Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([O:13]CC)=O)[N:7]=1.Cl.[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CO.[OH-].[Na+].O.CN(C=O)C>[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][CH2:32][NH:33][C:11]([C:8]1[N:7]=[C:6]([CH2:5][C:4]2[CH:16]=[CH:17][C:18]([Cl:19])=[C:2]([Cl:1])[CH:3]=2)[O:10][N:9]=1)=[O:13]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: CCOC(=O)c1noc(Cc2ccc(Cl)c(Cl)c2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1noc(Cc2ccc(Cl)c(Cl)c2)n1
Yield: 32.4 %

Procedure:
This compound was prepared according to method F with ethyl 5-(3,4-dichlorobenzyl)-1,2,4-oxadiazole-3-carboxylate (0.130 g; 0.433 mmol) in methanol (2 mL) and sodium hydroxide in water (2M, 2 mL); and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), HATU (0.164 g; 0.432 mmol), N,N diisopropylethylamine (0.075 mL; 0.432 mmol) in DMF (4 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.063 g (32%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(3,4-dichlorobenzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7](Br)=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:16][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]2=[N:4][CH:3]=1
Reactant: Brc1cncc2ncc(Br)n12
Reactant: CCCCN
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCNc1nccn2c(Br)cnc12
Temperature: 70 °C
Yield: 51.1 %

Procedure:
To a solution of 3,5-dibromo-imidazo[1,2-a]pyrazine (D) (200 mg, 0.72 mmol) in THF (3.6 ml) was added butylamine (2.2 ml, 21.6 mmol). The mixture was heated at 70° C. for 3 hr. The mixture was then cooled to rt, and diluted with DCM. The organic layer was washed with water, brine, dried and concentrated. The residue was purified on a silica gel column to afford 99 mg (yield 51%) of (3-bromo-imidazo[1,2-a]pyrazin-8-yl)-butyl-amine.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][C:23]([C:26]5[C:27]([O:32][CH2:33][C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=6)=[N:28][CH:29]=[CH:30][CH:31]=5)=[CH:22][N:21]4[C:40]=3[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl>C(Cl)Cl.CO>[CH2:33]([O:32][C:27]1[C:26]([C:23]2[CH:24]=[CH:25][C:20]3[N:21]([C:40]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[C:18]([C:15]4[CH:16]=[CH:17][C:12]([C:8]5([NH2:7])[CH2:9][CH2:10][CH2:11]5)=[CH:13][CH:14]=4)[N:19]=3)[CH:22]=2)=[CH:31][CH:30]=[CH:29][N:28]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(-c5cccnc5OCc5ccccc5)cn4c3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: NC1(c2ccc(-c3nc4ccc(-c5cccnc5OCc5ccccc5)cn4c3-c3ccccc3)cc2)CCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The crude product from Step 2 (240 mg) was dissolved in DCM/MeOH (1.2 mL/0.76 mL), cooled to 0° C. and treated with HCl (4 M soln in dioxane, 0.94 mL). The reaction was warmed to rt and stirred for 2 hours. The reaction was poured onto ice and extracted with DCM (3×). The organic phase was washed with brine, dried and concentrated in vacuo to give the crude title compound.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[C:7]([CH3:17])[C:8]([NH:13]C(=O)C)=[CH:9][C:10]=2[CH3:12])[CH:5]=[CH:4][NH:3]1.C(O)C.Cl>O>[O:1]=[C:2]1[C:11]2[C:6](=[C:7]([CH3:17])[C:8]([NH2:13])=[CH:9][C:10]=2[CH3:12])[CH:5]=[CH:4][NH:3]1
Reactant: CC(=O)Nc1cc(C)c2c(=O)[nH]ccc2c1C
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1c(N)cc(C)c2c(=O)[nH]ccc12

Procedure:
The mixture consisting of 10.6 g of the compound G, 175 ml of ethanol and 35 ml of concentrated hydrochloric acid was heated with reflux for 21/2 hours, 300 ml of water were added, the mixture was again heated to boiling point and filtered to eliminate a small insoluble fraction. To the cooled filtrate was added a N sodium hydroxide solution to bring the pH to 9 and the precipitate formed was filtered off then recrystallised from ethanol to give 7.35 g (85%) of cream flakes corresponding to the amine of formula H, melting point 242° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].CI.[C:15]([O-:20])(=[O:19])[C:16]([O-:18])=[O:17]>CN(C)C=O>[C:15]([OH:20])(=[O:19])[C:16]([OH:18])=[O:17].[C:15]([OH:20])(=[O:19])[C:16]([OH:18])=[O:17].[C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])C(=O)[O-]
Agent: CC(=O)Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: O=C(O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5 Grams of o-methoxycarbonyl- -[4-3,4-dimethoxybenzoyl)-1-piperazinyl]acetanilide was suspended in 50 ml of dimethylformamide, then 621 mg of 50% oily sodium hydride was added to the suspension and stirred at a room temperature for 1 hour. Next, under ice-cooled condition, 2.5 g of methyl iodide was added dropwise to the suspention and stirred at a room temperature for 4 hours. The solvent was removed by distillation under a reduced pressure, the residue obtained was extracted with chloroform and 1N-sodium hydroxide aqueous solution. The chloroform layer was washed with water, dried and then chloroform was removed by distillation. The residue obtained was purified by a silica gel column chromatography, and the product obtained was converted into an oxalate, recrystallized from methanol-ether to obtain 3.11 g of o-methoxy-carbonyl-N-methyl-α-[4-dimethoxy-benzoyl)-1-piperazinyl]-acetanilide dioxalate in the form of colorless powdery crystals. Melting point: 181.0°-182.0° C. (decomposed).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([N:17]3[C:18](=[O:29])[C:19]([NH:22][C:23]4[CH:28]=[CH:27][N:26]=[CH:25][N:24]=4)=[CH:20][CH:21]=[C:16]3[C:15](=[O:30])[NH:14]2)[CH2:9]1)C1C=CC=CC=1>O1CCOCC1.Cl>[N:26]1[CH:27]=[CH:28][C:23]([NH:22][C:19]2[C:18](=[O:29])[N:17]3[C:10]4([NH:14][C:15](=[O:30])[C:16]3=[CH:21][CH:20]=2)[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]4)=[N:24][CH:25]=1
Reactant: O=C1NC2(CCCN(Cc3ccccc3)C2)n2c1ccc(Nc1ccncn1)c2=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C1NC2(CCCNC2)n2c1ccc(Nc1ccncn1)c2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of l′-benzyl-6-(pyrimidin-4-ylamino)-1H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5(2H)-dione (5, 0.12 g, 0.29 mmol) in dioxane (1 mL), 4 M hydrogenchloride in dioxane (2 mL) was added at 0° C. and the reaction mixture was stirred at room temperature for 3 h. The solvent was removed under reduced pressure and the residue was purified by repeated washing with pentane. Compound was dissolved in water and passed through strata column to obtain 6-(pyrimidin-4-ylamino)-1H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5(2H)-dione (Cpd. No. 20) as a light brown solid. Yield: 0.062 g, 67%; MS (ESI) m/z 313.15 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 9.40 (s, 1H), 8.80-8.73 (m, 2H), 8.38 (d, J=5.9 Hz, 1H), 7.37 (dd, J=5.9, 1.3 Hz, 1H), 6.89 (d, J=7.7 Hz, 1H), 3.94 (d, J=12.5 Hz, 1H), 3.16-3.12 (m, 1H), 2.95 (d, J=13.1 Hz, 1H), 2.74-2.65 (m, 1H), 2.60 (s, 1H), 2.46 (d, J=11.7 Hz, 1H), 1.72 (d, J=8.2 Hz, 2H), 1.61 (d, J=13.0 Hz, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=1[OH:6].Cl[C:13]1[CH:14]=[CH:15][C:16]([N+:28]([O-:30])=[O:29])=[C:17]([N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:18]=1>CN(C)C=O>[OH:11][C:9]1[CH:8]=[CH:7][C:5]([O:6][C:13]2[CH:14]=[CH:15][C:16]([N+:28]([O-:30])=[O:29])=[C:17]([N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH:18]=2)=[C:4]([CH3:3])[CH:10]=1
Reactant: Cc1cc(O)ccc1O
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(O)ccc1Oc1ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.8 %

Procedure:
To a suspension of sodium hydride (55 wt. %, 0.87 g) in N,N-dimethylformamide (20 ml) was added methylhydroquinone (1.24 g). The mixture was stirred at ambient temperature for 15 minutes. To this mixture was added t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (2.87 g)in small portions and stirred at 120° C. for 2 hours. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane/ethyl acetate=3/1 as the eluant to afford a mixture (2.20 g) of t-butyl N-[5-(4-hydroxy-2-methylphenoxy)-2-nitrophenyl]-N-methylcarbamate and t-butyl N-[5-(4-hydroxy-3-methylphenoxy)-2-nitrophenyl]-N-methylcarbamate. A mixture of a solution of the above product and palladium on carbon (10%, 0.21 g) was vigorously stirred at ambient temperature under hydrogen atmosphere for 2 hours. At the end of this time the catalyst was removed by filtration and the filtrate was concentrated to give the title compound (1.88 g).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[N:36](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:35]=[N:34][N:33]=3)=[CH:22][CH:21]=2)[C:7](=[O:18])[N:8]([CH2:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]>C(O)(=O)C>[CH2:1]([C:5]1[N:6]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[CH:22][CH:21]=2)[C:7](=[O:18])[N:8]([CH2:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(CSc2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCCCc1nn(CSc2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 75 %

Procedure:
Deprotection of 5-n-butyl-2,4-dihydro-2-(phenylthiomethyl)-4-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]-3H-1,2,4-triazol-3-one in 50% aqueous acetic acid was accomplished by the procedure of Example 3, Step B. After work-up, the residue was flash chromatographed over silica gel (10 mL for 0.02 mmole, gradient elution using 2-10% MeOH/CH2Cl2) to give the desired material as an oil in 75% yield, homogeneous by TLC in 10% MeOH/CH2Cl2, mass spectrum (FAB) m/e 498 (M+1)+, mp 170° C. dec.
Reaction SMILES: CC(C(O)=O)C1C=CC(CC2C(=O)CCC2)=CC=1.[OH-].[K+].[C:21]([OH:40])(=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].[OH-].[Ca+2:42].[OH-].[C:44]([O:63]CC(CO)O)(=[O:62])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]>O>[C:21]([O-:40])(=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].[Ca+2:42].[C:44]([O-:63])(=[O:62])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO
Agent: CC(C(=O)O)c1ccc(CC2CCCC2=O)cc1
Agent: [Ca+2]
Agent: [K+]
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
A lubricant composition was formed by first adding 43.00 gms of oxidized CS-600 low viscosity byproduct wax (viscosity: 11 cps; acid number: 14.7 mg KOH/gram; Mettler drop point: 109.5° C.), 122.50 gms of stearic acid, 15.5 gms of calcium hydroxide and 19.0 gms of glycerol monostearate to a reactor vessel. The combination was melted and held at 140° C. with slight agitation. The calcium hydroxide reacted with the stearic acid, forming a calcium stearate product and water as a byproduct. The high temperatures converted the water to steam, generating foam, and the foam was dissipated by the glycerol monostearate. The mixture was mixed until water formation stopped, and it was slowly stirred to remove any entrapped air. The mixture was then held for a finishing step such as prilling or pastillating. The resulting lubricant composition contained 22.42% of the oxidized byproduct wax, 6.68% residual stearic acid, 9.90% residual glycerol monostearate, and 61.00% calcium stearate. This lubricant composition had an acid number of 23.2 mg KOH/gram and a viscosity of 1900 centipoise at 140° C.
Reaction SMILES: ClCC(OC)=O.C[O-].[Na+].[CH3:10][O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].[CH2:17](O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]C>>[CH3:10][O:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:14]
Reactant: COCC(=O)OC
Reactant: CCCCCCCCO
Agent: COC(=O)CCl
Agent: C[O-]
Agent: [Na+]
Product: CCCCCCCCOC(=O)COC
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 74 %

Procedure:
537.2 g (4.95 mol) of methyl chloroacetate are initially introduced and stirred at 25° C. 936.4 g (5.2 mol) of 30% strength sodium methoxide solution are added dropwise in the course of 2.5 h such that a reaction temperature of 65° is not exceeded. After the addition, stirring is continued at reflux temperature for a further 3 h. 511.9 g of methanol are then removed from the reaction mixture by distillation. 1,289.3 g (9.9 mol) of n-octanol are added to the residue and the mixture is heated under reflux. In the course of this, methanol is removed through a 0.5 m long Multifil column at a reflux ratio of approximately 1:1 (303.5 g of distillate), the bottom temperature rising to 210° C. during the removal. After 6.5 h, the conversion of the methyl methoxyacetate to the n-octyl methoxyacetate is >98%. The reaction mixture is fractionated through a 0.5 m long Multifil column. Initially, n-octanol and methyl methoxyacetate are distilled off n-Octyl methoxyacetate (740.0 g, yield 74%) is then obtained as a main fraction with a purity >99%, a chlorine content of 10 ppm and a water content of <0.05%.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([OH:29])[C@:7]1([OH:28])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C:22](=[O:26])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:27])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].I(C1C=CC=CC=1C(O)=O)(=O)=O>CS(C)=O.O>[CH3:2][C:1]([O:4][CH2:5][C:6]([C@:7]1([OH:28])[C@@:24]2([CH3:25])[CH2:23][C:22]([C@@H:21]3[C@:19]4([CH3:20])[C:14](=[CH:15][C:16]([CH2:17][CH2:18]4)=[O:27])[CH2:13][CH2:12][C@H:11]3[C@@H:10]2[CH2:9][CH2:8]1)=[O:26])=[O:29])=[O:3]
Reactant: CC(=O)OCC(O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3C(=O)C[C@@]21C
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3C(=O)C[C@@]21C
Reaction time: 0.17 h
Yield: 92.8 %

Procedure:
A solution of 21-acetoxy-17,20-dihydroxy-pregn-4-en-3,11-dione (730 mg, 1.81 mmol) and o-iodoxybenzoic acid I (1 g, 3.57 mmol) in DMSO (7 ml) was stirred at 50° C. for 3 h. The solution was then diluted with water (10 ml), stirred for 10 min, filtered and extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with brine and dried over sodium sulfate. The organic solvent was distilled under vacuum. The residue was crystallised from ethanol to give 676 mg (93%) of cortisone acetate, mp 238°-240° C. (lit. 238°-240° C.)
Reaction SMILES: [C:1]1([CH2:13][C:14]([NH2:16])=[O:15])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.C[O:18][C:19](=O)[C:20]([C:22]1[C:30]2[C:25](=[CH:26][C:27]([Br:31])=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=O>>[C:1]1([C:13]2[C:14](=[O:15])[NH:16][C:19](=[O:18])[C:20]=2[C:22]2[C:30]3[C:25](=[CH:26][C:27]([Br:31])=[CH:28][CH:29]=3)[NH:24][CH:23]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: NC(=O)Cc1cn2c3c(cccc13)CCC2
Reactant: COC(=O)C(=O)c1c[nH]c2cc(Br)ccc12
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2cc(Br)ccc12

Procedure:
Beginning with 2-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetamide and (6-Bromo-1H-indol-3-yl)oxoacetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[CH3:14])=[O:5].N1C=CC=CC=1.[F:28][CH2:29][C:30](Cl)=[O:31]>O1CCCC1>[F:28][CH2:29][C:30]([NH:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[CH3:14])=[O:5])=[O:31]
Reactant: O=C(Cl)CF
Reactant: Cc1ccc(NC(=O)c2cc([N+](=O)[O-])ccc2N)c(C)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cc([N+](=O)[O-])ccc2NC(=O)CF)c(C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.8 %

Procedure:
4.0 g of N-(2-amino-5-nitrobenzoyl)-2,4-dimethylaniline and 2.36 g of pyridine are dissolved in 50 ml of tetrahydrofuran, and 2.18 g of fluoracetyl chloride are added dropwise thereto under ice-cooling. The mixture is then stirred at room temperature for 5 hours. The mixture is concentrated under reduced pressure to remove tetrahydrofuran, and 100 ml of water are added to the residue. Crystalline precipitates are collected by filtration and recrystallized from a mixture of dimethylformamide and ethanol (1:2). 4.3 g of N-(2-fluoroacetamido-5-nitrobenzoyl)-2,4-dimethylaniline are obtained as colorless needles.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:13])[C:11]=1[CH3:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:14](=O)([O-])[O-].[K+].[K+].IC.Cl>CC(C)=O.O>[CH3:12][C:11]1[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3][C:2]=1[S:1][CH3:14]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(S)oc2ccccc2c1=O
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Solvent: O
Product: CSc1oc2ccccc2c(=O)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.4 %

Procedure:
To a solution containing 2-mercapto-3-methyl-chromen-4-one (2.26 g, 11.76 mmol) and potassium carbonate (1.62 g, 11.76 mmol) in acetone (120 mL) was added iodomethane (807 μL, 12.93 mmol). The reaction stirred under nitrogen atmosphere at room temperature for 16 hours before being concentrated to yield a crude oil. The residue was taken up in water and adjusted to pH 7 with 5% HCl. The resulting aqueous layer was washed with ethyl acetate. The organic layer was then washed with water and brine, dried over sodium sulfate, filtered, and concentrated to obtain the desired product as a yellow solid (1.95 g, 80% yield), which was taken on to the next step without further purification. 1H NMR (600 MHz, CDCl3): δ 8.21 (d, 1H, J=6.6 Hz), 7.61 (m, 1H), 7.38 (m, 2H), 2.66 (s, 3H), 2.09 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([C:24](=[O:27])[CH2:25]Br)=[C:5]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[C:34]([NH2:38])(=S)[CH2:35][CH3:36].C1COCC1>C(O)C>[NH2:38]/[C:34](/[CH2:35][CH3:36])=[CH:25]\[C:24]([C:6]1[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][CH:19]=2)[C:8](=[O:12])[C:9]2[C:4]([C:5]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)=[O:27]
Reactant: CS(=O)(=O)c1ccc(Cn2c(C(=O)CBr)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Reactant: CCC(N)=S
Solvent: C1CCOC1
Solvent: CCO
Product: CC/C(N)=C/C(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 34.7 %

Procedure:
A mixture of 6-bromo-3-(2-bromoacetyl)-2-(4-methanesulfonylbenzyl)-4-phenyl-2H-isoquinolin-1-one (300 mg), thiopropionamide (70 mg), THF (3 ml) and ethanol (3 ml) was stirred at 80° C. for 12 hrs. The reaction mixture was concentrated under reduced pressure and saturated aqueous sodium hydrogen carbonate was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1-hexane:ethyl acetate=1:2) and recrystallized (ethyl acetate-hexane) to give the title compound (100 mg).
Reaction SMILES: [CH:1]1[C:6]2=[C:7]3[C:15](=[CH:16][CH:17]=[C:5]2[CH:4]=[N:3][CH:2]=1)[C:14]1[C:13](=[O:18])[NH:12][CH2:11][CH2:10][C:9]=1[NH:8]3.[F:19][C:20]([F:31])([F:30])[CH2:21]OS(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.Cl>CN(C=O)C.CO>[F:19][C:20]([F:31])([F:30])[CH2:21][N:8]1[C:7]2[C:15](=[CH:16][CH:17]=[C:5]3[CH:4]=[N:3][CH:2]=[CH:1][C:6]3=2)[C:14]2[C:13](=[O:18])[NH:12][CH2:11][CH2:10][C:9]1=2
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=C1NCCc2[nH]c3c(ccc4cnccc43)c21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1NCCc2c1c1ccc3cnccc3c1n2CC(F)(F)F
Temperature: 65 °C
Reaction time: 3 h
Yield: 44.2 %

Procedure:
A mixture of 8,9,10,11-tetrahydro-3,8,11-triaza-benzo[a]fluoren-7-one (213 mg, 0.9 mmol), trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (317 mg, 1.35 mmol), potassium carbonate (253 mg, 1.8 mmol) and 18-crown-6 ether (481 mg, 1.8 mmol) in anhydrous DMF (20 mL) was stirred under heating at 65° C. for 3 hours. More trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (200 mg, 0.86 mmol), potassium carbonate (253 mg, 1.8 mmol) and 18-crown-6 (240 mg, 0.9 mmol) were added and heating continued for 3 hours. After cooling, the solvent was evaporated under vacuum and the crude product was purified by flash chromatography with DCM/MeOH 95:5 as eluant, affording a solid product. The solid product was then dissolved in methanol and treated with 1.25M HCl in methanol to pH 1. The solvent was removed under vacuum and the residue was treated with diethylether. The resulting solid was filtered, washed with diethylether, and dried under vacuum, affording 127 mg of the title compound as hydrochloric salt (39% yield).
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16](O)=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:23]=[CH:22][O:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[CH3:47][O:48][C:49](=[O:62])[C@H:50]([CH2:52][C:53]1[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=1)[NH2:51].CCN(C(C)C)C(C)C>CS(C)=O.CC(O)=O.O>[CH3:47][O:48][C:49](=[O:62])[C@@H:50]([NH:51][C:16]([C:14]1[CH:13]=[CH:12][C:11]2[N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]([C:19]3[CH:23]=[CH:22][O:21][CH:20]=3)=[N:9][C:10]=2[CH:15]=1)=[O:17])[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Reactant: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
The carboxylic acid of example 2 (0.500 g, 1.61 mmol), TBTU (0.621 g, 1.94 mmol) and 4-nitro-L-phenylalanine methyl ester hydrochloride (0.461 g, 1.77 mmol) were dissolved in DMSO (2.0 mL) and DIEA (6.44 mmol, 1.12 mL) was added. The mixture was stirred for 2 h at room temperature (HPLC: complete). The reaction mixture was added dropwise with stirring to a mixture of water (45 mL) and AcOH (0.8 mL). The precipitate that formed was collected by filtration, washed with water and dried (0.768 g, 92% yield).