Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[CH:10][C:11]3[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15][NH:14][C:12]=3[N:13]=2)[CH2:4][CH2:3]1.[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:22]([N:14]1[C:12]2[N:13]=[C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[N:9]=[CH:10][C:11]=2[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCc1ccccc1
Reactant: CN1CCN(c2ncc3c(=O)c(C(=O)O)c[nH]c3n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(c2ncc3c(=O)c(C(=O)O)cn(Cc4ccccc4)c3n2)CC1
Temperature: 95 °C

Procedure:
A mixture of 1.0 g of 5,8-dihydro-2-(4-methyl-1-piperazinyl)-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid, 0.6 ml of benzyl chloride, 20 ml of a 12% aqueous solution of potassium carbonate, and 150 ml of dimethylformamide was heated at 95°C for 2 hours. After removal of the solvent and an excess of the reagent, the resulting residue was taken up in water and the aqueous solution neutralized with acetic acid. The solid that separated was collected and recrystallized from dimethylformamide to give 0.7 g of the product, m.p. 251° - 255°C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12]O)=[CH:10][O:9][N:8]=1.S(Cl)([Cl:16])=O>C(Cl)Cl>[Cl:16][CH2:12][C:11]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:8][O:9][CH:10]=1
Reactant: OCc1conc1-c1ccccn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1conc1-c1ccccn1
Reaction time: 1 h
Yield: 102.8 %

Procedure:
To a solution of (3-pyridin-2-yl-isoxazol-4-yl)-methanol (3.0 g, 16 mmol) in DCM (30 mL) at 0° C. was added thionyl chloride (3.75 g, 32 mmol) and the resulting mixture stirred for 1 h and then evaporated. After 1 h the reaction mixture was quenched with a solution of sodium hydrogen carbonate (1 N, 15 mL) and extracted with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate, filtered and concentrated to give the title compound (3.2 g, 96%) as a grey solid. MS: m/e=195.1 [M+H]+.
Reaction SMILES: C(O[C:5](=O)[CH3:6])(=O)C.N1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>N1C=CC=CC=1>[CH3:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:9][CH:10]=[CH:11][CH2:12][CH2:5][CH3:6]
Reactant: c1ccncc1
Reactant: CC(=O)OC(C)=O
Product: CCCC=CCCCCCC

Procedure:
Subsequently, compound (10a) is acetylated with acetic anhydride-pyridine etc., thereby giving compound (11), followed by treatment with 1,8-diazabicyclo 5.4.0.!-7-undecene (DBU) in a solvent e.g. pyridine, whereby compounds (12) and (12') are formed. Compounds (12) and (12') are then hydrolyzed with a base such as sodium hydroxide, sodium methoxide, sodium ethoxide, sodium t-butoxide, etc., whereby compound (1) can be obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[O:17][CH2:18][O:19][CH3:20].[CH:21]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37]O)[CH:32]=2)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:23][CH2:22]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH:21]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][O:16][C:13]3[CH:14]=[CH:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([O:17][CH2:18][O:19][CH3:20])[CH:12]=3)[CH:32]=2)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:23][CH2:22]1
Reactant: COCOc1cc(O)ccc1-c1cc(OC)ccc1F
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(OCOC)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 50 h
Yield: 78 %

Procedure:
To a solution of 2′-fluoro-5′-methoxy-2-(methoxymethoxy)biphenyl-4-ol (1.29 g), ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (1.26 g) and tributylphosphine (2.3 mL) in toluene (30 mL) was added 1,1′-(azodicarbonyl)dipiperidine (2.32 g), and the mixture was stirred at room temperature for 50 hr. To the reaction mixture was added hexane, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.84 g) as a colorless oil.
Reaction SMILES: O[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:19])=O>ClCCl>[Cl:19][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccccc1-c1cc(O)ncc1C#N
Solvent: ClCCl
Product: Cc1ccccc1-c1cc(Cl)ncc1C#N
Temperature: 50 °C
Yield: 106.7 %

Procedure:
A mixture of 2.5 g (11.89 mmol) 6-hydroxy-4-o-tolyl-nicotinonitrile, 3.64 g (23.78 mmol) phosphorus oxychloride in 10.0 ml dichloromethane was heated at 50° C. for 80 minutes. The mixture was cooled down to 20-25° C., poured on water by keeping the internal temperature between 20-30° C. and extracted by adding additional 80.0 ml dichloromethane. Evaporation of the organic phase in vacuo gave 2.9 g of crude product of 6-chloro-4-o-tolyl-nicotinonitrile which was purified by chromatography over silica gel (ethylacetate:hexane=4:1) to afford 2.4 g of, m.p. 112.4° C.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[CH:6]=1.[C:27]([NH:31][S:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[CH:36]=[CH:37][CH:38]=[C:39]([C:2]2[N:3]=[CH:4][N:5]([C:7]3[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=4)[N:8]=3)[CH:6]=2)[CH:40]=1)(=[O:34])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)cc1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)c1

Procedure:
N-tert-Butyl-3-{1-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 2-(4-iodo-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.68) (0.73 g, 1.5 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.46 g, 1.8 mmol) according to the general procedure VI. Obtained as a light brown solid (0.128 g), which was subsequently deprotected.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]([CH2:16][CH3:17])[N:13]=[CH:14][CH:15]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:20]([O:26][CH2:27]Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]([CH2:16][CH3:17])[N:13]=[CH:14][CH:15]=3)=[CH:9][N:8]([CH2:27][O:26][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCn1nccc1-c1c[nH]c2ncc(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1nccc1-c1cn(COC(=O)C(C)(C)C)c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Bromo-3-(2-ethyl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine was dissolved in N,N-dimethylforamide at 4° C. To the solution was added sodium hydride in small portions. The flask was warmed to room temperature and stirred for 1 hour. To the mixture was added chloromethyl pivalate. The reaction mixture was stirred for 2 hours at room temperature, and quenched with methanol. Saturated ammonium chloride solution was added, and the mixture was concentrated in vacuo. The residue was dissolved in dichloromethane, and the organic layer was washed four times with a saturated solution of sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in acetone. The insoluble residue remaining was filtered off and discarded. The filtrate was concentrated in vacuo and the crude material re-crystallized to afford 2,2-dimethyl-propionic acid 5-bromo-3-(2-ethyl-2H-pyrazol-3-yl)-pyrrolo[2,3-b]pyridin-1-ylmethyl ester. MS: m/z 405.3+407.3 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH:16]=[C:15]([OH:18])[C:14](=[O:19])[C:13]=2[CH:20]=1.[H-].[Na+].[CH3:23]I.O>O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH:16]=[C:15]([O:18][CH3:23])[C:14](=[O:19])[C:13]=2[CH:20]=1
Reactant: O=c1c(O)coc2ccc(OCCCCCCCl)cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1coc2ccc(OCCCCCCCl)cc2c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5'-(6-chlorohexoxy)-2'-hydroxyacetophenone (32 g) and benzaldehyde (12 g) was dissolved in 250 mL of ethanol. A solution of 24 g of sodium hydroxide dissolved in 40 mL of water was added. This mixture was allowed to stand at room temperature for 6 hours. A solution of 8 g of sodium hydroxide dissolved in 40 mL of water was added, the solution was cooled to 15°-20° C., and then 20 mL of hydrogen peroxide (30% solution) was added and the solution was allowed to warm to room temperature and was stirred overnight. Then the solution's pH was adjusted to 3 using hydrochloric acid. The yellow precipitate was collected by vacuum filtration and washed with water, ethanol, and ether to give 16 g of 6-(6-chlorohexoxy)-3-hydroxy-4H-1-benzopyran-4-one. Next, 10 g of 6-(6-chlorohexoxy)-3-hydroxy-4H-1-benzopyran-4-one was dissolved in 100 mL of tetrahydrofuran. Then 800 mg of sodium hydride was added followed by 8.3 mL of methyl iodide and the resulting solution was stirred at room temperature for 48 hours. The reaction was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water and then with brine. After drying over sodium sulfate, the solvent was removed to give 8 g of 6-(6- chlorohexoxy)-3-methoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].N1C=CC=[CH:14][CH:13]=1>>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:11][C:13]([CH3:14])=[N:1][C:2]=2[CH:7]=1)([O-:10])=[O:9]
Reactant: c1ccncc1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Product: Cc1nc2cc([N+](=O)[O-])ccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A dye of the invention is prepared by dissolving about 369 parts of 2-amino-4-nitrophenol in about 600 ml of warm pyridine in a 2 liter three-necked flask equipped with a mechanical stirrer, a Dean & Stark adapter or glass trap to collect distilled off solvent, and a condenser. About 600 parts of triethyl orthoacetate are added to the flask while refluxing using an oil bath maintained at 120°-140° C. The ethanol formed is distilled off followed by the pyridine until about 500 ml of total solvent are removed. The reaction mixture is stirred overnight at room temperature after which about 1500 ml of ethanol are added to precipitate the product. Filtering provided 5-nitro-2-methylbenzoxazole (1) as a tannish-brown solid which is washed with ethanol, ethyl acetate, and then ligroin, and dried under vacuum.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[C:7]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:8][C:9]([CH3:11])=[O:10]>C(O)(=O)C>[C:7]([C:8]1[CH2:11][CH:9]([CH:8]=[CH2:7])[O:10][C:9]=1[CH3:11])([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: C=CC1CC(C(=O)OCC)=C(C)O1
Temperature: 60 °C
Yield: 99 %

Procedure:
4-Carbethoxy-5-methyl-2-vinyl-2,3-dihydrofuran was prepared in accordance with the oxidative addition procedure described by Vinogradov et. al. in Izv. Akad Nauk SSR, Ser. Khimm, 1981, (9), 2088-84. For the reaction, 98 grams manganous acetate tetrahydrate was combined with 300 mls acetic acid in a glass reaction vessel. The mixture was heated to 60° C. with stirring and 15.8 grams potassium permanganate slowly added. The temperature was maintained below 70° C. during the addition and, when the addition was complete, the mixture was stirred for thirty minutes and then cooled to approximately 20° C. Two grams cupric acetate and 180 grams ethyl acetoacetate were then charged to the reactor and, after the mixture was stirred for five minutes, butadiene was slowly bubbled into the mixture which was maintained at 25° C. After thirty grams butadiene was added, the mixture was stirred for five minutes at 30° C. and then heated at 60° C. for fifteen minutes. At this point, the color of the reaction mixture changed from pink to brown (indicating reduction of Mn (III) to Mn (II)) and essentially all of the starting ethyl acetoacetate was determined by gas chromatographic analysis to be reacted. The mixture was cooled and filtered to remove insoluble salts. The salts were washed twice with acetic acid (50 mls) and the combined filtrates stripped on a rotary evaporator at 90° C. and reduced pressure to remove the acetic acid. The resulting residue was poured into 250 mls water and extracted three times with n-hexane (75 mls). The combined organic extracts were then washed with aqueous sodium bicarbonate, dried over sodium sulfate, and stripped on a rotary evaporator under reduced pressure to remove the organic solvent. The crude product was vacuum distilled to obtain a 65% yield of essentially pure (99%) 4-carbethoxy-5-methyl-2-vinyl-2,3-dihydrofuran (B.P. 108-110 @ 10 mm Hg).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:12][NH:13][C:14]2[O:15][C:16]3[CH:22]=[C:21]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26]([C:30](=[O:33])[NH:31][CH3:32])[CH:25]=4)[CH:20]=[CH:19][C:17]=3[N:18]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].C1COCC1>CO>[CH3:32][NH:31][C:30]([C:26]1[CH:25]=[C:24]([O:23][C:21]2[CH:20]=[CH:19][C:17]3[N:18]=[C:14]([NH:13][CH2:12][C:6]4([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]4)[O:15][C:16]=3[CH:22]=2)[CH:29]=[CH:28][N:27]=1)=[O:33]
Reactant: CCOC(=O)C1(CNc2nc3ccc(Oc4ccnc(C(=O)NC)c4)cc3o2)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)c1cc(Oc2ccc3nc(NCC4(C(=O)O)CCCCC4)oc3c2)ccn1

Procedure:
1-{[6-(2-Methylcarbamoyl-pyridin-4-yloxy)-benzooxazol-2-ylamino]methyl}-cyclohexanecarboxylic acid ethyl ester (1 eq) was dissolved in 3 M sodium hydroxide (20 eq); THF and methanol were added to homogenize the solution. The mixture was allowed to react at room temperature overnight. The solvents were removed. The crude product was brought to a pH of 4 with 1 N HCl, then to pH of 7 with saturated aqueous sodium bicarbonate. This solution was saturated with solid sodium chloride then extracted three times with ethyl acetate. The combined organic extracts were washed once with brine, dried with anhydrous sodium sulfate, filtered and concentrated. The product was purified by silica gel column in isopropanol and dichloromethane (50%) MH+=425.1.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH2:28][C:29]([NH2:31])=[O:30])[C:17]([C:32]([F:35])([F:34])[F:33])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:36](=O)[CH3:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[CH2:36]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH2:28][C:29]([NH2:31])=[O:30])[C:17]([C:32]([F:33])([F:35])[F:34])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3]1)[CH3:37]
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCNCC3)cc2)ncc1C(F)(F)F
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCN1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.1 %

Procedure:
To a suspension of 2-(2-(2-(2-((4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (1) (0.020 g, 0.041 mmol) in anhydrous methanol (1.5 mL) were added acetaldehyde (0.0090 mL, 0.17 mmol) and sodium triacetoxyborohydride (0.044 g, 0.21 mmol) under an atmosphere of nitrogen The reaction was stirred at room temperature for 18 hours, the volatiles were removed in vacuo and the residue was diluted with EtOAc (15 mL) and sat. aq. NaHCO3 (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (10 mL), the combined organic layers were washed with water (10 mL), brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo to give a solid which was taken up in DCM (˜10 mL) and methanol (˜1 mL) and concentrated in vacuo. The process was repeated with only DCM twice after which the sample was further dried on high-vacuum to give the title compound (10) (0.016 g, 76% yield) as an white solid; 1H NMR (400 MHz, d6-DMSO) δ 9.97 (s, 1H), 8.60 (s, 1H), 7.57 (d, J=8.9 Hz, 2H), 7.43 (s, 1H), 7.26-7.13 (m, 4H), 6.97-6.87 (m, 3H), 3.50 (s, 2H), 3.13-2.94 (m, 8H), 2.36 (q, J=7.2 Hz, 2H), 1.03 (t, J=7.2 Hz, 3H). 4 Aliphatic protons obscured by the residual DMSO. LCMS Method C: rt 4.82 min; m/z 513.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C=CC=CC=1.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[C:31]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)(=[O:33])[CH3:32]
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2ccc(Cl)cc21
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(C)=O)c2ccc(Cl)cc21
Reaction time: 4 h
Yield: 54 %

Procedure:
To a solution of 3-amino-2-benzoyl-6-chloro-1-(ethoxycarbonyl)indole (300 mg, 0.88 mmol; example 1, step 2) in a mixture of dichloromethane (10 ml) and pyridine (0.08 ml, 0.96 mmol) was added acetyl chloride (0.07 ml, 0.96 mmol). After stirring for 4 h, the mixture was partitioned between 10% aqueous citric acid (50 ml) and diethyl ether (100 ml). The organic extract was washed consecutively with water (50 ml), saturated sodium bicarbonate (50 ml), water (50 ml) and brine (50 ml). After drying (MgSO4) and removal of solvent, the crude product was purified by flash chromatography eluting with ethyl acetate/hexane (1:1) to afford 183 mg (54%) of the titled compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]3[CH2:15][CH2:14][CH2:13][CH:7]3[C:8](=O)[NH:9][C:10]=2[CH:11]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]3[CH2:15][CH2:14][CH2:13][CH:7]3[C:8](=[S:25])[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc2c(c1)NC(=O)C1CCCC21
Product: Cc1ccc2c(c1)NC(=S)C1CCCC21
Yield: 105.8 %

Procedure:
Analogously to Example 4, 7-methyl-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (200 mg, 1.0 mmol) is reacted with Lawesson's reagent (425 mg, 1.1 mmol) to form 230 mg of product.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:38])[CH2:8][CH2:9][N:10]([CH3:37])[C:11]1[C:12]([NH2:36])=[CH:13][C:14]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([CH3:35])[CH:27]=3)[CH:23]=[CH:22][N:21]=2)=[C:15]([O:17][CH3:18])[CH:16]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:38][N:7]([CH3:6])[CH2:8][CH2:9][N:10]([CH3:37])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([CH3:35])[CH:27]=3)[CH:23]=[CH:22][N:21]=2)=[CH:13][C:12]=1[NH:36][C:1](=[O:4])[CH:2]=[CH2:3]
Reactant: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cn(C)c4ccccc34)n2)c(OC)cc1N(C)CCN(C)C
Reaction time: 1.5 h
Yield: 39.5 %

Procedure:
A solution of acryloyl chloride (34.5 mg, 0.38 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred mixture of N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine (Intermediate 100, 170 mg, 0.38 mmol) and DIPEA (0.073 mL, 0.42 mmol) in CH2Cl2 (5 mL), which was cooled in an ice/water bath. The mixture was stirred for 1.5 h and then diluted with CH2Cl2 (25 mL) and washed with sat.NaHCO3 (50 mL). The aqueous washes were extracted with CH2Cl2 (2×25 mL). The combined organic solutions were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-4% 7N methanolic ammonia in CH2Cl2 gave the title compound (75 mg, 39%) as a cream solid after trituration with diethyl ether; 1H NMR: 2.21 (6H, s), 2.29 (2H, t), 2.72 (3H, s), 2.89 (2H, t), 3.86 (3H, s), 3.92 (3H, s), 5.77 (1H, dd), 6.27 (1H, dd), 6.43 (1H, dd), 7.04 (1H, s), 7.15 (1H, t), 7.20-7.27 (2H, m), 7.53 (1H, d), 7.91 (1H, s), 8.24 (1H, d), 8.33 (1H, d), 8.68 (1H, s), 9.14 (1H, s), 10.22 (1H, s); m/z: ES+ MH+ 500.42.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13]/[N:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[S:12])([CH3:3])[CH3:2].Br[CH:39]([CH3:43])[C:40](=[O:42])[CH3:41].C(N(CC)CC)C>CC(=O)CC>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:40]([CH3:41])([OH:42])[CH:39]([CH3:43])[S:12]/[C:11]/1=[N:13]/[N:14]=[CH:15]\[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=3)[N:23]=2)=[CH:20][CH:21]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1NC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CC(=O)C(C)Br
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)c1ccccc1N1/C(=N\N=C/c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)SC(C)C1(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To a solution of (E)-N-(2-isopropylphenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (114 mg, 0.22 mmol) in butanone (2.2 mL) was added 3-bromo-2-butanone (0.03 mL, 0.28 mmol) and triethylamine (0.06 mL, 0.44 mmol), and the reaction was stirred at room temperature overnight. The reaction mixture was directly applied to a silica gel cartridge and purified by flash chromatography (0-30% ethyl acetate/B, where B=1:1 dichloromethane/hexanes) to provide the title compound as a yellow solid (108 mg, 84% yield): mp 140° C. (dec); 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.22-8.16 (m, 3H), 7.82-7.74 (m, 4H), 7.55-7.47 (m, 1H), 7.42-7.35 (m, 4H), 7.29-7.24 (m, 1H), 3.92-2.96 (m, 3H), 1.57 (s, 1H), 1.57-1.50 (m, 3H), 1.35-1.17 (m, 9H); 19F NMR (376 MHz, CDCl3) δ −58.02; ESIMS m/z 595 ([M+H]+).