Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=O.O>C1COCC1.CCCCCC.CCOCC>[Br:16][C:13]1[CH:14]=[CH:15][C:7]2[C:21]3([O:11][C:9](=[O:10])[C:8]=2[CH:12]=1)[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]3
Reactant: O=C(O)c1cc(Br)ccc1Br
Reactant: CN1CCCCC1=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN1CCC2(CC1)OC(=O)c1cc(Br)ccc12
Temperature: -78 °C
Reaction time: 2 h
Yield: 19.7 %

Procedure:
Butyllithium (97.2 ml of 1.47 M solution in hexane, 143 mmol) was added dropwise to a solution of 2,5-Dibromo-benzoic acid (20 g, 72 mmol) in dry THF (300 ml) at −78° C. over a period of 3.5 h under a nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 2 h. A solution of N-methyl piperidone (11.31 g, 99 mmol) in hexane (40 mL) was added dropwise during 30 min to the reaction mixture at −78° C. The reaction mixture was allowed to come to room temperature and stirring was continued for overnight. The reaction mixture was added to a mixture of water (500 ml) and ether (300 mL). The aqueous layer was extracted with ether (5×150 mL) and acidified with concentrated HCl (to pH 2-3) and extracted with ether (2×150 ml). The acidic solution was boiled for 1 h and then cooled to 0-5° C. and made alkaline (to pH 9-10) with aqueous NaOH. The cold solution was rapidly extracted with chloroform (5×300 mL). The combined chloroform extracts were washed with water (150 ml), dried over sodium sulfate and evaporated under reduced pressure. The residue was purified was purified by silica gel (100-200) column chromatography eluting with methanol in dichloromethane (0.5% to 2.5%) to afford the desired product (4.2 g, 20%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].Cl.Cl[CH2:13][CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][CH2:14][C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: ClCCc1c[nH]cn1
Reactant: CC(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCCc2c[nH]cn2)cc1

Procedure:
816 mg (6 mmol) of 4-hydroxyacetophenone, 251 mg (1.5 mmol) of 4-[2-chloroethyl]-1H-imidazole hydrochloride, 500 mg (3.6 mmol) of potassium carbonate and sodium iodide (catalyst) are stirred at 80° C. for 5 days in 5 ml of dimethylformamide. The reaction mixture is cooled, filtered and the filtrate is evaporated under reduced pressure to give an oily residue, from which 4-hydroxyacetophenone is extracted with ether at pH=1. Subsequent extraction with ethyl acetate at pH=9 gives the title compound. The latter was treated with oxalic acid in 2-propanol to give the oxalate of the title compound which is crystallized from a methanol/ether (10/1) mixture, M.p.: 178°-182° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[CH:6])[CH3:2].[Li]CCCC.CON(C)[C:18](=[O:28])[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.Cl>C1COCC1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[C:6][C:18]([C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1)=[O:28])[CH3:2]
Reactant: C#CC(OCC)OCC
Reactant: CON(C)C(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(C#CC(=O)c1ccc([N+](=O)[O-])cc1)OCC
Temperature: -70 °C
Reaction time: 0.75 h

Procedure:
3,3-Diethoxyprop-1-yne (8.5 ml, 59 mmol) was dissolved in THF (100 ml). The solution was cooled to −70° C., and nBuLi (19 ml of 2.5 M soln in hexanes, 47.5 mmol) was added over 5 min. The solution was warmed to 0° C. for 15 min, then cooled to −70 ° C. again. A solution of N-methoxy-N-methyl-4-nitrobenzamide (Intermediate 8, 8.04 g, 38.1 mmol) in THF (50 ml) was added dropwise over 15 min. The solution was warmed to 0° C. after 15 min, and held there for 45 min. The reaction mixture was poured into 1M HCl, extracted with ethyl acetate and dried over sodium sulfate. Purification by chromatography on silica gel eluting with 30 to 50% dichloromethane: hexane, gave the title compound as a light orange oil which solidified on standing (7.14 g).
Reaction SMILES: [C:1]([C:3]1[CH:49]=[CH:48][C:6]2[N:7]([CH2:36][C:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:40]=[CH:39][C:38]=3[CH3:47])[C:8](=[O:35])[C@@H:9]([NH:20][C:21](=[O:34])[C@@H:22]([N:24]([CH2:32][CH3:33])C(=O)OC(C)(C)C)[CH3:23])[C@H:10]([CH3:19])[N:11]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:5]=2[CH:4]=1)#[N:2].[ClH:50]>O1CCOCC1.CCOCC>[ClH:50].[C:1]([C:3]1[CH:49]=[CH:48][C:6]2[N:7]([CH2:36][C:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:40]=[CH:39][C:38]=3[CH3:47])[C:8](=[O:35])[C@@H:9]([NH:20][C:21](=[O:34])[C@@H:22]([NH:24][CH2:32][CH3:33])[CH3:23])[C@H:10]([CH3:19])[N:11]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CCN(C(=O)OC(C)(C)C)[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(C)ccc3ccccc23)c2ccc(C#N)cc2N(C(=O)CS(C)(=O)=O)[C@H]1C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(C)ccc3ccccc23)c2ccc(C#N)cc2N(C(=O)CS(C)(=O)=O)[C@H]1C
Yield: 76 %

Procedure:
A rt solution of tert-butyl(S)-1-((3S,4S)-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(ethyl)carbamate (104 mg, 151 μmol) in 4 M HCl in dioxane (754 μl) was stirred for 1 h. The reaction was diluted with Et2O (10 mL) and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((3S,4S)-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(ethylamino)propanamide hydrochloride (72.1 mg, 76%) as a white solid. MS m/z 590 (MH)+.
Reaction SMILES: CC1C=CC(C[N:9]2[CH2:14][CH2:13][N:12]3[C:15](=[O:30])[O:16][C:17]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:11]3[CH2:10]2)=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[C:24]1([C:17]2([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:11]3[CH2:10][NH:9][CH2:14][CH2:13][N:12]3[C:15](=[O:30])[O:16]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1ccc(CN2CCN3C(=O)OC(c4ccccc4)(c4ccccc4)C3C2)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Yield: 80.7 %

Procedure:
Hexahydro-7-[(4-methylphenyl)methyl]-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (65 g, 0.16 mol) was dissolved in 1,2-dichloroethane (300 mL). 1-Chloroethyl chloroformate (22 mL, 0.2 mol) was added thereto, and the mixture was warmed and refluxed for 3 hours. The solvent was distilled off under reduced pressure, and then methanol (300 mL) was added thereto. The mixture was warmed and refluxed for 3 hours. The solvent was distilled off under reduced pressure, and to the residue was added ethyl acetate (500 mL) to obtain powder. The obtained powder was collected by filtration, washed with ethyl acetate, and dried under reduced pressure. To the obtained powder (54 g) were added an aqueous saturated sodium hydrogen carbonate solution (500 mL) and ethyl acetate (500 mL), and the process of phase separation was performed. The resulting organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution (400 mL) and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from diethyl ether and the resulting crystals (42 g) were recrystallized from ethyl acetate again to obtain the title compound (38 g, yield 78%). 1H NMR of the above obtained compound corresponded with the compound obtained in Reference Example 2.
Reaction SMILES: S(C)C.C1(C)C=CC=CC=1.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:33])=[C:16]([CH:32]=1)[C:17]([C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]1)=[O:18]>C1COCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:33])=[C:16]([C@H:17]([OH:18])[C@@H:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:20]2)[CH:32]=1
Reactant: Cc1ccc(Cl)cc1C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CSC
Product: Cc1ccc(Cl)cc1[C@H](O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
A mixture of 10 M BH3.Me2S in THF (25.4 mL, 0.254 mol) and 1 M R-CBS-oxazaborolidine in toluene (38 mL, 0.038 mol) were dissolved in 100 mL anhydrous THF and cooled to −15° C. (R)-tert-butyl 3-(5-chloro-2-methylbenzoyl)piperidine-1-carboxylate in 200 mL anhydrous THF was added dropwise to the above solution and stirred at −15° C. for 2 hr. The reaction was quenched with methanol (300 mL). The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give (R)-tert-butyl 3-((R)-(5-chloro-2-methylphenyl)(hydroxy)methyl)piperidine-1-carboxylate (32 g), which contained 30% isomer.
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24]4[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:20][CH2:19]3)[N:15]=[C:14]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[N:13]=2)[CH:7]=1.O.O[Li].O.Cl>C1COCC1.C(O)C>[N:34]1([C:14]2[N:13]=[C:12]([C:8]3[CH:7]=[C:6]([CH2:5][CH2:4][C:3]([OH:40])=[O:2])[CH:11]=[CH:10][CH:9]=3)[CH:17]=[C:16]([N:18]3[CH2:19][CH2:20][N:21]([C:24]4[C:29]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:22][CH2:23]3)[N:15]=2)[CH2:35][CH2:36][O:37][CH2:38][CH2:39]1
Reactant: COC(=O)CCc1cccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(N3CCOCC3)n2)c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(N3CCOCC3)n2)c1
Temperature: 55 °C

Procedure:
To a solution of 3-(3-{2-morpholin-4-yl-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidin-4-yl}-phenyl)-propionic acid methyl ester in THF, add water dropwise until the cloudiness almost persists. To this mixture add LiOH.H2O (10 equivalents) followed by a small amount of ethanol to achieve heterogeneity. Heat the mixture at 55° C. for 2 hours then concentrate under reduced pressure. Add a small amount of water to the residue followed by 10 equivalents of HCl (3M solution). Adjust the final pH to 4 and collect the off-white solid via filtration. Wash the solid with water and dry to afford the title compound. 1H NMR (DMSO-D6): δ 2.58 (t, 2H), 2.89 (t, 2H), 3.29 (br m, 4H), 3.66 (br m, 4H), 3.72 (br m, 4H), 3.79 (br m, 4H), 6.72 (s, 1H), 7.22 (m, 1H), 7.31-7.37 (m, 2H), 7.95 (m, 2H), 8.09 (d, 1H, J=7.87 Hz), 8.54 (d, 1H, J=3.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22])[CH:15]=[C:14]([Cl:24])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](OCC)=[O:10].[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22])[CH:15]=[C:14]([Cl:24])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[O:10]
Reactant: CCOC(=O)CCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=CCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: -70 °C
Yield: 97 %

Procedure:
To a mixture of 4.06 g of ethyl 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)valerate and 50 ml of toluene was added dropwise 10.27 ml of 0.95 mol/liter diisobutyl aluminum hydride (hexane solution) over 30 minutes with stirring at −70° C. in a stream of nitrogen gas. After further stirring at −70° C. for 1 hour, 50 ml of saturated aqueous ammonium chloride solution was added. The reaction mixture was returned to room temperature, and poured into 50 ml of diluted hydrochloric acid, and extracted twice with toluene. The toluene layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated, which afforded 3.52 g (yield, 96%) of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentanal.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.Cl[C:18]1[N:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:3]([O:16][C:18]2[N:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2
Reactant: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Reactant: Clc1ncc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(Br)c(Oc3ncc4ccccc4n3)c2CC[C@@H]1C
Temperature: 100 °C
Reaction time: 4 h
Yield: 63.4 %

Procedure:
A mixture of (S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.025 g, 0.088 mmol), 2-chloroquinazoline (0.017 g, 0.106 mmol), and potassium carbonate (0.024 g, 0.176 mmol) in N,N-dimethylformamide (1.0 mL) was stirred in the microwave at 100° C. for 4 h. The reaction mixture was cooled to room temperature and water was added. The mixture was extracted with dichloromethane and the combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a yellow oil. This material was purified via column chromatography on silica gel (Biotage 10 g column, gradient elution with 50-100% ethyl acetate-hexane) to afford (S)-1-(6-bromo-2-methyl-5-(quinazolin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.023 g, 63%). MS (ESI, pos. ion) m/z 412, 414 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([CH3:18])=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH2:54]([O:56][C:57]([O:71][CH2:72][CH3:73])([C:60]1[CH:65]=[C:64]([CH3:66])[N:63]=[C:62]([CH2:67][CH:68]([CH3:70])[CH3:69])[CH:61]=1)[CH2:58][NH2:59])[CH3:55]>CN(C=O)C.CC(=O)OCC>[CH2:1]([O:8][C:9]1[C:17]([CH3:18])=[CH:16][C:12]([C:13]([NH:59][CH2:58][C:57]([O:71][CH2:72][CH3:73])([O:56][CH2:54][CH3:55])[C:60]2[CH:65]=[C:64]([CH3:66])[N:63]=[C:62]([CH2:67][CH:68]([CH3:69])[CH3:70])[CH:61]=2)=[O:15])=[CH:11][C:10]=1[CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(C(=O)O)cc(C)c1OCc1ccccc1
Reactant: CCOC(CN)(OCC)c1cc(C)nc(CC(C)C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(CNC(=O)c1cc(C)c(OCc2ccccc2)c(CC)c1)(OCC)c1cc(C)nc(CC(C)C)c1
Reaction time: 16 h
Yield: 60.5 %

Procedure:
To a solution of 4-benzyloxy-3-ethyl-5-methylbenzoic acid (115 mg, 0.425 mmol) in DMF (1.5 mL), EDC HCl (46 mg, 0.467 mmol) followed by HOBT (63 mg, 0.467 mmol) is added. The mixture is stirred at rt for 15 min before DIPEA (219 mg, 1.70 mmol) and a solution of 2,2-diethoxy-2-(2-isobutyl-6-methyl-pyridin-4-yl)-ethylamine dihydrochloride (150 mg, 0.425 mmol) in DMF (0.5 mL) is added. The mixture is stirred at rt for 4.5 h before another portion of EDC HCl (20 mg) and HOBT (30 mg) is added. Stirring is continued at rt for 16 h. The mixture is diluted with EA (30 mL), washed with sat. aq. NaHCO3 solution (15 mL), water (15 mL) and brine (15 mL), dried over Na2SO4, filtered and concentrated. The crude product is purified on prep. TLC with heptane:EA 1:1 to give 4-benzyloxy-N-[2,2-diethoxy-2-(2-isobutyl-6-methyl-pyridin-4-yl)-ethyl]-3-ethyl-5-methyl-benzamide (137 mg) as a pale yellow wax; LC-MS: tR=1.13, [M+1]+=533.15.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:17])[CH:12]=3)[S:7][C:6]=2[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH2:25]>>[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH:25][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:17])[CH:12]=3)[S:7][C:6]=2[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1
Reactant: O=c1c2cc(O)ccc2sc2c([N+](=O)[O-])ccc(Cl)c12
Reactant: CN(C)CCN
Product: CN(C)CCNc1ccc([N+](=O)[O-])c2sc3ccc(O)cc3c(=O)c12

Procedure:
1-[[2-(Dimethylamino)ethyl]amino]-7-hydroxy-4-nitro-9H-thioxanthen-9-one was prepared similarly from 10 g of 1-chloro-7-hydroxy-4-nitrothioxanthone and 5.7 g of N,N-dimethylethylenediamine to provide 7.2 g, mp>300°.
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:68])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]([F:67])([F:66])[F:65])[CH2:53][CH2:52]1)=[O:50]>CN(C=O)C.C(OCC)(=O)C.O>[O:50]=[C:49]([N:51]1[CH2:52][CH2:53][N:54]([C:57](=[O:68])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]([F:67])([F:66])[F:65])[CH2:55][CH2:56]1)[CH2:48][NH:47][C:20](=[O:22])[C:19]1[CH:18]=[CH:17][C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=2)=[CH:24][CH:23]=1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
DIPEA (116.32 mg, 0.15 mL, 0.9 mmol) was added to a stirred solution of 4-pyridin-2-yl-benzoic acid (60 mg, 0.3 mmol) in DMF (1.5 mL). HOBT (48 mg, 0.36 mmol) and EDCI (70 mg, 0.36 mmol) were then added at room temperature. After 2 minutes 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (127 mg, 0.36 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and then extrated with ethyl acetate. The organic layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure to afford 29 mg (19.46%) of N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-4-pyridin-2-yl-benzamide. LCMS Purity: 89.36%. 1H NMR (DMSO-d6): δ 9-8.9 (d, 1H), 8.6 (d, 1H), 8.5 (m, 1H), 8.2-8.1 (dt, 1H), 8.0 (d, 2H), 7.9-7.6 (m, 5H), 7.6-7.5 (m, 2H), 4.2 (m, 2H), 3.8-3.6 (m, 4H), 3.2-3.4 (m, 2H), 3.2-3 (m, 2H).
Reaction SMILES: C(O[C:4](=[O:10])[NH:5][C:6](=[O:9])[CH2:7]Cl)C.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=1[CH3:19].CN(C)C1C=CC=CC=1>>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:7][C:6](=[O:9])[NH:5][C:4]2=[O:10])=[CH:14][C:13]=1[CH3:19]
Reactant: CCOC(=O)NC(=O)CCl
Reactant: Cc1cc(N)ccc1Br
Solvent: CN(C)c1ccccc1
Product: Cc1cc(N2CC(=O)NC2=O)ccc1Br
Temperature: 130 °C
Reaction time: 5 h
Yield: 54.3 %

Procedure:
(2-Chloro-acetyl)-carbamic acid ethyl ester (356 mg, 2.15 mmol) was added to 4-bromo-3-methyl-phenylamine (400 mg, 2.15 mmol) and dimethylphenylamine (273 μL, 2.15 mmol) at room temperature. The mixture was stirred at 130° C. for five hours, and the reaction solution was then cooled. The precipitate was collected by filtration and washed with CH3CN to give 1-(4-bromo-3-methyl-phenyl)-imidazolidine-2,4-dione as a colorless solid (314 mg, 54%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[N:9]3[C:10](=[N:15][C:16]([CH3:17])=[C:8]3[C:7]1=[O:18])[CH:11]=[CH:12][CH:13]=2.C(N(CC)CC)C.[CH2:26]([S:29](Cl)(=[O:31])=[O:30])[CH2:27][CH3:28]>C(Cl)Cl>[CH3:17][C:16]1[N:15]=[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[N:9]2[C:8]=1[C:7](=[O:18])[N:6]3[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:29]([CH2:26][CH2:27][CH3:28])(=[O:31])=[O:30]
Reactant: Cc1nc2cccc3n(CCCCN)c(=O)c1n23
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)NCCCCn1c(=O)c2c(C)nc3cccc1n32
Yield: 74.9 %

Procedure:
To a solution of 1.22 g (5.0 mmol) of 1-[4-(amino) butan-1-yl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 1.1 ml (7.9 mmol) of triethylamine in 40 ml of methylene chloride was added, while stirring under ice-cooling, 0.73 ml (6.5 mmol) of propan-1-ylsulfonyl chloride. The mixture was stirred for 0.5 hour at room temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, which was then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from methylene chloride—methanol—ether to give 1.313 g of the desired compound (75.0%, pale brown crystals), m.p.150.0-151.0° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].CI>C(O)C>[Cl:1][C:2]1[C:7]([N:8]([CH3:17])[C:9](=[O:16])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(Nc1cccnc1Cl)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCO
Product: CN(C(=O)c1ccccc1)c1cccnc1Cl
Temperature: 25 °C
Yield: 110.1 %

Procedure:
5.0 g N-(2-chloro-pyridin-3-yl)-benzamide (18.6 mmol), 7.7 g potassium carbonate (K2CO3) (56 mmol), and 60 mL ethanol were added and stirred in a round-bottomed flask. 3.97 g methyl iodide (MeI) (27.9 mmol) was then added and reacted for 12 hr. After cooling to room temperature, the reaction was quenched by water. After extraction three times by ethyl acetate, removal of water by magnesium sulphate (MgSO4), concentration, and purification by column, 5.05 g white solid was obtained, with a yield of 96%.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[Cl:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=[C:8]([C:21]2[CH:22]=[N:23][C:24](S(CCC)(=O)=O)=[N:25][CH:26]=2)[CH:7]=1.C(N(CC)C(C)C)(C)C>CCOC(C)=O>[Cl:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][CH2:11][C:12]([OH:14])=[O:13])=[C:8]([C:21]2[CH:26]=[N:25][C:24]([N:3]([CH3:4])[CH3:2])=[N:23][CH:22]=2)[CH:7]=1
Reactant: CNC
Reactant: CCCS(=O)(=O)c1ncc(-c2cc(Cl)ccc2OCC(=O)OC(C)(C)C)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(C)c1ncc(-c2cc(Cl)ccc2OCC(=O)O)cn1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
Dimethylamine hydrochloride (0.82 g) was added to a stirred solution of the product from step (iv) (0.2 g) and N,N-diisopropylethylamine (0.9 ml) in No (5 ml). The reaction mixture was heated at 90° C. for 6 h then diluted with EtOAc, washed with water, brine, dried and evaporated under reduced pressure. The residue was dissolved in DCM (10 ml) then trifluoroacetic acid (10 ml) added and stirred for 18 h at RT. The reaction mixture was evaporated to dryness and the residue purified by reverse phase HPLC followed by trituration with methanol to give a white solid. Yield 0.035 g
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[OH:14])([O-])=O.[H][H]>[Pd].C(O)(C)C>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[OH:14]
Reactant: O=[N+]([O-])c1cccc2c(O)cccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: Nc1cccc2c(O)cccc12
Reaction time: 2 h
Yield: 95 %

Procedure:
In an autoclave was placed 1.9 g of 5-nitro-1-naphthol, 0.02 g of 5% Pd/C (containing 50% by weight of water), and 50 g of isopropanol, and the hydrogen pressure was set at 0.8 MPa. The reaction was carried out at 50° C. for 2 hours. After the reaction mixture was cooled, the catalyst was filtered off, and the reaction mass thus obtained was analyzed by gas chromatography. As a result, the content of 5-amino-1-naphthol produced was 1.5 g (yield 95%).