Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:11]=[CH:12][N:13]3[C:18]=2[C:17](=[O:19])[N:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([C@@H:26]([NH:28]C(=O)OC(C)(C)C)[CH3:27])=[N:14]3)[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C(O)=O>>[NH2:28][C@H:26]([C:15]1[N:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](=[O:19])[C:18]2=[C:10]([S:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:11]=[CH:12][N:13]2[N:14]=1)[CH3:27]
Reactant: COc1cccc(Sc2ccn3nc([C@H](C)NC(=O)OC(C)(C)C)n(-c4ccccc4)c(=O)c23)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(Sc2ccn3nc([C@H](C)N)n(-c4ccccc4)c(=O)c23)c1
Yield: 84.7 %

Procedure:
(S)-tert-Butyl (1-(5-((3-methoxyphenyl)thio)-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)carbamate (154 mg, 0.31 mmol) was treated with trifluoroacetic acid (240 μl, 3.12 mmol) according to the method of Preparation 6 to obtain 103 mg (78% yield) of the title compound as an oil. Purity 92%.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C1C(=O)N([Br:17])C(=O)C1>ClCCl>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Br:17])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccccc1N
Solvent: ClCCl
Product: N#Cc1cc(Br)ccc1N
Temperature: 0 °C
Reaction time: 3 h
Yield: 86.4 %

Procedure:
2-Aminobenzonitrile (5.0 g, 42.3 mmol) was taken into dichloromethane (60 mL). NBS (7.54 g, 42.3 mmol) was added and stirred at 0° C. for 3 h. The reaction mixture was diluted with dichloromethane and washed with brine, dried over MgSO4. The crude product was purified by column chromatography (hexane/ethyl acetate=10/1) to afford the titled compound (7.20 g, 87%). 1H NMR (400 MHz, DMSO-d6): δ 6.22 (s, 2H), 6.75 (d, J=9.2 Hz, 1H), 7.42 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.58 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=O.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[Cl:1][CH2:2][CH2:3][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2
Reactant: O=C1Cc2cc(C(=O)CCl)ccc2N1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1Cc2cc(CCCl)ccc2N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 100 ml round-bottomed flask equipped with condenser and N2 inlet were added 5.0 g (23.9 mmol) of 5-chloroacetyl oxindole and 18.5 ml trifluoroacetic acid. To the stirring solution was added 8.77 ml (54.9 mmol) of triethylsilane while cooling to prevent exotherm, and the reaction stirred 16 hours at room temperature. The reaction was then poured into ice water, stirred, and the beige solid filtered, washed with water and hexane, and dried to give 5-(2-chloroethyl)oxindole, m.p. 168°-170° C., 3.0 g (64%).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.S(=O)(=O)(O)O.O.O.[I:22](O)(=O)(=O)=O.S([O-])(O)=O.[Na+]>O.C(O)(=O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([I:22])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)Cc1ccccc1-2
Reactant: [O-][I+3]([O-])([O-])O
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Brc1ccc2c(c1)Cc1cc(I)ccc1-2
Temperature: 75 °C
Yield: 382.7 %

Procedure:
A mixture of 2-bromofluorene (compound 19) (25.0 g, 0.1020 mol), glacial acetic acid (250 cm3), concentrated sulphuric acid (3 cm3) and water (20 cm3) became homogeneous on heating to 75° C. Periodic acid dihydrate (H5IO6, 4.56 g, 0.0200 mol) and pulverised 12 (10.2 g, 0.0402 mol) were added. The initial deep-purple colour changed to a brown during 2 h of heating and stirring at 75° C. Upon dilution with sodium hydrogensulphite (2.50 g) in water (25 cm3), the colour changed to yellow. The solution was subsequently diluted with water (500 cm3) and cooled to 0° C. to give a yellow precipitate. The excess liquid was decanted and the solid filtered off, washed repeatedly with cold ethanol (4×50 cm3), aqueous NaOH (5% solution, 4×50 cm3) and with water (4×50 cm3) to leave a yellow powder. The product was recrystallised from a solvent mixture of DCM and ethanol to yield a yellow powder (28.4 g, 74.9%). Melting point/° C.: 185.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[CH2:13][CH2:12][N:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([N+:23]([O-:25])=[O:24])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][NH2:37].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:26]([F:29])([F:27])[F:28])[CH2:13][CH2:12][N:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:37][CH2:36][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=4)=[O:20])=[C:16]([N+:23]([O-:25])=[O:24])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: NCc1ccccn1
Reactant: O=C(O)c1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccccn1)c1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.4 %

Procedure:
To the solution of 4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-nitrobenzoic acid (0.3 g) and 2-picolylamine (0.07 g) in DMF was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.13 g) and 1-hydroxybenzotriazole monohydrate (0.01 g), and the mixture was stirred for 6 hour at room temperature. The reaction solution was poured into water, which was then extracted twice with ethyl acetate. The organic layer was combined, which was then washed with water and dried over anhydrous magnesium sulfate. After the drying agent, was filtered off, the solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield 4-[3(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-nitro-N-(pyridine-2-ylmethyl)benzamide (0.19 g). 1H-NMR (CDCl3) δ: 2.54-2.65 (1H, m), 2.89-2.97 (1H, m), 3.51-3.67 (2H, m), 3.83 (1H, d), 4.13 (1H, d), 4.74 (2H, d), 6.75 (1H, dd), 7.08 (1H, d), 7.15-7.23 (2H, m), 7.28 (2H, br s), 7.37 (1H, d), 7.41 (1H, t), 7.49 (1H, d), 7.70 (1H, td), 8.52 (1H, d).
Reaction SMILES: Cl[C:2]1[C:3]([F:23])=[CH:4][C:5]2[C:6]([CH:22]=1)=[N:7][C:8]1[N:9]([CH:19]3[CH2:21][CH2:20]3)[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:36][NH:35][CH2:34][CH2:33][NH:32]2)=[CH:27][CH:26]=1>C(N(CC)CC)C>[CH:19]1([N:9]2[C:8]3[N:7]=[C:6]4[CH:22]=[C:2]([N:35]5[CH2:34][CH2:33][NH:32][CH:31]([C:28]6[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=6)[CH2:36]5)[C:3]([F:23])=[CH:4][C:5]4=[CH:14][C:13]=3[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]2)[CH2:21][CH2:20]1
Reactant: Fc1ccc(C2CNCCN2)cc1
Reactant: O=C(O)c1cn(C2CC2)c2nc3cc(Cl)c(F)cc3cc2c1=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(C2CC2)c2nc3cc(N4CCNC(c5ccc(F)cc5)C4)c(F)cc3cc2c1=O
Yield: 37.4 %

Procedure:
(RS)-1-Cyclopropyl-7-fluoro-8-[3-(4-fluorophenyl)-1-piperazinyl]-4-oxo-1,4-dihydrobenzo [b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 11 below, but starting with 8-chloro-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (2 g), (RS)-2-(4-fluorophenyl)piperazine (6.534 g) and triethylamine (9 cc). The reaction mixture is concentrated under reduced pressure (20 kPa) at a temperature in the region of 60° C. The dry extract is taken up with water (20 cc) and acetic acid (0.5 cc). The insoluble matter is drained and washed with water (2×5 cc). After 1 recrystallization in a mixture of dimethylformamide (37 cc) and ethanol (37 cc), (RS)-1-cyclopropyl-7-fluoro-8-[3-(4-fluorophenyl) -1-piperazinyl]-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid (1.07 g) is obtained in the form of a yellow solid, m.p. 306° C.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([NH2:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:11]([NH:23][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCN
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCNS(=O)(=O)c1ccccc1
Temperature: 40 °C
Yield: 82.8 %

Procedure:
Benzenesulfonyl chloride (353 g, 2 mol) was added dropwise to a toluene (2000 mL) solution of dodecylamine (371 g, 2 mol) and triethylamine (203 g, 2 mol) with ice bath cooling. During the one hour addition period, the temperature increased to about 40° C. After filtration of the triethylamine hydrochloride, the toluene solution was washed with dilute HCl, dilute NaOH and water. After drying over magnesium sulfate, the toluene was removed in vacuo and the precipitate slurried in hexane and filtered to give 539 g of product. Melting point 57-60° C. Calculated for C18H32NO2S 326, found 326. 1H NMR (CDCl3) δ0.88 (t, 3, CH3), 1.24 (d, 18, CH2), 1.45 (s, 2, CH2), 4.66 (sb, 1, NH), 7.49-7.84 (m, 5, arom.).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.O[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([C@:21]1([CH3:27])[CH2:25][O:24][C:23](=[O:26])[NH:22]1)[CH:15]=[CH:14]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CC(=O)OCC>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH:5]([O:8][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([C@:21]2([CH3:27])[CH2:25][O:24][C:23](=[O:26])[NH:22]2)[CH:15]=[CH:14]3)[CH2:4][CH2:3]1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Reactant: CC1(C)CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4,4-Dimethylcyclohexanol (63.2 mg, 0.000493 mol), (R)-4-(6-hydroxynaphthalen-2-yl)-4-methyl-oxazolidin-2-one (100 mg, 0.0004 mol), triphenylphosphine (129 mg, 0.000493 mol), and tetrahydrofuran (4 mL, 0.05 mol), diisopropyl azodicarboxylate (0.0971 mL, 0.000493 mol) was added dropwise and was stirred at room temperature overnight. The mixture was diluted with EA and washed with 5% citric acid and brine then dried with magnesium sulfate and concentrated. The crude was taken up into DCM and subjected to ISCO combiflash purification with EtOAc/hexane (0-70) to give product.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[O:11][C:12]([C:16]([O:18]CC)=[O:17])=[CH:13][C:14](=[O:15])[C:3]1=2>[OH-].[Na+]>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[O:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][C:14](=[O:15])[C:3]1=2
Reactant: CCOC(=O)c1cc(=O)c2c(o1)c1ccccc1n2C
Agent: [Na+]
Agent: [OH-]
Product: Cn1c2ccccc2c2oc(C(=O)O)cc(=O)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5.40g (0.020 mole) of ethyl 4,5-dihydro-5-methyl-4-oxopyrano[3,2-b]indole-2-carboxylate in 80ml of 1% aqueous sodium hydroxide was stirred at room temperature for 30 min. The nearly one-phase mixture was extracted twice with 50ml CH2Cl2 and the aqueous layer was cooled in ice and acidified with 4N HCl. The gelatinous yellow crude product was filtered, digested for a few minutes on a steam bath with 100ml hot water and then re-filtered. Recrystallization from ab. EtOH gave yellow needles of mpt. 280°-dec.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][C:4](=[O:6])[NH2:5].ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:40][CH2:41][C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43]>CN(C=O)C>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:40][CH2:41][C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])=[O:9])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
58 g BocAsnOH (0.25 moles) and 29 g HOSu are dissolved in 250 ml DMF and cooled to -20°. 52 g DCC dissolved in 250 ml DMF is added. After 4 hours stirring at room temperature 85 g GlyOBzl, pTos and 35 ml TEA is added. After stirring overnight the DCU i filtered off, DMF removed in vacuo on a Rotavap, and the resulting oil dissolved in EtAc. After extraction with sat. NaCl, sat. NaHCO3, and 10% citric acid, the solvent is dried with Na2SO4 and evaporated. The resulting crystalline ma is dried in a desiccator. Yield: 64 g (67%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[CH2:10][C@@H:11]([OH:16])[CH2:12][C:13]([NH2:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:17])[CH2:10][C@@H:11]([O:16][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:12][C:13]([NH2:15])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)C[C@H](O)CC(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CC(N)=O)CC(=O)OCc1ccccc1
Temperature: 5 °C

Procedure:
(S)-Benzyl-3-hydroxyglutaramate (100 g) was dissolved in dimethyl formamide. To this Imidazole (35 g) was added and the solution was cooled to 5° C. To this a solution of tert-butyldimethylsilylchloride (68.5 g) dissolved in dimethyl formamide (250 ml) was added under cooling. The mixture was warmed to 20-25° C. and stirred. The reaction mixture was cooled and quenched with water. To the reaction mixture ethyl acetate and water was added and stirred. The layers were separated and the organic phase was washed thrice with water. The organic phase was evaporated under reduced pressure to yield (S)-benzyl-3-(tert-butyl dimethylsilyloxy)glutaramate as oil.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[O:15][CH2:14][CH2:13][O:12]2)[N:6]=1)=[NH:4].N[CH2:17][CH2:18][SH:19]>C(Cl)(Cl)Cl>[S:19]1[CH2:18][CH2:17][N:4]=[C:3]1[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[O:12][CH2:13][CH2:14][O:15]2)[N:6]=1
Reactant: NCCS
Reactant: COC(=N)c1cccc(C2OCCO2)n1
Solvent: ClC(Cl)Cl
Product: c1cc(C2=NCCS2)nc(C2OCCO2)c1
Temperature: 130 °C
Yield: 97 %

Procedure:
1 g of 6-[1,3]dioxolan-2-yl-pyridine-2-carboximidic acid methyl ester (4.80 mmol) and 0.47 g of 2-aminoethanethiol (2.16 mmol) are mixed. The mixture is heated at 130° C. for 1 hour 30 minutes. The reaction mixture is taken up in chloroform, washed with water and then dried over magnesium sulfate. After filtration and evaporation of the solvent, the title product is isolated by chromatography on a silica column (eluent: chloroform/methanol; 98:2). 1.10 g of solid are recovered.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:15][C:14](=[O:16])[CH:13]([CH3:17])[CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:15]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:28])([F:29])[F:30])[CH:21]=2)[C:14](=[O:16])[CH:13]([CH3:17])[CH2:12]1
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Reactant: COc1cccc(OC)c1C1CC(C)C(=O)N1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(OC(F)(F)F)c1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 5-(2,6-dimethoxyphenyl)-3-methylpyrrolidin-2-one with commercially available 1-(bromomethyl)-3-(trifluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.93 min.; [M+H]+: 410.18 g/mol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[CH:15]3[CH:10]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14]3)[N:9]=2)=[CH:4][CH:3]=1.[C:27]1([CH2:33][C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>C(#N)C.C(O)C>[CH3:25][O:24][C:19]1[C:20]([O:22][CH3:23])=[CH:21][C:16]2[C@H:15]3[C@H:10]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:34](=[O:35])[CH2:33][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:3][CH:4]=3)[C:17]=2[CH:18]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1cc2c(cc1OC)C1CN(C)CCC1N=C2c1ccc(N)cc1
Agent: Cl
Solvent: CCO
Solvent: CC#N
Product: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(NC(=O)Cc2ccccc2)cc1

Procedure:
30g of 6-(4-aminophenyl)-8,9-dimethoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridine and 6,0 g of phenylacetic acid chloride are heated to the boil under reflux in 70 ml of acetonitrile for 7 hours. After working up in a manner analogous to that described in Example 31, and upon adding dilute hydrochloric acid in ethanol to the crude product, the dihydrochloride form of the title compound slowly crystallizes (melting point 240°-245°).
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(O[C:6](C)([CH3:8])[CH3:7])=O.[N+:17]([C:20]1[CH:21]=[N:22][NH:23][CH:24]=1)([O-:19])=[O:18].CC(O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:6]([N:22]1[CH:21]=[C:20]([N+:17]([O-:19])=[O:18])[CH:24]=[N:23]1)([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)n1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 149 %

Procedure:
Di-tert-butyl azodicarboxylate (1.59 g, 6.91 mmol) was added to a solution of 4-nitro-1H-pyrazole (601 mg, 5.32 mmol), 2-propanol (319 mg, 5.32 mmol) and triphenylphosphine (1.67 g, 6.36 mmol) in tetrahydrofuran (25 mL) over 3 minutes and the mixture was stirred at room temperature for 16 h. After this time, the reaction was concentrated under reduced pressure and the resulting residue purified by chromatography (silica, gradient, 1:4 ethyl acetate/heptane to 7:3 ethyl acetate/heptane) to afford 1-isopropyl-4-nitro-1H-pyrazole (1) (1.23 g, >100%) as an impure off-white solid, which was used without further purification: 1H NMR (300 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.24 (s, 1H), 4.58 (m, 1H), 1.42 (d, J=6.6 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Br:9])[CH:6]=[CH:7][CH:8]=1.[C:10](Cl)(=[O:14])[C:11]([CH3:13])=[CH2:12].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Br:9][C:5]1[CH:6]=[CH:7][C:8]([C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(Br)c1
Reactant: C=C(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=C(C)C(=O)c1ccc(Br)cc1OC
Yield: 44.7 %

Procedure:
3-methoxybromobenzene (238 mg), methacryloyl chloride (110 mg), and aluminium chloride (160 mg) were reacted in dichloromethane (1.5 mL) at from 0° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (120 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:37]1([CH2:43][CH2:44]O)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[N:37]1([CH2:43][CH2:44][O:1][C:2]2[CH:7]=[N:6][C:5]([C:8]3[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=3)[C:11]([O:13][CH3:14])=[O:12])=[N:4][CH:3]=2)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1
Reactant: OCCN1CCOCC1
Reactant: COC(=O)c1cccc(-c2ncc(O)cn2)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(-c2ncc(OCCN3CCOCC3)cn2)c1

Procedure:
A solution, kept under nitrogen, of 10.1 g (44 mmol) of methyl 3-(5-hydroxypyrimidin-2-yl)benzoate, 17.3 g (66 mmol) of triphenylphosphine and 5.9 ml (48.4 mmol) of 2-morpholin-4-ylethanol in 100 ml of THF is cooled in an ice bath, and 12.95 ml (66 mmol) of diisopropyl azodicarboxylate are slowly added dropwise with stirring. After stirring at room temperature for 2 hours, the reaction mixture is evaporated in vacuo. The residue is taken up in 100 ml of dichloromethane and 100 ml of water. The organic phase is dried over sodium sulfate and evaporated. The residue is recrystallised from isopropanol: methyl 3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzoate as beige crystals; m.p. 89-91°; ESI 344 (M+H); HPLC: 2.06 min (method A).
Reaction SMILES: OO.[C:3]([C:5]1[C:6]([O:11][CH:12]2[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[O:17][CH2:16][CH2:15][N:14]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:13]2)=[N:7][CH:8]=[CH:9][CH:10]=1)#[N:4].C(=O)([O-])[O-:35].[K+].[K+].O>CS(C)=O>[C:3]([C:5]1[C:6]([O:11][CH:12]2[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[O:17][CH2:16][CH2:15][N:14]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:13]2)=[N:7][CH:8]=[CH:9][CH:10]=1)(=[O:35])[NH2:4]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(Oc2ncccc2C#N)C1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(Oc2ncccc2C(N)=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.9 %

Procedure:
33% Aqueous hydrogen peroxide (1 mL) was added to a solution of tert-butyl (6RS,7SR)-6-[(3-cyanopyridin-2-yl)oxy]-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (100 mg) and potassium carbonate (45 mg) in DMSO (3 mL), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and HPLC to give the title compound (57 mg).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.S([N:32]=[N+:33]=[N-])(C1C=CC(C)=CC=1)(=O)=O>C(O)C>[N+:32](=[C:10]1[C:9](=[O:14])[CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][C:11]1=[O:13])=[N-:33]
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: [N-]=[N+]=C1C(=O)CC(c2ccccc2)CC1=O
Yield: 36.9 %

Procedure:
A solution of 20.0 g (0.106 mol) of 5-phenylcyclohexane-1,3-dione in 75 ml ethanol was cooled to -10° C. and stirred magnetically under nitrogen. To the mixture was added 10.75 g (0.106 mol) of triethylamine. The tosyl azide (20.95 g 0.106 mol) was added all at once, and the mixture stirred for one hour at C-5° C. The solvent was removed under vacuum at a temperature less than 40° C. To the residue was added 200 ml ether, and the mixture extracted with a solution containing 3.1 g potassium hydroxide in 200 ml of water. The ethereal solution was dried over anhydrous MgSO4 filtered and the solvent removed to give a yellow solid which was recrystallized from ethanol-hexane to give 8.38 g (32%) of 2-diazo-5-phenylcyclohexane-1,3-dione as yellow crystals, mp 122°-124° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:11][CH2:12][P:13]([CH2:16][NH2:17])(=[O:15])[OH:14]>N1C=CC=CC=1>[C:1]([NH:11][CH2:12][P:13]([CH2:16][NH:17][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:14])[OH:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCP(=O)(O)CN
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(NCP(=O)(O)CNC(=O)c1ccccc1)c1ccccc1
Yield: 78.5 %

Procedure:
Benzoyl chloride (1.8 ml; 15.49 mmol) is added slowly with stirring at 0° C. to a solution of bis(aminomethyl)phosphinic acid hydrochloride (1.20 g; 7.48 mmol) in pyridine (8 ml). The reaction mixture is concentrated under reduced pressure. The residue is taken up in 5% hydrochloric acid (60 ml). The aqueous phase is extracted with ethyl acetate (3×60 ml). The combined organic phases are dried (sodium sulfate) and concentrated under reduced pressure. The phosphinic acid 2 (1.95 g) is obtained as a crude product.