Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](F)=[CH:7][C:6]=1[CH3:15])[CH3:3].[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:15][C:6]1[C:5]([O:4][CH:2]([CH3:3])[CH3:1])=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([NH:16][CH:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]2)[CH:7]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1OC(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1OC(C)C
Temperature: 80 °C
Yield: 37.7 %

Procedure:
A solution of 4-fluoro-2-methyl-5-nitrophenyl 1-methylethyl ether (D73) (0.53 mmol, 115 mg) in dimethylformamide (3 mL) was treated with 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (0.53 mmol, 106 mg, 1 eq) and diisopropylethylamine (0.53 mmol, 68.5 mg, 1 eq) under argon at room temperature and then heated at 80° C. overnight. The mixture was then concentrated under reduced pressure, then treated with 10% aqueous sodium carbonate solution and extracted with ether/ethyl acetate. The organics were dried, concentrated under reduced pressure and purified by chromatography on silica (ethyl acetate/petrol ether) to give the title compound as a solid (0.2 mmol, 80 mg, 39% yield). M+H 338.1 for main fragment (loss of tert-butyl group).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([O-:4])=[O:3].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl.C(Cl)(Cl)Cl>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:11][CH:12]=1)([O-:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: NCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)NCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 84.3 %

Procedure:
To a solution of 25.0 g (133 mmol, 1.0 equiv.) of 4-nitro benzylamine hydrochloride in 500 mL of methylene chloride at 0° C. was added 46.4 mL (331 mmol, 2.5 equiv.) of triethylamine followed by 11.3 mL (146 mmol, 1.1 equiv.) of methanesulfonyl chloride dropwise. The reaction was stirred for thirty minutes at 0° C. then diluted with 500 mL of chloroform. The organic layer was washed with 150 mL portions of 1N HCl and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated to give 25.8 g (85%) of N-[(4-nitrophenyl)methyl]methanesulfonamide.
Reaction SMILES: [CH:1](=[N:8][NH:9][CH:10]([CH3:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.C(=O)=O.C(O[CH:24]=[C:25]([C:28]#[N:29])[C:26]#[N:27])C>C1COCC1>[CH:1](=[N:8][N:9]([CH:24]=[C:25]([C:28]#[N:29])[C:26]#[N:27])[CH:10]([CH3:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)NN=Cc1ccccc1
Reactant: CCOC=C(C#N)C#N
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)N(C=C(C#N)C#N)N=Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of Intermediate 1-benzylidene-2-isopropylhydrazine (12.9 g, 0.079 mol) in 200 ml anhydrous THF was cooled in a dry ice/acetone bath under an argon atmosphere. To this solution was added n-butyllithium (1.6 M in hexanes, 66 ml, 0.106 mol) via syringe. Following completion of the addition, the mixture was stirred at dry-ice temperature for an additional 5 minutes. A solution of (2-(ethoxymethylene)malononitrile (13.6 g, 0.11 mol) in THF (30 ml) was added. The mixture was stirred at dry-ice temperature for 0.5 h, and then was quenched with saturated aqueous sodium bicarbonate solution. The quenched reaction mixture was allowed to warm to rt and was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The residue was suspended in ethanol with sonication. The resulting precipitate was collected via filtration and washed with a small amount of cold ethanol to obtain 2-((2-benzylidene-1-isopropylhydrazinyl)methylene)malononitrile as a yellow solid. The mother liquor was concentrated and the residue purified by silica gel column chromatography (1:1 hexanes/ethyl acetate eluant) to afford additional 2-((2-benzylidene-1-isopropylhydrazinyl)methylene)malononitrile. MS m/z 239.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:13](Cl)(Cl)=[O:14].[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:23][NH:24][C:25]([C@H:27]([C@@H:37]([CH2:46][CH:47]([CH3:49])[CH3:48])[C:38]([NH:40][NH:41][CH2:42][CH:43]([CH3:45])[CH3:44])=[O:39])[CH2:28]/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:26]>C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.ClCCl>[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:23][NH:24][C:25]([C@H:27]([C@@H:37]([CH2:46][CH:47]([CH3:49])[CH3:48])[C:38]([NH:40][N:41]([CH2:42][CH:43]([CH3:44])[CH3:45])[C:13]([N:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:14])=[O:39])[CH2:28]/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:26]
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CCCN1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)N1CCCN1C(=O)OC(C)(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 0.241 g of 2-tert.butyloxycarbonyl-pyrazolidine in 5 ml of toluene as added slowly, at 0° C. under nitrogen, to a solution of 0.725 ml of phosgene in 5 ml of toluene. The mixture was allowed to warm to room temperature over 2 hours and then a solution of 0.459 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 5ml toluene/dichloromethane (1:1) was added dropwise. The mixture was stirred for 48 hours at room temperature and evaporated. The residue was dissolved in ethyl acetate and washed with 2N aqueous hydrogen chloride and water and then dried over anhydrous magnesium sulphate and evaporated. The residue was triturated with ether to give 0.267 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-[(2-tert.butyloxycarbonyl-1-pyrazolidinyl)carbonyl]valerohydrazide in the form of a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.C1COCC1.[C:19]([C:21]1[CH:22]=[C:23]([NH2:27])[CH:24]=[CH:25][CH:26]=1)#[CH:20]>CCN(CC)CC>[C:19]([C:21]1[CH:22]=[C:23]([NH:27][C:7]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[CH3:1])=[O:9])[CH:24]=[CH:25][CH:26]=1)#[CH:20]
Reactant: C#Cc1cccc(N)c1
Reactant: Cc1ccsc1C(=O)O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: C#Cc1cccc(NC(=O)c2sccc2C)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
A dry 25 mL flask was charged with 3-methylthiophene-2-carboxylic acid (0.201 g, 1.41 mmol) followed by thionyl chloride (10 mL). The reaction was heated to 50° C. for 2 h after which the reaction was cooled to room temperature and concentrated to afford the crude acid chloride. The crude acid chloride was dissolved into 10 mL of THF and 3-ethynyl-phenylamine (0.165 g, 1.41 mmol) was added to the solution followed by NEt3, and the mixture was allowed to stir at 55° C. for 4 hours. The reaction mixture was allowed to cool to room temperature and then partitioned between EtOAc and water. The organic layer was then washed once with of 1M HCl (˜10 mL) and then twice with of saturated aqueous NaHCO3 (˜10 mL). The organic extracts were combined, dried over anhydrous Na2SO4(S) and then concentrated to give the title compound as a tan solid (265 mg, 1.10 mmol, 78%).
Reaction SMILES: O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:24][C:25]1[C:26]([CH:40]([C:52]2[CH:57]=[C:56]([F:58])[CH:55]=[CH:54][C:53]=2[F:59])[S:41]([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[C:46]([F:51])[CH:45]=2)(=[O:43])=[O:42])=[CH:27][C:28]([N:31](S(C)(=O)=O)[S:32]([CH3:35])(=[O:34])=[O:33])=[N:29][CH:30]=1.CCCCCC>C(OCC)(=O)C>[Cl:24][C:25]1[C:26]([CH:40]([C:52]2[CH:57]=[C:56]([F:58])[CH:55]=[CH:54][C:53]=2[F:59])[S:41]([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[C:46]([F:51])[CH:45]=2)(=[O:43])=[O:42])=[CH:27][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[N:29][CH:30]=1
Reactant: CS(=O)(=O)N(c1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)c(F)c2)c(Cl)cn1)S(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)c(F)c2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
Under a nitrogen atmosphere, a tetrahydrofuran solution (1M, 0.147 ml, 0.15 mmol) of tetrabutylammonium fluoride was added to a tetrahydrofuran (2 ml) solution of N-[5-chloro-4-[(2,5-difluorophenyl)(3,4-difluorophenylsulfonyl)methyl]pyridin-2-yl]-N-(methylsulfonyl)methanesulfonamide (72 mg, 0.12 mmol). The resulting mixture was stirred at room temperature for 2 hours. After the reaction mixture was concentrated under reduced pressure, the residue thus obtained was dissolved in ethyl acetate. The resulting solution was washed sequentially with 1N hydrochloric acid and a saturated aqueous solution of ammonium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated under reduced pressure. The residue thus obtained was washed with a mixed solvent of diethyl ether/hexane and collected by filtration to give the title compound (53 mg, 0.10 mmol, 84%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=[C:7]([C:8]([OH:10])=O)[C:6]=1[C:18]([OH:20])=[O:19])([O:3][CH3:4])=[O:2].C(OC(=O)C)(=O)C>>[C:1]([C:5]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=[C:7]2[C:8]([O:20][C:18](=[O:19])[C:6]=12)=[O:10])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(C(=O)O)c(C(=O)O)c1C(=O)OC
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc2c(c1C(=O)OC)C(=O)OC2=O
Yield: 75.7 %

Procedure:
In a 100 mL round bottomed flask fitted with a condenser closed with a calcium chloride tube, 156.3 mg (0.55 mmol) of 7 and 0.5 mL of acetic anhydride were placed. The contents of the flask were refluxed gently for 15 min. On cooling white crystals appeared. The crystals were collected on a filter, washed with ether and purified by sublimation under high vacuum (0.05 torr) at an oil bath temperature of 130° C. to yield 110 mg (75%) of the anhydride 8. White solid; mp: 178.5°-179.5° C.; IR: 3110, 3040, 2980, 1860, 1790, 1770, 1740, 1720, 1440, 1300, 1250, 1100, 910, 900 cm-1 ; 1H NMR: δ8.38 (s, 2H, Aryl H), 3.95 (s, 6H, CH3).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([O:16][CH2:17][C:18]([Cl:20])=[O:19])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCOCC>C1C=CC=CC=1>[ClH:20].[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:18](=[O:19])[CH2:17][O:16][C:8](=[O:15])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1
Reactant: O=C(Cl)COC(=O)c1ccccc1
Reactant: CN1CCNCC1
Solvent: c1ccccc1
Solvent: CCOCC
Product: CN1CCN(C(=O)COC(=O)c2ccccc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
A solution of 1-methylpiperazine (0.40 g, 4 mmole) in 5 ml benzene was added dropwise while stirring to a solution of (benzoyloxy)acetylchloride (0.80 g, 4 mmole) in 10 ml of benzene. After the addition was completed (about 10 min) the reaction mixture was stirred at room temperature for 1 h. Ether (10 ml) was added and the mixture was filtered. The white crystalline compound on the filter was washed with ether and finally recrystallized from ethanol, yielding 0.70 g (59%) of the title compound. Mp 227°-228° C.
Reaction SMILES: [C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([C:22](O)=[O:23])[N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:48][O:49][C:50]([C@H:52]1[CH2:56][CH2:55][CH2:54][NH:53]1)=[O:51].C(N(CC)CC)C>CN(C)C=O.ClCCl>[CH3:48][O:49][C:50]([C@H:52]1[CH2:56][CH2:55][CH2:54][N:53]1[C:22]([C:15]1[N:16]2[C:17]([CH2:18][O:19][CH2:20][CH2:21]2)=[C:13]([C:11](=[O:12])[NH:10][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH3:9])[CH:14]=1)=[O:23])=[O:51]
Reactant: COC(=O)[C@H]1CCCN1
Reactant: CC[C@@H](NC(=O)c1cc(C(=O)O)n2c1COCC2)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C(=O)OC)n2c1COCC2)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 21 %

Procedure:
To a solution of 8-((R)-1-phenyl-propylcarbamoyI)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboxylic acid (Comp. No. 11a) (200 mg, 0.61 mmol) in dimethylformamide (2 ml) was added 1-hydroxybenzotriazole (91 mg, 0.670 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (128 mg, 0.670 mmol). The mixture was stirred for 45 min at 25° C., then (R)-pyrrolidine-2-carboxylic acid methyl ester hydrochloride (111 mg, 0.670 mmol) and triethylamine (123 mg, 1.218 mmol) were added and the mixture was stirred at 25° C. overnight. Excess dichloromethane was added and the mixture was washed consecutively with water, aqueous sodium hydrogencarbonate and brine. The organic layer was evaporated to dryness. The crude product was purified by flash chromatography (silica gel, elution with heptane/ethyl acetate) to give 55 mg (21%) of (R)-1-[8-((R)-1-phenyl-propylcarbamoyI)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbonyl]-pyrrolidine-2-carboxylic acid methyl ester). LC/MS (method 4): Rt=1.21 min; m/z=440.29 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:23][CH2:19][CH2:20][CH2:21][CH3:22])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CCCCN
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: CCCCNc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and butylamine in DME. ES-MS m/e (%): 258 (M+H+, 100).
Reaction SMILES: [CH2:1]([C:5]1([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]#[N:24])[CH:6]1[OH:25])[CH2:2][CH2:3][CH3:4].[OH-:30].[Na+].OO>C(O)C.C(OCC)(=O)C>[CH2:1]([C:5]1([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23](=[O:30])[NH2:24])[CH:6]1[OH:25])[CH2:2][CH2:3][CH3:4]
Reactant: [OH-]
Reactant: CCCCC1(CCCC)CCc2c(OCc3ccccc3C#N)cccc2C1O
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCC1(CCCC)CCc2c(OCc3ccccc3C(N)=O)cccc2C1O
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of 2,2-dibutyl-5-(2-cyanobenzyloxy)-1,2,3,4-tetrahydro-1-naphthol (500 mg) in a mixture of ethanol (3.5 ml) and aqueous 6N-sodium hydroxide solution (0.275 ml) was added aqueous 30% hydrogen peroxide (2.62 ml) in one portion at ambient temperature. The mixture was stirred for 5 hours at 50° C. and allowed to stand overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate (40 ml). The separated organic layer was washed with aqueous hydrochloric acid, aqueous sodium bicarbonate solution, and brine, and then dried, and evaporated under reduced pressure. The residue was crystallized from aqueous ethanol to yield 2,2-dibutyl-5-(2-carbamoylbenzyloxy)-1,2,3,4-tetrahydro-1-naphthol (425 mg). mp: 73°-75° C. IR (CHCl3) 3480, 3400, 2910, 1665, 1580 cm-1. NMR (CDCl3, δ): 0.86 (3H, t, J=7 Hz), 0.93 (3H, t, J=7 Hz), 1.03-1.80 (15H, m), 2.47 (1H, m), 2.76 (1H, m), 4.33 (1H, s), 5.27 (2H, s), 5.77 (1H, br s), 6.38 (1H, br s), 6.90 (1H, d, J=8 Hz), 7.03 (1H, d, J=8 Hz), 7.20 (1H, t, J=8 Hz), 7.41 (1H, t, J=8 Hz), 7.51 (1H, t, J=8 Hz), 7.62 (1H, d, J=8 Hz), 7.68 (1H, d, J=8 Hz).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:9]=[C:10]([CH2:23][C:24](O)=[O:25])[CH:11]=[CH:12][C:13]=2[NH:14][C:15]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[O:16])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][NH2:28].C1COCC1>>[CH:1]1([C:6]([C:8]2[CH:9]=[C:10]([CH2:23][C:24]([NH:28][CH3:27])=[O:25])[CH:11]=[CH:12][C:13]=2[NH:14][C:15]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[O:16])=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)Cc1ccc(NC(=O)Nc2nccs2)c(C(=O)C2CCCC2)c1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)Cc1ccc(NC(=O)Nc2nccs2)c(C(=O)C2CCCC2)c1

Procedure:
2-[3-Cyclopentanecarbonyl-4-(3-thiazol-2-yl-ureido)phenyl]-N-methylacetamide (154 mg) is prepared from [3-cyclopentanecarbonyl-4-(3-thiazol-2-ylureido)phenyl]acetic acid (186 mg, 0.5 mmol) and 1 M solution of methylamine in THF (0.5 ml, 0.5 mmol) following the general procedure K.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH:3]=1.[CH2:22]1COC[CH2:23]1.C([Mg]Br)C>C(OCC)(=O)C>[F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH2:22][CH3:23])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH:3]=1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1ccc(F)cc1Nc1ccccc1F
Agent: CC[Mg]Br
Solvent: CCOC(C)=O
Product: CCC(=O)c1ccc(F)cc1Nc1ccccc1F
Temperature: 0 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
In a 500 mL round bottom flask, 4-fluoro-2-(2-fluoro-phenylamino)-N-methoxy-N-methyl-benzamide (6.0 g, 20.5 mmol) was added to THF (60 mL) to give a colorless solution. The reaction was cooled to 0° C. in an ice bath and ethyl magnesium bromide (3.0 M in THF, 27.4 mL, 82.2 mmol) was added slowly over a 15 min. period. The mixture was stirred at 0° C. for 4 hr. The reaction mixture was poured into ethyl acetate (250 mL) and washed with 1N HCl (1×150 mL), water (2×150 mL) and brine (2×150 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuum. The crude material was purified by flash chromatography using 20% ethyl acetate-hexanes to give 1-[4-fluoro-2-(2-fluoro-phenylamino)-phenyl]-propan-1-one (3.0 g, 56%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:15]2[CH2:24][C:23]([CH3:26])([CH3:25])[C:22]3[C:17](=[C:18]([C:27]([O:29]C)=[O:28])[CH:19]=[CH:20][CH:21]=3)[CH2:16]2)=[N:6][C:7]=1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[Li+].[OH-].Cl>O1CCCC1.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:15]2[CH2:24][C:23]([CH3:26])([CH3:25])[C:22]3[C:17](=[C:18]([C:27]([OH:29])=[O:28])[CH:19]=[CH:20][CH:21]=3)[CH2:16]2)=[N:6][C:7]=1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: COC(=O)c1cccc2c1CN(c1ccc(Br)c(C(=O)OC(C)(C)C)n1)CC2(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1nc(N2Cc3c(C(=O)O)cccc3C(C)(C)C2)ccc1Br
Reaction time: 8 h

Procedure:
To an ambient solution of EXAMPLE 14A (245 mg) in tetrahydrofuran (2.1 mL) was added a solution of LiOH (30.9 mg) in water (0.52 mL). The reaction was stirred overnight, diluted with 2 mL water and 2 mL ethyl acetate, and acidified to pH˜3 with 10% aqueous HCl solution. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate (2×8 mL). The combined organic layers were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([O:23][C:24]2[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=2[C:26]([OH:28])=O)[N:16]=1.[CH3:33][CH:34]([S:36]([NH2:39])(=[O:38])=[O:37])[CH3:35].N12CCCN=C1CCCCC2.Cl>O1CCCC1>[CH3:33][CH:34]([S:36]([NH:39][C:26]([C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[O:23][C:17]1[N:18]=[C:19]([O:21][CH3:22])[CH:20]=[C:15]([O:14][CH3:13])[N:16]=1)=[O:28])(=[O:38])=[O:37])[CH3:35]
Reactant: COc1cc(OC)nc(Oc2ccccc2C(=O)O)n1
Reactant: CC(C)S(N)(=O)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1cc(OC)nc(Oc2ccccc2C(=O)NS(=O)(=O)C(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.2 %

Procedure:
To a stirred suspension of 0.33 gram (0.002 mole) of 1,1'-carbonyldiimidazole in 2 mL of tetrahydrofuran was added dropwise a solution of 0.55 gram (0.002 mole) of 2-(4,6-dimethoxypyrimidin-2-yloxy)benzoic acid in 3 mL of tetrahydrofuran. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 30 minutes, and then it was heated to reflux where it was stirred for an additional 30 minutes. After this time the reaction mixture was cooled, and 0.25 gram (0.002 mole) of 1-methylethylsulfonamide (prepared as in Example 1--Step H) was added. Upon completion of addition, the reaction mixture was stirred for 10 minutes, and 0.31 gram (0.002 mole) of 1,8-diazabicyclo[5.4.0]undec-7-ene was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for five hours. The reaction mixture was then poured into aqueous dilute hydrochloric acid. The mixture was extracted with ethyl acetate, and the extract was dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 10% and 20% ethyl acetate in methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure to yield 0.2 gram of 2-[2-(1-methylethylsulfonylaminocarbonyl)phenoxy]-4,6-dimethoxypyrimidine; m.p. 128°-130° C., Compound 9 in Table I. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: N1CCCC1=O.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[C:20]2[CH:21]=[C:22]([N:25]=C=O)[CH:23]=[CH:24][C:19]=2[N:18]([CH3:28])[C:17](=[O:29])[C:16]([CH3:31])([CH3:30])[N:15]=1.ClC1C=CC=CC=1C1C2C=C(NC(N3CCCC3)=O)C=CC=2N(C)C(=O)C(C)(C)N=1>C(OCC)(=O)C.CCOCC>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]2[N:18]([CH3:28])[C:17](=[O:29])[C:16]([CH3:31])([CH3:30])[N:15]=[C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[Cl:7])[C:20]=2[CH:21]=1
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc(N=C=O)ccc21
Agent: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc(NC(=O)N3CCCC3)ccc21
Agent: O=C1CCCN1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc(N)ccc21

Procedure:
From 5.1 g (0.015 mol) of 7-amino-5-(o-chlorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one and pyrrolidone there is obtained, in analogy to the details in Example 4, via [5-(o-chlorophenyl)-2,3-dihydro-1,3,3-trimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]isocyanate, N-[5-(o-chlorophenyl)-2,3-dihydro-1,3,3-trimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-1 -pyrrolidinecarboxamide of melting point 248°-150° (ethyl acetate/ether).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:15]I>C1COCC1>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:15])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c[nH]c2ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1cn(C)c2ccccc12
Reaction time: 0.5 h

Procedure:
3-Acetyl-1H-indole (4.00 g, 0.025 mol) was dissolved in dry THF (100 ml), and treated with 80% sodium hydride (0.794 g, 0.0263 mol) with stirring under Ar. After 0.5 h, methyl iodide (2.36 ml, 0.038 mol) was added. After 20 h, the reaction mixture was evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The organic layer was then dried (Na2SO4), and evaporated under reduced pressure to give the title compound as a pale brown oil which crystallised on standing (4.20 g, 97%).