Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([CH2:17][CH2:18][CH3:19])[CH2:3][C@H:4]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[C:5]([OH:7])=O.Cl.[NH2:22][CH:23]([CH2:34][CH3:35])[C@@H:24]([C:26]1[O:30][N:29]=[C:28]([CH:31]2[CH2:33][CH2:32]2)[N:27]=1)[OH:25].C(NC(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[CH:31]1([C:28]2[N:27]=[C:26]([CH:24]([OH:25])[CH:23]([NH:22][C:5]([CH:4]([NH:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[O:10])[CH2:3][C:2]([F:1])([F:20])[CH2:17][CH2:18][CH3:19])=[O:7])[CH2:34][CH3:35])[O:30][N:29]=2)[CH2:32][CH2:33]1
Reactant: CCC(N)[C@H](O)c1nc(C2CC2)no1
Reactant: CCCC(F)(F)C[C@H](NC(=O)N1CCOCC1)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CCCC(F)(F)CC(NC(=O)N1CCOCC1)C(=O)NC(CC)C(O)c1nc(C2CC2)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
To a mixture of (S)-4,4-difluoro-2-[(morpholine-4-carbonyl)-amino]-heptanoic acid (104 mg, 0.35 mmol), (S)-2-amino-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-butan-1-ol hydrochloride (86.7 mg, 0.37 mmol) and diisopropyl amine (219 mg, 0.42 mmol) in dry dichloromethane (5 mL) is added PyBOP (113 mg, 0.87 mmol). The mixture is stirred at room temperature for 16 hr and the evaporated in vacuum. The residue is diluted with ethyl acetate (25 mL) and washed with saturated NaHCO3 (30 mL), dilute HCl (30 mL), then saturated NaHCO3 (30 mL). The organic layer is dried over magnesium sulfate and concentrated in vacuum. The residue is purified over 12 g silica gel, eluting with ethyl acetate: heptane (2:1 then 1:0) to afford morpholine-4-carboxylic acid (1-{1-[(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-hydroxy-methyl]-propylcarbamoyl}-3,3-difluoro-hexyl)-amide (146 mg, 88%) as a solid. LC/MS shows 2 isomers, total 100% M+1 474.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7].[H-].[Na+].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.O>CN(C=O)C>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:7])=[O:8]
Reactant: CN(C)CCNS(=O)(=O)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCN(c1ccc([N+](=O)[O-])cc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.8 g (29.8 mmol) of N-(2-dimethylamino-ethyl)-phenylsulphonamide are dissolved in 100 ml of DMF and combined with 1.3 g (30 mmol) of sodium hydride (55% in oil). The mixture is stirred for one hour at ambient temperature. Then 4.2 g (29.8 mmol) of 4-fluoro-nitrobenzene are added, and stirring is continued for another 16 hours. After the addition of 300 ml of water the mixture is extracted with ethyl acetate. The organic phase is washed with water, dried and evaporated down. The residue is acidified with 1 N hydrochloric acid and washed with ethyl acetate. The aqueous phase is then made basic again with sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried and evaporated down.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12]CC)=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](O)=O)=[CH:19][CH:18]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C(C)=CC=CC=1>O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]2[O:8][C:7]3[CH:6]=[CH:5][C:4]([CH:9]([CH3:15])[C:10]([OH:12])=[O:11])=[CH:3][C:2]=3[N:1]=2)=[CH:19][CH:18]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: CCOC(=O)C(C)c1ccc(O)c(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(C(=O)O)c1ccc2oc(Cc3ccc(F)cc3)nc2c1

Procedure:
A mixture of ethyl 3-amino-4-hydroxy-phenyl-propionate (4 g.), 4-fluoro-phenyl-acetic acid (3 g.), p-toluene sulphonic acid (0.1 g.) and xylene (50 ml.) was heated under reflux for 20 hours and the water which formed was removed using a Dean and Stark apparatus. The solution was evaporated to dryness and the residue dissolved in ether. The solution was washed with 2N-sodium hydroxide solution (x2) and water, then stirred with charcoal and anhydrous sodium sulphate, filtered and evaporated to dryness. The residual oil (3.7 g., ND22.5 1.5469) was dissolved in ethanol (30 ml.) and 2N-sodium hydroxide solution (30 ml) was added with stirring over 15 minutes. The reaction mixture was stirred for 21/2 hours during which time water (250 ml) was slowly added. The solution was extracted with ether (x2), acidified with concentrated hydrochloric acid and then extracted with ether (x3). These ethereal extracts were washed with water, dried over anhydrous sodium sulphate and evaporated to give an oil. This oil was purified using prep. tlc plates to give 2-[2-(4-fluorobenzyl)-5-benzoxazolyl]propionic acid as a white solid, mpt 91°-93° C., which was characterised by IR UV and NMR spectroscopy and by microanalysis which gave C 68.40%, H 3.86%, N4.64%; C17H14FNO3 requires C 68.23%, H 4.68%, N 4.68%
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.C(N(CC)CC)C.Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=1>CN(C)C=O>[Cl:37][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][NH:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23
Reactant: Clc1cccc(CBr)c1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NN=Cc2c(-c3ccccc3)[nH]c3cc(NCc4cccc(Cl)c4)cc1c23
Yield: 69.2 %

Procedure:
To the title compound of Example 7 (hydrochloride) (40 mg, 0.13 mmol), and triethylamine (0.053 mL, 0.38 mmol) in N,N-dimethylformamide (0.9 mL) was added 1-bromomethyl-3-chloro-benzene (0.17 mL, 0.13 mmol) dropwise with stirring. After stirring overnight, the mixture was chromatographed on silica eluting with 2:1 hexane:ethyl acetate to afford, after isolation, the title compound (36 mg, 0.090 mmol) as a yellow powder in 71% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:4][C:3]=1[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].[O:29]=[C:30]1[NH:34][C:33](=[O:35])[CH:32]([CH2:36][C:37]2[CH:47]=[CH:46][C:40]([O:41][CH2:42][C:43](O)=[O:44])=[CH:39][CH:38]=2)[S:31]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:29]=[C:30]1[NH:34][C:33](=[O:35])[CH:32]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:41][CH2:42][C:43]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:15]4[CH2:16][CH2:17][CH2:18][CH2:19]4)=[CH:4][C:3]=3[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:44])=[CH:46][CH:47]=2)[S:31]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2N2CCCC2)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2N2CCCC2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 97 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-{2-amino-5-[2-(pyrrolidin-1-yl)phenoxy]phenyl}-N-methyl-carbamate (0.77 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.90 g), diethyl cyanophosphonate (0.52 g), triethylamine (0.32 g) and anhydrous tetrahydrofuran (30 ml) and the reaction mixture was purified to give the desired product (1.26 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[C:27]2[O:26][CH2:25][CH2:24][N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22][C:21]=2[CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[C:27]2[O:26][CH2:25][CH2:24][N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22][C:21]=2[CH:20]=[CH:19][CH:18]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCOc2c(O)cccc2C1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2OS(=O)(=O)C(F)(F)F)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
Trifluoromethanesulfonic anhydride (6.04 ml, 35.7 mmol) was added to an ice cooled solution of 1,1-dimethylethyl 9-hydroxy-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 62) (6.32 g, 23.82 mmol) in pyridine (100 ml) and stirred at 0° C. for 2 hrs. The pyridine was evaporated and the residue dissolved in EtOAc. Washed with 2M HCl, sat sodium bicarbonate solution, dried over magnesium sulphate and evaporated to give the title compound (9 g) as a yellow oil. MS (ES): C15H18F3NO6S requires 397; found 298 [M+H−100]+.
Reaction SMILES: [CH3:1][OH:2].N1C=CC=CC=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[C:20](=[N:21][S:22]Cl)[C:19](=[O:24])[N:18]([CH3:25])[C:17]1=[O:26]>C(Cl)Cl>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[C:20](=[N:21][S:22][O:2][CH3:1])[C:19](=[O:24])[N:18]([CH3:25])[C:17]1=[O:26]
Reactant: CO
Reactant: CN1C(=O)C(=NSCl)N(c2ccccc2F)C1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COSN=C1C(=O)N(C)C(=O)N1c1ccccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3.2 g (0.1 mole) methanol and 7.9 g (0.1 mole) pyridine in 20 ml of methylene chloride was added dropwise to a solution of about 0.1 mole of 1-(2-fluorophenyl)-3-methyl-5-chlorothioimino-2,4-imidazolidinedione in 100 ml of methylene chloride at 0°C. The resulting reaction mixture was stirred for about 30 minutes at 0°C., washed with water, washed with sodium bicarbonate, dried over magnesium sulfate, and evaporated under reduced pressure to give a yellow solid residue. The solid was washed with isopropyl alcohol to give the product as a pale yellow solid, m.p. 124°-127° C. Elemental analysis showed:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]=[N:10][NH:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[F:19].[F:20][P-:21]([F:26])([F:25])([F:24])([F:23])[F:22].[K+].Br/[CH:29]=[CH:30]\[C:31]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=1[F:38].ClOC(C)(C)C>ClCCl>[F:20][P-:21]([F:26])([F:25])([F:24])([F:23])[F:22].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH+:9]1[CH:29]=[C:30]([C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=2[F:38])[N:11]([C:12]2[C:13]([F:19])=[CH:14][CH:15]=[CH:16][C:17]=2[F:18])[NH:10]1
Reactant: Fc1cccc(F)c1/C=C\Br
Reactant: Fc1cccc(F)c1N=NNc1c(F)cccc1F
Agent: CC(C)(C)OCl
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Product: Fc1cccc(F)c1C1=C[NH+](c2c(F)cccc2F)NN1c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of triazene 8d (808 mg, 3 mmol) and anhydrous potassium hexafluorophosphate (750 mg, 4 mmol) and (Z)-1-Bromo-2-(2,6-difluorophenyl)ethene 11q (1.32 g, 6 mmol) in dry dichloromethane (20 mL) in the dark at −78° C. is added tert-butyl hypochlorite (500 μL, 4.4 mmol), upon which the mixture instantly darkens. The mixture is stirred overnight as it is slowly allowed to warm to room temperature. The contents are then filtered, and the solid residue is washed with dichloromethane. The filtrate is collected, and volatiles are evaporated under reduced pressure. Diethyl ether is then added, and the mixture is vigorously triturated for ca. 1 hour, with occasional scratching of the glass surfaces to ensure efficient mixing. Filtration and washing with copious quantities of diethyl ether afford, after drying under vacuum, triazolium salt 10dq as an off-white solid (1.45 g, 88%). Analytical samples were obtained after recrystallization by vapor diffusion of diethyl ether in an acetonitrile solution of 10dq. 1H-NMR ((CD3)2SO, 300 MHz): δ=10.37 (s, 1H), 8.05-7.90 (m, 2H), 7.89-7.81 (m, 1H), 7.69 (t, J=8.9 Hz, 2H), 7.61 (t, J=8.9 Hz, 2H), 7.44 (t, J=8.9 Hz, 2H). 13C-NMR (((CD3)2SO, 75 MHz): δ=159.4 (dd, J=253, 4 Hz), 155.7 (d, J=257 Hz), 155.3 (d, J=257 Hz), 137.1 (2t, J=10 Hz), 136.2, 135.9 (t, J=10 Hz), 134.6, 114.0 (d, J=18 Hz), 113.8 (d, J=18 Hz), 113.0 (d, J=20 Hz), 112.6 (t, J=14 Hz), 110.3 (t, J=15 Hz), 99.1 (t, J=18 Hz). 19F-NMR (CD3CN, 282 MHz): δ=−71.9 (d, J=705 Hz, 6F), −110.3 (2F), −118.8 (2F), −119.0 (2F). HR-MS (ESI): Calcd. for C20H10F6N3 [M+]: 406.0773. found 406.0784.
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[C:8]([O:11][C:12](=O)C)(=O)[CH3:9].C(O)(=O)C>C(O)C>[CH2:8]([O:11][CH:12]=[CH:2][C:1]([CH2:4][C:5](=[O:7])[CH3:6])=[O:3])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)CC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC=CC(=O)CC(C)=O
Reaction time: 2.5 h

Procedure:
253 g (2.5 moles) of acetylacetone, 1,110 g (7.5 moles) of orthformic acid triethyl ester and 8 g of acetic anhydride are heated to ebullition in a flask with vigorous stirring. During the reaction, about 23 g of acetic acid is added and the ethanol formed is distilled off. After 2 to 3 hours the reaction is completed. The unreacted orthoformic acid triethyl ester is distilled out at reduced pressure (5 to 1 Torr) through the top of the column and fed back to the next batch. Following this, 355 g of ethoxymethylene acetylacetone is evaporated, separated from the residue through a simple distillation bridge at 0.1 to 0.3 Torr. The yield, referred to acetylacetone, was 91% of theory.
Reaction SMILES: Cl.C(OCC)(=O)C.[CH2:8]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=O)[CH2:21][C@H:20]1[O:32][CH3:33])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC1[CH:36]=[CH:37][C:38]([N+:45]([O-:47])=[O:46])=[C:39]([CH:44]=1)[C:40]([O:42][CH3:43])=[O:41].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CO>[CH2:8]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:36]=[CH:37][C:38]([N+:45]([O-:47])=[O:46])=[C:39]([CH:44]=2)[C:40]([O:42][CH3:43])=[O:41])[CH2:21][C@H:20]1[O:32][CH3:33])=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanol (15 ml) and a 4 N hydrochloric acid/ethyl acetate solution (30 mL) were added to tert-butyl cis(±)-4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidine-1-carboxylate obtained in Example (40a) (1.5 g, 4.12 mmol), and the mixture was stirred at room temperature for two hours. The reaction solution was concentrated under reduced pressure, azeotropically dehydrated by adding toluene, and dissolved in DMF (10 ml). Methyl 5-chloro-2-nitrobenzoate (900 mg, 4.17 mmol) and potassium carbonate (2.1 g, 15.2 mmol) were added, and the mixture was stirred at 175° C. for 24 hours. The reaction solution was diluted with ethyl acetate, washed with water, and concentrated under reduced pressure. Thereafter, the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane) to obtain the title compound. The total resulting compound was used for the next reaction.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:23][CH3:24])[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:3]1=[O:30].OO.C(O)(=[O:35])C>C(Cl)Cl.CC#N>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:23]([CH3:24])=[O:35])[N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=3)[N:11]=[C:5]2[N:4]([CH2:25][C:26]([CH3:27])([CH3:29])[CH3:28])[C:3]1=[O:30]
Reactant: CC(=O)O
Reactant: CSc1c2c(=O)n(C)c(=O)n(CC(C)(C)C)c2nn1Cc1ccc(S(C)(=O)=O)cc1
Agent: OO
Solvent: CC#N
Solvent: ClCCl
Product: Cn1c(=O)c2c(S(C)=O)n(Cc3ccc(S(C)(=O)=O)cc3)nc2n(CC(C)(C)C)c1=O
Temperature: 25 °C
Yield: 58.5 %

Procedure:
5-methyl-2-(4-(methylsulfonyl)benzyl)-3-(methylthio)-7-neopentyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (11.4 mg, 0.022 mmol) is dissolved in CH2Cl2 (200 μL) and CH3CN (100 μL), and then 30% H2O2 aqueous solution (75 μL, 0.66 mmol) is added, followed by acetic acid (6.6 mg, 0.11 mmol). The reaction mixture is stirred at room temperature over a weekend, and then purified by a semi-preparative HPLC to give 6 mg of product as white solids. MS (ESI) m/z 467.1 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:9]1[CH:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[N:10]1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:2]([N:9]1[CH:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cnn(Cc2ccccc2)c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Bromomethyl-benzene (610 mg, 3.57 mmol) was suspended in Acetone (25 ml), ethyl 1H-pyrazole-4-carboxylate (500 mg, 3.57 mmol) and K2CO3 (2465 mg, 17.84 mmol) were added. The suspension was stirred 16 h at 50° C. The reaction mixture was filtrated and evaporated in vacuum to give the title compound which was used for the next step without further purification. HPLC/MS (Method A) RtA=1.82 min, MS [M+H]+=230.9.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:23]3[CH:24]=[C:25]4[O:30][CH2:29][O:28][C:26]4=[CH:27][C:22]=3[CH2:21][C:20]([CH3:31])=[N:19][N:18]=2)=[CH:13][CH:12]=1>CN(C)C=O.C(OCC)C>[C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:23]4[CH:24]=[C:25]5[O:30][CH2:29][O:28][C:26]5=[CH:27][C:22]=4[CH2:21][C:20]([CH3:31])=[N:19][N:18]=3)=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1=NN=C(c2ccc(N)cc2)c2cc3c(cc2C1)OCO3
Reactant: O=C=Nc1ccccc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1=NN=C(c2ccc(NC(=O)Nc3ccccc3)cc2)c2cc3c(cc2C1)OCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
0.22 ml (2.04 mmol) of phenyl isocyanate was added to a solution of 0.50 g (1.7 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in 4 ml of dimethylformamide and the reaction mixture was stirred at 25° C. for one hour. Then it was diluted with 20 ml of diethyl ether and filtered at 5° C. The crystals were washed with 2×5 ml of diethyl ether and dried at 60°-100° C. The resulting 0.70 g of raw product, m.p. 239°-240° C. (sintering at 180° C.) was refluxed in 15 ml of ethanol, filtered after cooling, washed wtih 3×1 ml of ethanol and dried at 100° C. to yield 0.55 g (78.6%) of the aimed product, m.p. 240°-241° C. (decomp.).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1)=S.[N:16]#[C:17][NH2:18].[Pb]>>[C:17]([NH:18][C:3]([NH:2][CH3:1])=[N:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1)#[N:16]
Reactant: CNC(=S)NCCSCc1csc(N)n1
Reactant: N#CN
Agent: [Pb]
Product: CNC(=NCCSCc1csc(N)n1)NC#N

Procedure:
Reaction of N-methyl-N'-[2-((2-amino-4-thiazolyl)-methylthio)ethyl]thiourea with lead cyanamide by the procedure of Example 3(b) gives the title compound.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([N+:10]([O-])=O)[CH:7]=[CH:8][CH:9]=1.O>[Zn].CCOCC>[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Solvent: CCOCC
Product: Clc1cccc(NNc2cccc(Cl)c2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
To a stirred solution of 50% NaOH (3 mL) was added 3-chloronitrobenzene (10 g, 64 mM). The suspension was warmed to 60° C. and zinc (9 g, 138 mM) was added. During the addition, the temperature of the reaction mixture was kept between 60° and 80° C. After the addition was complete, a solution of 20% NaOH (18 mL, 90 mM) was added followed by water (30 mL). An additional portion of zinc (12 g, 189 mM) was then added and the resulting mixture was stirred between 75°-80° C. for 2 hours. After cooling to room temperature, the mixture was added to ether (200 mL), stirred, and the liquid was decanted. The solids were then resuspended in ether and the extraction was repeated 3 times. The ether extracts were combined, dried (Na2SO4), and concentrated to give a yellow solid. This was purified by flash column chromatography using CH2Cl2 as elutant which afforded the titled compound as a yellow solid (5.5 g, 68%). NMR (CDCl3): 7.12 (t, J=8 Hz, 2H), 6.80 (m, 4H), 6.67 (dd, J1 =1 Hz, J2 =8 Hz, 2H), 5.66 (br s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]([C:26]1[N:27]([CH3:38])[C:28]2[C:33]([C:34]=1O)=[CH:32][C:31]([O:36][CH3:37])=[CH:30][CH:29]=2)=[O:25].C(OCC)(=O)C>CCCCCC>[CH3:22][O:23][C:24]([C:26]1[N:27]([CH3:38])[C:28]2[C:33]([C:34]=1[O:20][C:19](=[O:21])[CH2:18][O:17][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=1)=[CH:32][C:31]([O:36][CH3:37])=[CH:30][CH:29]=2)=[O:25]
Reactant: COC(=O)c1c(O)c2cc(OC)ccc2n1C
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1c(OC(=O)COc2ncc(C(=O)Nc3ccc(F)cc3)cn2)c2cc(OC)ccc2n1C
Yield: 15 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 3-hydroxy-5-methoxy-1-methyl-1H-indole-2-carboxylic acid methyl ester (40 mg, 0.17 mmol) as the source alcohol. Chromatography (1:1 ethyl acetate:hexane) through SiO2 yielded 13 mg (15%) of the titled compound. ESI-MS m/z 509 (MH+), 507 (M−H−).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>C(O)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][CH:24]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Reactant: Nc1cccc(Cl)c1
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1cccc(Cl)c1
Temperature: 25 °C

Procedure:
A mixture of 10.0 g (42.9 mmol)) 4-chloro-6-nitro-quinoline-3-carbonitrile, 260 ml ethanol, and 5.40 ml 3-chloroaniline was heated to reflux under N2. Removed heat at 4 hours, cooled to 25° C. and added saturated sodium bicarbonate until the pH was basic. Stripped solvents and azeotroped with ethanol. Slurried residue with hexane, collected solid, and air dried. Washed solids with water and dried in vacuo. Dissolved in boiling ethyl acetate, stirred with Darco, and filtered. Stripped solvent and dried residue in vacuo, giving 6.5 g of yellow solid: mass spectrum (electrospray m/e): M+H=325.0, 327.0.