Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][N:7]1[C:11]([NH2:12])=[C:10]([NH2:13])[CH:9]=[N:8]1.[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][C@H:24]([OH:28])[C:25](O)=[O:26])=[O:20])([CH3:17])([CH3:16])[CH3:15].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(=O)([O-])O.[Na+].[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[NH2:12][C:11]1[N:7]([CH3:6])[N:8]=[CH:9][C:10]=1[NH:13][C:25](=[O:26])[C@@H:24]([OH:28])[CH2:23][CH2:22][NH:21][C:19](=[O:20])[O:18][C:14]([CH3:15])([CH3:16])[CH3:17]
Reactant: Cn1ncc(N)c1N
Reactant: CC(C)(C)OC(=O)NCC[C@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1ncc(NC(=O)[C@@H](O)CCNC(=O)OC(C)(C)C)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
To a suspension of 1-methyl-1H-pyrazole-4,5-diamine sulfate (86 g) in tetrahydrofuran (1.3 L) was added triethylamine (117 ml), and then (2S)-4-[(tert-butoxycarbonyl)amino]-2-hydroxybutanoic acid (82.5 g) was added to the mixture. To the mixture were added 1-hydroxybenzotriazole (58.3 g) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (82.7 g) under ice-cooling. The reaction mixture was stirred at room temperature for 8 hours. To the reaction mixture were added ethyl acetate (1.3 L), saturated aqueous sodium hydrogen carbonate solution and sodium chloride, and the mixture was stirred for 30 minutes. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (1.0 L) six times. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate/tetrahydrofuran (1/1) to give tert-butyl {(3S)-4-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-3-hydroxy-4-oxobutyl}carbamate (69.5 g).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:36][CH:37]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:38][NH:39][C:40]([CH:42]1[CH2:47][CH:46]([CH3:48])[CH2:45][CH2:44][CH:43]1[CH:49]([CH3:51])[CH3:50])=[O:41]>O.C(OCC)(=O)C.C1COCC1>[C:4]([O:3][C:1](=[O:2])[NH:8][CH:9]([C:11](=[O:13])[NH:36][CH:37]([C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[CH2:38][NH:39][C:40]([CH:42]1[CH2:47][CH:46]([CH3:48])[CH2:45][CH2:44][CH:43]1[CH:49]([CH3:51])[CH3:50])=[O:41])[CH3:10])([CH3:5])([CH3:6])[CH3:7]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1CCC(C(C)C)C(C(=O)NCC(N)c2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1CCC(C(C)C)C(C(=O)NCC(NC(=O)C(C)NC(=O)OC(C)(C)C)c2ccccc2)C1
Reaction time: 3 h
Yield: 25.5 %

Procedure:
A 15 mL reaction vessel equipped with a stir bar was charged with THF (15 mL), Boc-(R)-alanine (52 mg, 0.273 mmoles), HOBt (37.87 mg, 0.273 mmoles), EDCl (53 mg, 0.273 mmoles) and TEA (37 μl, 0.273 mmoles). The reaction mixture was stirred for 15 min. whereupon 2-isopropyl-5-methyl-cyclohexanecarboxylic acid (2-amino-2-phenyl-ethyl)-amide (75 mg, 0.248 mmol) was added and stirred for an additional 3 h. Ethyl acetate (10 mL) and H2O (10 mL) were added to the reaction mixture. The heterogeneous mixture was transferred to a separatory funnel where the aqueous phase was separated and re-extracted with ethyl acetate (2×10 mL). The organic phases were combined and washed with 1N HCl (2×10 mL), H2O (1×10 mL), sat NaHCO3 (3×10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (20% ethyl acetate/hexane for elution) provided the title compounds as colorless solid (30 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.C([Li])CCC.[Br:17]C(Cl)(Cl)C(Br)(Cl)Cl>O1CCCC1.CCCCCC>[Br:17][C:10]1[N:5]2[N:4]=[C:3]([O:2][CH3:1])[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: COc1cc2ccccn2n1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc2cccc(Br)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
A solution of 2-methoxypyrazolo[1,5-a]pyridine (7.15 g) [CAS No.59942-88-0] in tetrahydrofuran (140 mL) was cooled to −78° C. under a nitrogen stream, and then a solution of n-butyllithium in hexane (1.6 M; 46 mL) was added dropwise and the mixture was stirred for 30 minutes. A solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (18.9 g) in tetrahydrofuran (30 mL) was added dropwise at −78° C., and stirring was continued for 1 hour. After increasing the temperature of the reaction mixture to room temperature and adding water, extraction was performed with ethyl acetate and the extract was washed with brine. After drying the obtained organic layer over anhydrous magnesium sulfate and filtering it, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (7.1 g) was obtained from the n-hexane:ethyl acetate (50:1) fraction as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([N+:22]([O-])=O)[CH:14]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].C(N(CC)CC)C.[CH3:32][CH:33](N)[CH2:34][OH:35].C(OCC)C>CN(C)C=O>[Br:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([NH:22][CH:33]([CH3:32])[CH2:34][OH:35])[CH:14]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:9])([F:8])[F:10]
Reactant: CC(N)CO
Reactant: Cn1nc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)c(Br)c1C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(CO)Nc1cc(Oc2nn(C)c(C(F)(F)F)c2Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 21 h
Yield: 95.1 %

Procedure:
The dinitrobenzene obtained in Step A (10.0 g, 24.3 mmol) was dissolved in N,N-dimethylformamide (60 cm 3). Triethylamine (5.1 cm3, 36.5 mmol) and DL 2-aminopropanol 2.9 cm3, 36.5 mmol) were added, and the mixture was stirred at room temperature for 21 hours, and then heated at 70° C. for a further 3 hours. The mixture was cooled to room temperature, poured into diethyl ether (500 cm3) and washed with water (3×300 cm3). The organic layer was dried (MgSO4), filtered and evaporated under reduced pressure to give DL 2-[5-(4-bromo-1-methyl-5-trifluoromethyl-1H-pyrazol -3-yloxy)-2-nitrophenylamino]propan-1-ol (10.15 g) as an orange solid m.p 116°-118° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH2:10])=[N:2]1.N[C:12]1[CH:21]=[N:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16]C)=[O:15]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:18]2[CH:19]=[N:20][CH:21]=[CH:12][C:13]=2[C:14]([OH:16])=[O:15])=[N:2]1
Reactant: Nc1noc2ccccc12
Reactant: COC(=O)c1ccncc1N
Product: O=C(O)c1ccncc1Nc1noc2ccccc12
Yield: 2 %

Procedure:
The title compound was prepared in 2% yield from 1,2-benzoxazol-3-amine and methyl 3-aminoisonicotinate according to the procedure for Preparation 1C, followed by hydrolysis according to Example 1. 1H NMR (400 MHz, DMSO-d6): δ 7.49 (1H, s), 7.73-7.90 (4H, m), 8.38 (1H, s), 9.62 (1H, s), 11.32 (1H, br s). [M+H] calc'd for C13H9N3O3, 256; found 256.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:18])[N:4]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5](=[O:11])[N:6]([CH2:8][O:9][CH3:10])[CH:7]=1.N1C(C)=CC(C)=CC=1C.[CH2:28]([S:35](Cl)(=[O:37])=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1.C(OCC)(=O)C>[CH2:28]([S:35]([NH:1][C:2]1[C:3](=[O:18])[N:4]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5](=[O:11])[N:6]([CH2:8][O:9][CH3:10])[CH:7]=1)(=[O:37])=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CCOC(=O)Cn1c(=O)c(N)cn(COC)c1=O
Solvent: C1CCOC1
Solvent: Cc1cc(C)nc(C)c1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1c(=O)c(NS(=O)(=O)Cc2ccccc2)cn(COC)c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred solution of ethyl 5-amino-1-methoxymethyl-uracilylacetate (8.0 g, 31 mmole) and 2,4,6-collidine (13.7 mL, 62 mmole) in tetrahydrofuran (50 mL) is cooled in an ice bath. A solution of benzylsulfonyl chloride (5.93 g, 31 mmole) in tetrahydrofuran (50 mL) is added over a 30-minute period. After addition is complete, the solution is stirred for 1 hour at 0° C., then 3 hours at room temperature. The reaction mixture is diluted with ethyl acetate, washed with 1.0N HCl (until aqueous layer is pH 1), water, saturated sodium bicarbonate, and brine. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is removed. The title compound is isolated.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:7][C:8](=[O:34])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22](=[O:25])[N:21]([CH3:26])[CH:20]=2)=O)=[CH:11][CH:10]=1)[CH:4]([CH3:6])[CH3:5].Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[OH:1][CH2:2][C@H:3]([NH:7][C:8](=[O:34])[C:9]1[CH:10]=[CH:11][C:12]([CH:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH2:16]/[C:17](=[N:36]\[OH:37])/[C:19]2[CH:24]=[CH:23][C:22](=[O:25])[N:21]([CH3:26])[CH:20]=2)=[CH:13][CH:14]=1)[CH:4]([CH3:5])[CH3:6]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N[C@@H](CO)C(C)C)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N[C@@H](CO)C(C)C)cc1

Procedure:
In analogy to example 151, step 3, N—((R)-1-hydroxy-3-methylbutan-2-yl)-4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as an off-white solid containing <10% of the corresponding Z isomer, MS (ESI+): m/z=476.2 [M+H]+.
Reaction SMILES: C1(SC)C=CC=CC=1.C([O:16][C:17]1[CH:26]=[C:25]2[C:20]([C:21]([O:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)=[CH:22][CH:23]=[N:24]2)=[CH:19][C:18]=1[O:37][CH3:38])C1C=CC=CC=1>FC(F)(F)C(O)=O>[CH3:38][O:37][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:17]=1[OH:16])[N:24]=[CH:23][CH:22]=[C:21]2[O:27][C:28]1[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
After adding trifluoroacetic acid (30 ml) and thioanisole (3 ml) to 7-benzyloxy-6-methoxy-4-(4-nitrophenoxy)quinoline (4.0 g), the mixture was heated and stirred at 70° C. for 2 hours.
Reaction SMILES: [I-].CC(OC([N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)(C)C.[H-].[Na+].[I:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41](=[O:46])[C:40]2=O.CC(C)=O>CN(C=O)C>[I:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41](=[O:46])/[C:40]/2=[CH:14]\[C:10]1[NH:9][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: CC(C)(C)OC(=O)n1cccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(I)cc2/C1=C/c1ccc[nH]1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of [[1-[[(1,1-dimethylethyl)oxy]carbonyl]-1H-pyrrol-2-yl]methyl]triphenylphosphonium iodide (2.3 g, 4.0 mmol) (prepared according to the procedure of: V. H. Rawal et. al., J. Org. Chem. 1987, 52(1), 19-28) in 36 mL DMF at 0° C. under argon, was added slowly NaH (0.13 g, 5.4 mmol). The mixture was stirred at 0° C. for 45 min. The solution was then allowed to warm to room temperature and 5-iodoisatin (1.0 g, 3.66 mmol) was added. The solution was heated at reflux for 15 h, at which time acetone (1 mL) was added and the solvent mixture was evaporated. The residue was then purified via flash column chromatography (25% EtOAc/hex) to yield (Z)-1,3-dihydro-5-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 1.05 g, 83%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12](C2C=CC=CC=2C(OCC)=O)[C:11](=[O:24])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:25])[CH:9]=2)[N:4]=1.[NH3:26]>C(OCCO)C>[Cl:25][C:8]1[CH:7]=[CH:6][C:5]2[N:4]=[C:3]3[CH2:2][NH:26][C:11](=[O:24])[C:10]4[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=4[N:12]3[C:11](=[O:24])[C:10]=2[CH:9]=1
Reactant: N
Reactant: CCOC(=O)c1ccccc1-n1c(CCl)nc2ccc(Cl)cc2c1=O
Solvent: CCOCCO
Product: O=C1NCc2nc3ccc(Cl)cc3c(=O)n2-c2ccccc21
Yield: 83 %

Procedure:
18.9 g (0.05 mol) of 2-chloromethyl-3-(2-ethoxycarbonylphenyl)-6-chloro-4H-quinazolin-4-one and 50 ml of liquid ammonia in 150 ml of ethylene glycol monoethyl ether are heated to 60° C. for 3 hours in an autoclave. After cooling the mixture, the colourless crystals are filtered off and washed several times with methanol. 13 g (83% of theory) of 11-chloro-6,7-dihydro-5H,13H-quinazolino[3,2-a][1,4]benzodiazepine-5,13-dione are obtained.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12](OC)=[O:13])[CH:10]=[N:11][C:5]=2[N:4]2[CH2:16][CH2:17][S:18][CH2:19][C@@H:3]12.[H-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-].CO>O1CCCC1.O.C(OCC)(=O)C>[OH:13][CH2:12][C:9]1[CH:10]=[N:11][C:5]2[N:4]3[CH2:16][CH2:17][S:18][CH2:19][C@H:3]3[C:2](=[O:1])[NH:7][C:6]=2[CH:8]=1
Reactant: COC(=O)c1cnc2c(c1)NC(=O)[C@@H]1CSCCN21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C1Nc2cc(CO)cnc2N2CCSC[C@@H]12
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
(R)-methyl 6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazine-3-carboxylate (887 mg, 3.18 mmol) was taken up in tetrahydrofuran (40 mL) in an inert environment. To the stirred suspension at room temperature was added NaH (191 mg, 4.76 mmol, 60% dispersion in mineral oil) and stirred 30 minutes. The reaction was then cooled to −45° C. and lithium aluminum hydride (4.76 mL, 2M in THF) was added. The reaction was stirred at a temperature between −20 and −10° C. for 1 hour. The reaction was then cooled back to −78° C. and methanol (5 ml) followed by water (1 ml) was added. The reaction was allowed to stir at ambient temperature for 2 hours and then poured into ethyl acetate (400 ml) and water (100 ml). The biphasic mixture was stirred vigorously and then filtered through a medium frit. The filtrate was collected. The layers were separated and the aqueous phase was extracted with ethyl acetate (1×100 ml). The organic layers were combined, washed with brine (100 ml), and concentrated to yield 710.8 mg (89%) of the title compound as a white solid. [M+H] calc'd for C11H13N3O2S, 252; found, 252.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N+:10]([O-])=[CH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].C[Si]([C:19]#[N:20])(C)C.CCN(CC)CC>CC#N>[C:19]([C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=1)#[N:20]
Reactant: O=[N+]([O-])c1ccc2c(ccc[n+]2[O-])c1
Reactant: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ccc2cc([N+](=O)[O-])ccc2n1
Temperature: 75 °C
Yield: 35.9 %

Procedure:
To a suspension of compound 45A (400 mg, 2.1 mmol) in MeCN (15 mL) was added trimethylsilylcyanide (0.34 mL, 2.5 mmol), followed by a slow addition of Et3N (0.65 mL, 4.6 mmol). The reaction mixture was heated to 75° C. for 30 min, then cooled to rt, concentrated, dried under vacuum, and purified by silica gel flash chromatography, eluting with CH2Cl2 to give the title compound (150 mg, 36%) as a white solid. LC/MS m/z 200 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:15][O:14][C:13]3[CH:16]=[C:17]4[C:21](=[CH:22][C:12]1=3)[CH2:20][CH2:19][O:18]4)[C:5](=[O:11])[NH:6]2.N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O.Br[CH2:45][C:46]1[O:47][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:49][CH:50]=1.BrCC1CCCCO1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:15][O:14][C:13]3[CH:16]=[C:17]4[C:21](=[CH:22][C:12]1=3)[CH2:20][CH2:19][O:18]4)[C:5](=[O:11])[N:6]2[CH2:45][C:46]1[O:47][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:49][CH:50]=1
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: O=C1Nc2cccc(Cl)c2C12COc1cc3c(cc12)CCO3
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(Cl)c2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 4′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)-5-(trifluoromethyl)furan to replace 2-(bromomethyl)tetrahydro-2H-pyran, 4′-chloro-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b']difuran-3,3′-indol]-2′(1′H)-one was obtained (73%) as a colorless solid: mp 166-169° C.; 1H NMR (300 MHz, CDCl3) δ7.29-7.18 (m, 1H), 7.01 (d, J=8.2 Hz, 1H), 6.89 (d, J=7.82 Hz, 1H), 6.74 (d, J=2.3 Hz, 1H), 6.45-6.34 (m, 2H), 5.11 (d, J=16.2 Hz, 1H), 4.99 (d, J=9.2 Hz, 1H), 4.88 (d, J=9.2 Hz, 1H), 4.81 (d, J=16.2 Hz, 1H), 4.52 (t, J=8.6 Hz, 2H), 2.98 (t, J=8.60 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ177.2, 162.2, 162.0, 151.6, 143.1, 141.8 (q, J=43.0 Hz), 131.6, 130.0, 128.7, 124.6, 118.8 (q, J=267.1 Hz), 119.7, 118.4, 117.1, 112.7, 109.5, 107.2, 92.9, 77.1, 72.4, 58.2, 37.1, 28.9; MS (ES+) m/z 461.9 (M+1), 463.9 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].Cl[C:8]1([F:23])[C:12](Cl)([F:13])[O:11][C:10]([C:19]([F:22])([F:21])[F:20])([C:15]([F:18])([F:17])[F:16])[O:9]1>[Ti](Cl)(Cl)(Cl)Cl.O1CCCC1>[F:13][C:12]1[O:11][C:10]([C:19]([F:20])([F:21])[F:22])([C:15]([F:16])([F:18])[F:17])[O:9][C:8]=1[F:23]
Reactant: FC(F)(F)C1(C(F)(F)F)OC(F)(Cl)C(F)(Cl)O1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: FC1=C(F)OC(C(F)(F)F)(C(F)(F)F)O1

Procedure:
This example was conducted in the same manner as Example 1, except that the reactants were the following: Lithium aluminum hydride (8.0 g, 0.211 mole), titanium tetrachloride (9.84 g, 0.052 mole), 4,5-dichloro-4,5-difluoro- 2,2-bis(trifluoromethyl)-1,3-dioxolane (31.5 g, 0.1 mole) and tetrahydrofuran (100 mL). The yield of this reaction was 53% with 100% conversion.
Reaction SMILES: N1([C:6]([NH:8][CH2:9][CH2:10][O:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])=[O:7])C=CN=C1.Cl.ClCl>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[N:8]([CH2:9][CH2:10][O:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])=[C:6]=[O:7]
Reactant: C=C(C)C(=O)OCCNC(=O)n1ccnc1
Agent: Cl
Agent: ClCl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)OCCN=C=O
Reaction time: 1 h
Yield: 52 %

Procedure:
In a round bottom flask 35.7 g (156 mmole, 97.8%) 2-Methyl-acrylic acid 2-[(imidazole-1-carbonyl)-amino]-ethyl ester (Example 1) were dissolved in about 100 ml chloroform at room temperature (30 min). The clear yellow solution was diluted with about 100 ml toluene. To the resulting turbid dispersion 11.5 g (313 mmole=200% of theory) dry hydrogen chloride were added at about 23° C. within about 30 min, while cooling. A second liquid phase was formed. The reaction mixture was stirred for another hour. At ambient pressure 123 g of chloroform were distilled from the reaction mixture at about 69-74° C. Thereafter, the vessel was kept at about 91-92° C. for about 1 h. Meanwhile imidazolium hydrochloride began to crystallize giving a greenish suspension. After about 1 hour of stirring at room temperature the toluene phase was decanted, precipitated washed with more toluene. The clear yellow phase was evaporated at about 40° C. and about 25 mbar under exclusion of light. This raw product (according to NMR) consisted of MOI with about 18% residual toluene. It was distilled at about 48° C. and about 1.4 mbar. The clear product was stabilized with 200 ppm phenothiazine. A yield of 52% was obtained with the distilled product. Analytics showed 96.8% purity (GC) and 400 ppm residual chlorine.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[C:10](=[O:15])[N:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1)[CH2:8]2)=O.[NH2:28][NH2:29]>C(O)C>[CH3:14][C:12]1[CH:13]=[C:5]([C:3]([NH:28][NH2:29])=[O:2])[CH:6]=[C:7]2[C:11]=1[C:10](=[O:15])[N:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1)[CH2:8]2
Reactant: COC(=O)c1cc(C)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Reactant: NN
Solvent: CCO
Product: Cc1cc(C(=O)NN)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2

Procedure:
7-Methyl-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid methyl ester (190.0 mg, 0.5 mmol) was mixed with hydrazine (in water) 125.0 mg, 2.50 mmol) in ethanol (0.5 mL) and the reaction was refluxed for five hours. The reaction was concentrated to provide the title compound as an off white solid (200.0 mg, 100%). 1H NMR (300 MHz, CDCl3): δ 7.63 (s, 1H), 7.54 (broad s, 1H), 7.31 (m, 2H), 7.18 (d, 2H), 4.75 (s, 2H), 4.22 (s, 2H), 2.74 (s, 3H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:24])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][N:28]=1>>[OH:21][CH2:20][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:30]2[CH:29]=[N:28][C:27]([O:26][CH3:25])=[N:32][CH:31]=2)[N:7]=3)=[O:24])=[CH:14][CH:15]=1)([CH3:23])[CH3:22]
Reactant: COc1ncc(B(O)O)cn1
Reactant: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Product: COc1ncc(-c2ccc3nc(NC(=O)c4ccc(C(C)(C)CO)cc4)sc3n2)cn1
Yield: 33 %

Procedure:
The titled compound (yield=33%, white solid) was prepared using a procedure analogous to that described in connection with 9 (Example 9) except 2F (Example 2) and 2-methoxypyrimidin-5-yl boronic acid were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (s, 6H) 3.49 (d, J=5.05 Hz, 2H) 4.01 (s, 3H) 4.78 (t, J=5.31 Hz, 1H) 7.58 (d, J=8.59 Hz, 2H) 8.10 (d, J=8.59 Hz, 2H) 8.16 (d, J=8.59 Hz, 1H) 8.22-8.29 (m, 1H) 9.33 (s, 2H) 13.02 (s, 1H); ESI-MS: m/z 436.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:35]=[CH:34][C:17]([C:18]([NH:20][C@H:21]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:19])=[CH:16][CH:15]=1)[CH:8]=[CH:7]2)([O-])=O.NN>C(O)C.C1COCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:20][C@H:21]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:19])=[CH:34][CH:35]=1)[CH:8]=[CH:7]2
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(Cn2ccc3cc([N+](=O)[O-])ccc32)cc1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(Cn2ccc3cc(N)ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A large excess of Raney® nickel was added in portions to a stirred solution of ethyl N-{4-[(5-nitro-1H-indol-1-yl)methyl]benzoyl}-L-phenylalaninate (2.36 g, 5 mmol), and hydrazine (1.2 mL, 38 mmol) in 100 mL of ethanol and 15 mL of THF. After stirring at room temperature for 2 h the catalyst was then removed by filtering through a short pad of Celite®521. The filtrate was concentrated to give ethyl N-{4-[(5-amino-1H-indol-1-yl)methyl]benzoyl}phenylalaninate as an off-white solid: MS (ESI) m/z 442.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.[CH2:16]=[O:17]>C(O)C>[OH:17][CH2:16][N:11]1[C:10](=[O:13])[CH:9]=[CH:8][C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=2)=[N:12]1
Reactant: C=O
Reactant: O=c1ccc(Oc2ccc(Cl)cc2)n[nH]1
Solvent: CCO
Product: O=c1ccc(Oc2ccc(Cl)cc2)nn1CO
Reaction time: 1 h

Procedure:
Into a solution, at reflux, of 7 g 6-(4-chlorophenoxy)-3-pyridazinone in 100 ml ethanol, there are poured 30 ml of a 20% aqueous formaldehyde solution, and then after 1 hour a further 30 ml. After refluxing for 3 hours, the solution is concentrated to half, and 100 ml water are introduced into the mixture from which 4.5 g of final product are extracted in chloroform. After recrystallisation from benzene, the product melts at 162° C. (with decomposition)