[Cl:64][CH2:63][CH2:62][O:49][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=1[C:40]([NH:39][C:35]1[C:34](=[O:52])[N:33]([C:28]2[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=2[CH3:32])[C:25]([NH:24][CH:21]2[CH2:23][CH2:22]2)=[O:53])[CH:38]=[CH:37][N:36]=1)([CH2:41][CH3:42])[CH2:50][CH3:51]
Reactant: ClCCBr
Reactant: CCC(CC)(Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2C)c1=O)c1ccccc1O
Agent: CCC(N)(CC)c1ccccc1OCc1ccccc1
Solvent: Oc1ccccc1
Product: CCC(CC)(Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2C)c1=O)c1ccccc1OCCCl

Procedure:
α,α-Diethyl-2-(phenylmethoxy)-benzenemethanamine (Example 266d) was converted to N-cyclopropyl-3-[3-[[1-ethyl-1-(2-hydroxyphenyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide using the method described in Example 134. This phenol was alkylated with 1-bromo-2-chloroethane as described in example 167e to afford the subtitle product.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8]2[C:9]([CH3:19])=[CH:10][C:11]([CH3:18])=[C:12]([CH:17]=2)[C:13]([O:15]C)=[O:14])=[C:5]([CH3:7])[N:6]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1[NH:3][C:4]([C:8]2[C:9]([CH3:19])=[CH:10][C:11]([CH3:18])=[C:12]([CH:17]=2)[C:13]([OH:15])=[O:14])=[C:5]([CH3:7])[N:6]=1
Reactant: COC(=O)c1cc(-c2[nH]c(C)nc2C)c(C)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc(C)c(-c2cc(C(=O)O)c(C)cc2C)[nH]1
Temperature: 55 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
Into a 50-mL round-bottom flask, were placed methyl 5-(2,4-dimethyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 1.7, 300 mg, 1.16 mmol) and sodium hydroxide (465 mg, 11.6 mmol) in methanol (20 mL) and H2O (5 mL). The resulting solution was stirred at 55° C. for 4 h, then after cooling to room temperature, aqueous HCl (2 M) was added to adjust the pH to 5. The resulting mixture was concentrated under reduced pressure and the residue was dissolved in methanol (5 mL). The solids were removed by filtration and the filtrate was concentrated under reduced pressure to yield the title compound as a light yellow solid (280 mg, crude), which was used in the next step without further purification.
Reaction SMILES: C[Al](C)C.[CH:5]1([NH2:10])[CH2:9][CH2:8][CH2:7][CH2:6]1.[SH:11][C:12]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:13]=1[C:14](OC)=[O:15]>C(Cl)Cl>[CH:5]1([NH:10][C:14](=[O:15])[C:13]2[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:12]=2[SH:11])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COC(=O)c1ccc(OC)cc1S
Reactant: NC1CCCC1
Agent: C[Al](C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)NC2CCCC2)c(S)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
AlMe3 (10 mmol, 2.0 M in toluene) was added dropwise to a cooled (0° C.) suspension of cyclopentylamine (0.85 g, 10 mmol) in CH2Cl2 (30 mL). When the addition was complete, the reaction mixture was allowed to warm to room temperature and stirring was continued for 30 minutes until the gas evolution ceased. Then, a solution of methyl 2-mercapto-4-methoxy-benzoate (0.990 g, 5 mmol) was added. After stirring at 60° C. for 12 h, the mixture was cooled, and carefully quenched with 5% aq HCl (20 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3×15 mL). The combined organic extracts were washed with a saturated aqueous solution of NaHCO3 (15 mL) and brine. The organic phase was dried using MgSO4 and evaporated, filtered and the solvent was evaporated in vacuo. The resulting residue was purified by crystallization from Et2O to afford N-cyclopentyl-2-mercapto-4-methoxybenzamide as a tan solid (1.18 g, 94%). 1H NMR (DMSO-d6, 300 MHz): δ 8.26 (s, 1H), 7.51 (d, 1H, J=8.7 Hz), 7.01 (s, 1H), 6.72 (d, 1H, J=8. Hz), 5.62 (s, 1H), 4.16-4.14 (m, 1H), 3.78 (s, 3H), 1.99-1.80 (m, 2H), 1.79-1.68 (m, 2H), 1.66-1.53 (m, 4H). LC-MS (ESI) Calcd for C13H17NO2S [M+H]+: 252.09. Found: 251.95.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.[N:17]1([C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][N:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CCN(C(C)C)C(C)C.[I-].C(C[P+](C)(C)C)#N>C(#N)CC.C([O-])([O-])=O.[K+].[K+].O>[O:16]=[C:7]1[NH:6][C:5]2[CH:4]=[C:3]([CH2:2][N:20]3[CH2:21][CH2:22][N:17]([C:23]4[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][N:24]=4)[CH2:18][CH2:19]3)[CH:12]=[N:11][C:10]=2[N:9]2[CH2:13][CH2:14][CH2:15][C@@H:8]12
Reactant: CCOC(=O)c1ccc(N2CCNCC2)nc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCC#N
Product: CCOC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)nc1
Temperature: 90 °C
Yield: 0.1 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (233 mg, 1.06 mmol), ethyl 6-(piperazin-1-yl)nicotinate (270 mg, 0.1.15 mmol), DIPEA (0.80 mL), and (cyanomethyl)trimethylphosphonium iodide (369 mg, 01.82 mmol) were suspended in propionitrile (3 mL) and heated in a closed vial at 90° C. for 5 h. The mixture was cooled, diluted with a solution of K2CO3 (2.50 g) in water (15 mL) and extracted with dichloromethane (2×10 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The resulting oil was crystallized with ethyl ether—ethanol (10:1, 22 mL) to afford the title compounds as a tan solid (0.355 mg, 77%). [M+H] calc'd for C23H28N6O3, 437; found, 437.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[Cl:11]N1C(=O)CCC1=O>CC#N>[Cl:11][C:10]1[C:2](=[O:1])[NH:3][CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(O)c1ccc(O)nc1
Solvent: CC#N
Product: O=C(O)c1c[nH]c(=O)c(Cl)c1
Temperature: 80 °C

Procedure:
To a solution of 6-hydroxy nicotinic acid (0.500 g, 3.59 mmol, TCI) in MeCN (20 mL), was added N-chlorosuccinimide (0.436 mL, 5.39 mmol, Aldrich). The resulting mixture was then heated at 80° C. for 72 h. A white precipitate was present. The mixture was filtered and the white solid was washed with EtOAc (2×1 mL) and dried in vacuo to afford the title compound as a white solid. MS (ESI, positive ion) m/z: 174,176 (M+H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH3:5].[CH3:6][O:7][C:8](=[O:20])[C:9]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[N:12]=[C:11](Cl)[CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:6][O:7][C:8](=[O:20])[C:9]1[CH:10]=[C:11]([N:2]([CH3:1])[CH2:3][CH2:4][CH3:5])[N:12]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:14]=1
Reactant: CCCNC
Reactant: COC(=O)c1cc(Cl)nc(S(C)(=O)=O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCCN(C)c1cc(C(=O)OC)cc(S(C)(=O)=O)n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 63.2 %

Procedure:
Add methylpropylamine (0.21 mL, 2.0 mmol) to a suspension of 2-chloro-6-methanesulfonyl-isonicotinic acid methyl ester (0.25 g, 1.0 mmol), palladium acetate (0.022 g, 0.1 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.062 g, 0.1 mmol), and cesium carbonate (0.325 g, 1.0 mmol) in toluene (5 mL) at room temperature and stir 18 h at 80° C. Cool, filter through a filtering agent and purify (silica gel chromatography, eluting with 20:80 to 40:60 ethyl acetate:hexanes) to give the title compound (0.181 g, 63%).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([N+:11]#[C-:12])[CH2:4][CH2:3]1.C1(C)C=CC(S(O)(=O)=[O:20])=CC=1.CCOCC>CS(C)=O>[O:1]=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([N:11]=[C:12]=[O:20])[CH2:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: [C-]#[N+]C1CCC(=O)c2sccc21
Solvent: CCOCC
Solvent: CS(C)=O
Product: O=C=NC1CCC(=O)c2sccc21

Procedure:
A solution of 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylisocyanide (9.5 g) in dry dimethylsulfoxide (4.63 g) is stirred under a nitrogen atmosphere while anhydrous p-toluenesulfonic acid (0.93 g) is added in small portions over an hour. The mixture is heated below 50° C. After 1.25 hours the reaction mixture is cooled and ether (3 × 3 ml) added, and the ether solution is then decanted. The ether solution contains the title isocyanate, and is used as is.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH:4]([C:14]1[N:15]=[CH:16][N:17]([C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=1.[OH-].[Li+].Cl>C1COCC1>[C:32]1([C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:17]2[CH:18]=[C:14]([CH:4]([CH2:5][C:6]3[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=3)[C:3]([OH:38])=[O:2])[N:15]=[CH:16]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)C(Cc1ccc(C#N)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1ccc(CC(C(=O)O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1

Procedure:
A solution of the 2-{1-(triphenylmethyl)-1H-imidazol-4-yl}-2-(4-cyanobenzyl)-acetic acid methyl ester in THF was treated with 1 equivalent of 1M lithium hydroxide solution. Upon consumption of starting material as determined by t.l.c, 1 equivalent of hydrochloric acid was added and the solution evaporated to dryness in vacuo. The material obtained in this manner could be used without further purification.
Reaction SMILES: [CH2:1](/[C:3](/[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=[CH:4]/[CH3:5])[CH3:2].[OH2:16]>>[CH3:15][O:14][C:8]1[CH:7]=[C:6]([CH:3]([CH2:1][CH3:2])[CH:4]([OH:16])[CH3:5])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: C/C=C(/CC)c1ccc(OC)c(OC)c1
Reactant: O
Product: CCC(c1ccc(OC)c(OC)c1)C(C)O

Procedure:
Addition of H2O to 4-((1Z)-1-ethylprop-1-enyl)-1,2-dimethoxybenzene to yield 3-(3,4-dimethoxyphenyl)pentan-2-ol.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].ClC1C=CC=CC=1Cl.[Br:16][C:17]1[C:30]2[C:29](=[O:31])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:32])[C:21]=2[C:20]([NH:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:19][CH:18]=1>CO.S(=O)(=O)(O)O>[C:1]([N:33]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:20]1[C:21]2[C:22](=[O:32])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29](=[O:31])[C:30]=2[C:17]([Br:16])=[CH:18][CH:19]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1c2ccccc2C(=O)c2c(NC3CCCCC3)ccc(Br)c21
Agent: O=S(=O)(O)O
Solvent: Clc1ccccc1Cl
Solvent: CO
Product: CC(=O)N(c1ccc(Br)c2c1C(=O)c1ccccc1C2=O)C1CCCCC1
Temperature: 110 °C
Reaction time: 6 h
Yield: 70.1 %

Procedure:
102 g of acetic anhydride was placed in a 20 g 1,2-dichlorobenzene solution of 76.9 g of 4-bromo1-cyclohexylaminoanthraquinone, and 1 g of concentrated sulfuric acid was placed to the solution. The solution was stirred at 110° C. for 6 hours. After the reaction was completed, the solution was diluted with 1000 g of methanol and filtered to obtain 59.8 g of 1-(acetylcyclohexylamino)-4-bromoanthraquinone (yield of 70.1%). Further, a solution of 12 g of sodium hydroxide/150 g of water was dropped to a 150 g isobutanol solution of 1-(acetylcyclohexylamino)-4-bromoanthraquinone, and the obtained solution was stirred at 90° C. for 6 hours. After the reaction was completed, the solution was cooled, the obtained solid was filtered to obtain 28.7 g of 4-bromo-1,9-N-cyclohexylanthrapyridone (70.4%). Next, 25.8 g of 2-ethylhexylamine, 8.6 g of sodium carbonate, and 6.8 g of copper powder were placed in a 40 g 1,3-dimethyl-2-imidazolidine solution of 20.4 g of 4-bromo-1,9-N-cyclohexylanthrapyridone, and the reaction was made at 190° C. for 4 hours. After the reaction was completed, the solution was cooled, diluted with ethyl acetate, and filtered. Column chromatography refining (toluene/THF) was performed to obtain 18 g of a compound (2) (yield of 82.7%). FIG. 1 illustrates a 1H NMR spectrum of the compound (2) in CDCl3 at room temperature and 400 MHz.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH:16]([Si:19]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])Cl)([CH3:18])[CH3:17]>CN(C=O)C>[CH3:13][O:12][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[N:1]([Si:19]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:16]([CH3:18])[CH3:17])[CH:2]=[CH:3]2)=[O:11]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a solution of 1 g of methyl indole-5-carboxylate (5.7 mmol) in 10 mL of dry DMF 273 mg of NaH (mineral oil dispersion 50-60%, 5.7 mmol) were added and the mixture cooled to 0° C. Triisopropylchlorosilane (1.06 g, 5.7 mmol) were added drop wise and after 1 hour LC-MS showed complete conversion of the starting material to the title product. The mixture was diluted with 30 mL of DCM and washed with saturated Na2CO3. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude was purified with SiO2 column eluting with n-hexane. The title compound was obtained (500 mg, yield 26%)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:27][C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])(=O)=O)=CC=1>CN(C=O)C.C(OCC)(=O)C>[F:33][C:28]([F:34])([C:29]([F:32])([F:31])[F:30])[CH2:27][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCC(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.2 %

Procedure:
A solution of 4-hydroxybenzaldehyde (2 g, 16.7 mmol) in DMF (33 mL) was stirred as solid potassium carbonate (4.1 g, 29.7 mmol) was added, and the reaction mixture was then stirred at RT. After 30 min, solid 2,2,3,3,3-pentafluoropropyl 4-methylbenzenesulfonate (5 g, 16.4 mmol) was added into the reaction mixture. The mixture was stirred and heated at 100° C. for 7 h. The reaction mixture was allowed to cool, diluted with ethyl acetate, washed with water (3×) and brine, and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexane afforded 4-(2,2,3,3,3-pentafluoropropoxy)benzaldehyde (1.26 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH:11]=[N:10][C:9]([S:17][CH3:18])=[CH:8][C:7]2=1)([O-])=O.C(O)C>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH:11]=[N:10][C:9]([S:17][CH3:18])=[CH:8][C:7]2=1
Reactant: CSc1cc2c(cn1)[nH]c1ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CSc1cc2c(cn1)[nH]c1ccc(N)cc12

Procedure:
950 mg of 6-nitro-3-methylthio-β-carboline are hydrogenated in 80 ml of tetrahydrofuran and 80ml of ethanol with 200 mg of palladium/carbon (10%) for 7.5 hours at room temperature under normal hydrogen pressure. After filtration and concentration, the residue is chromatographed on silica gel with methylene chloride/acetone=1:1 as eluant. 600 mg of 6-amino-3-methylthio-β-carboline with a 202° C. melting point are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([N+:15]([O-])=O)=[C:11]([CH:14]=1)[C:12]#[N:13]>O1CCOCC1.[Pd]>[NH2:15][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]2[CH:18]=[C:19]([F:21])[CH:20]=[C:2]([F:1])[CH:3]=2)=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: N#Cc1cc(OCc2cc(F)cc(F)c2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1COCCO1
Product: N#Cc1cc(OCc2cc(F)cc(F)c2)ccc1N
Reaction time: 4 h
Yield: 86 %

Procedure:
A mixture of 5-[(3,5-difluorobenzyl)oxy]-2-nitrobenzonitrile (1 g, 3.44 mmol) and palladium 5% on carbon (150 mg) in 1,4-dioxane (20 mL) was treated under hydrogen atmosphere (40 psi) at room temperature. After 4 hours, the mixture was filtered on a celite pad and evaporated to dryness affording 770 mg (yield 86%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([OH:8])[CH:7]=1.C(OCC)(=O)C.C(O)(=O)C>[Fe].O>[NH2:9][C:5]1[CH:4]=[C:3]([C:12]([F:13])([F:14])[F:15])[C:2]([Cl:1])=[CH:7][C:6]=1[OH:8]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1O
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(C(F)(F)F)c(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
A mixture of 7.55 g of 5-chloro-2-nitro-4-trifluoromethylphenol and 10 ml of ethyl acetate was added dropwise to a mixture, which was heated to 80° C., of 8.7 g of electrolytic iron, 30 ml of acetic acid and 50 ml of water, and then the reaction mixture was stirred at the same temperature for 30 minutes. The mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and a saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 5.4 g of 2-amino-5-chloro-4-trifluoromethylphenol.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:15]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccnc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2cccnc2)sc2ccccc12
Yield: 43.3 %

Procedure:
Methyl thiosalicylate (1.8 g, 10.7 mM) and 3-cyanopyridine (1.1 g, 10.56 mM) were dissolved in toluene (5 ml), and triethylamine (2 ml, 14.4 mM) was added to the solution. After heating for 48 hours under reflux, the same procedures as in REFERENCE EXAMPLE 1 were carried out to give the title compound as crystals (1.1 g, 43.4%).
Reaction SMILES: [CH:1]1([N:4]([C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][C:21](OC)=[O:22])[CH2:16][CH2:15]2)[C:5](=[O:13])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH:1]1([N:4]([C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]2)[C:5](=[O:13])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)C[C@H]1CC[C@H](N(C(=O)c2cccc(F)c2)C2CC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1cccc(F)c1)N(C1CC1)[C@H]1CC[C@H](CCO)CC1

Procedure:
To a solution of methyl 2-(trans-4-(N-cyclopropyl-3-fluorobenzamido)cyclohexyl)acetate (0.100 g, 0.30 mmol) in THF (3 mL) was added lithium aluminum hydride (1.0 M solution in THF) (0.15 ml, 0.15 mmol) at 0° C. The reaction was quenched with saturated NH4Cl (10 mL) after 15 minutes. The mixture was extracted with EtOAc twice. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by prep TLC eluting with 50% EtOAc-hexane. The alcohol product was obtained as a sticky white solid (42 mg). MS: 306 (M+1), C18H24FNO2.