Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][NH2:11])=[O:9])[CH:5]=[N:6][CH:7]=1.CN1CCOCC1.[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][NH:11][C:21](=[O:22])[CH2:20][Cl:19])=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: NNC(=O)c1cncc(Br)c1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(CCl)NNC(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.1 %

Procedure:
To an ice-cold suspension of 5-bromo-3-pyridinecarbohydrazide (3.0 g, 13.88 mmol) in anhydrous CH2Cl2 (60 mL) was added 4-methyl-morpholine (2.1 g, 20.82 mmol), followed by dropwise addition of chloroacetyl chloride (1.88 g, 16.67 mmol). The cold bath was then removed and the mixture stirred at rt for 15 h. Heavy precipitation occurred and the mixture was diluted with additional CH2Cl2 (50 mL) and stirring continued for 24 h. The solids were collected by filtration and washed with CH2Cl2 to afford the title compound (3.66 g, 90% yield): MS (ES) m/z 292 and 294 (M+1 Br isotopes).
Reaction SMILES: [CH2:1]([N:4]([CH2:12][C:13](N(OC)C)=[O:14])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3].[C:19]1([Mg]Br)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH2:1]([N:4]([CH2:12][C:13]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:14])[C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10])[CH:2]=[CH2:3]
Reactant: C=CCN(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: C=CCN(CC(=O)c1ccccc1)C(=O)OC(C)(C)C
Yield: 75 %

Procedure:
To a solution of tert-butyl N-allyl-N-[2-(methoxy(methyl)amino)-2-oxo-ethyl]carbamate (4.0 g, 15.5 mmol) in THF (54 mL) cooled to −20° C. is added drop wise phenyl magnesium bromide (10.3 ml, 3 M in diethyl ether). The reaction is monitored by TLC, carefully quenched with saturated ammonium chloride in water (20 mL), diluted with water (100 mL) and extracted with dichloromethane. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by silica gel flash chromatography, eluting with hexane/ethyl acetate (1:0) to hexane/ethyl acetate (5:1) to give the title compound (3.2 g, 75%). 1H NMR (CDCl3) Mixture of two rotamers (51:49) δ 1.47, 1.35 (s, 9H), 3.91, 3.99 (d, 2H), 4.52, 4.65 (s, 2H), 5.07-5.16 (m, 2H), 5.72-5.87 (m, 1H), 7.41-7.50 (m, 2H), 7.52-7.60 (m, 1H), 7.88-7.95 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7][C:6]2=[O:13])[CH3:2].[CH2:14](N(CC)CC)C.IC>C1COCC1>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:14])[CH2:8][CH2:7][C:6]2=[O:13])[CH3:2]
Reactant: CCc1ccc2c(c1)C(=O)CCN2
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CI
Product: CCc1ccc2c(c1)C(=O)CCN2C
Temperature: 70 °C
Yield: 30 %

Procedure:
To a solution of 6-ethyl-2,3-dihydroquinolin-4(1H)-one (1.00 g) in THF (25 mL) was added triethylamine (0.64 g) followed by iodomethane (0.89 g). The mixture was refluxed at 70° C. overnight. The solvent was stripped under reduced pressure, and the residue was partitioned between aqueous sodium bicarbonate and dichloromethane. The organics were extracted three times, washed with brine, dried with sodium sulfate, filtered, and concentrated. Chromatography was used to purify the title compound using a 40% ethyl acetate in heptane solvent solution. 0.32 g of the title product were recovered. (30% yield). MS (ESI+) for C12H15NO m/z 190.10 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH2:12])[CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][N:16]=1.CN1C(=O)CCC1>O>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([C:14]([F:25])([F:13])[F:24])=[N:16][CH:17]=2)[CH:3]=1
Reactant: Cc1cc2nc(N)cc(Cl)n2n1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)nc1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc2nc(NC(=O)c3ccc(C(F)(F)F)nc3)cc(Cl)n2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 20 ml scintillation vial was added 7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-amine (1J, 237 mg, 1.30 mmol), 6-(trifluoromethyl)nicotinoyl chloride (328 mg, 1.57 mmol), and NMP (5 mL) and the reaction mixture was stirred at rt for 1 hr. The reaction mixture was then diluted with water, filtered, and the filter cake rinsed thoroughly with water. Drying with suction under a stream of dry nitrogen resulted in the desired product N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-6-(trifluoromethyl)nicotinamide (12A) as a pink solid. 1H NMR (DMSO-d6) δ: 11.87 (s, 1H), 9.29 (d, J=2.3 Hz, 1H), 8.62 (dd, J=8.0, 1.9 Hz, 1H), 8.11 (d, J=8.3 Hz, 1H), 8.04 (s, 1H), 6.51 (s, 1H), 2.46 (s, 3H); ESI-MS: m/z 356.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)[CH2:5][O:4][CH2:3]1.[H-].[Na+].[CH3:16]I>CN(C=O)C.O>[CH3:16][O:1][C:2]1([C:6]2[CH:7]=[CH:8][C:9]([C:10]#[N:11])=[CH:12][CH:13]=2)[CH2:3][O:4][CH2:5]1
Reactant: CI
Reactant: N#Cc1ccc(C2(O)COC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1(c2ccc(C#N)cc2)COC1

Procedure:
To a solution of 4-(3-hydroxyoxetan-3-yl)benzonitrile (Step 1 of Intermediate O, 600 mg, 3.43 mmol) in DMF (12.5 mL) was added sodium hydride (60% suspension in mineral oil, 151 mg, 3.77 mmol) at a temperature of ˜5° C. The reaction mixture was allowed to stirr for 1 h at this temperature, before methyl iodide (256 μL, 4.11 mmol) was added. Stirring was continued at rt over night. The mixture was diluted with water and extracted with diethyl ether. The organic extract was dried with anhydrous magnesium sulfate and filtered. After evaporation of the solvent, the crude product was purified by MPLC (silica, cyclohexane/ethyl acetate 20:1→4:1) to afford the title compound in pure form (566 mg, 87%): 1H NMR (500 MHz, DMSO-d6) δ 7.93 (d, 2H), 7.68 (d, 2H), 4.81 (d, 2H), 4.73 (d, 2H), 3.05 (s, 3H); ES-MS m/z 190 (MH)+; HPLC RT (Method E) 1.22 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:25])[CH:3]=1.[S:26]1(=[O:32])(=[O:31])[CH2:30][CH2:29][CH2:28][NH:27]1>>[O:31]=[S:26]1(=[O:32])[CH2:30][CH2:29][CH2:28][N:27]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:25])[CH:3]=1
Reactant: O=S1(=O)CCCN1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C)CC2)c(C)c1
Yield: 68.7 %

Procedure:
Using (4-bromo-2-methylphenyl) [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (402 mg) described in Preparation Example 253 and isothiazolidine 1,1-dioxide (158 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (304 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][N:8]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=2)[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[N-:33]=[N+:34]=[N-:35].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[NH:33]1[C:29]([C:25]2[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=2)[CH2:22][N:8]([CH2:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:32][CH:31]=2)[CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)=[N:30][N:35]=[N:34]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(N(CCc2ccc(Cl)cc2)Cc2cccc(C#N)c2)CC1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(N(CCc2ccc(Cl)cc2)Cc2cccc(-c3nnn[nH]3)c2)CC1
Temperature: 25 °C
Yield: 60 %

Procedure:
tert-Butyl 4-((4-chlorophenethyl)(3-cyanobenzyl)amino)piperidine-1-carboxylate obtained in Step 1 was dissolved in toluene (5 mL/mmol) and sodium azide (3 equiv) and triethylamine hydrochloride (0.1 equiv) were added to this solution. The heterogeneous mixture was refluxed for 3 days after which time the starting material could no longer be detected. After cooling down to ambient temperature the solids were filtered off and the solvent was stripped off in vacuo. The crude product was purified by silica gel chromatography (yield 60%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:27])[CH2:18][CH:19]2[CH2:24][C:23](=[O:25])[NH:22][C:21](=[O:26])[CH2:20]2)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]([O:32][CH3:33])=[O:31].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:27])[CH2:18][CH:19]2[CH2:24][C:23](=[O:25])[N:22]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:21](=[O:26])[CH2:20]2)[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)CC2CC(=O)NC(=O)C2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN1C(=O)CC(CC(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)CC1=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 79.2 %

Procedure:
A suspension of 4-{2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}piperidine-2,6-dione (Example 14, 0.500 g, 1.35 mmol), methyl bromoacetate (0.247 g, 1.62 mmol), and potassium carbonate (0.56 g, 4.05 mmol) in DMF (6 mL) was stirred at 60° C. for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate solution and brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to give the crude product. The product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=50:50 to 0:100) to provide methyl (4-{2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}-2,6-dioxopiperidin-1-yl)acetate (0.474 g, 79%) as a white amorphous.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[O:9][C:8]([C:14]([O-:16])=[O:15])=[C:7]([C:17]1[S:18][CH:19]=[C:20]([CH3:22])[N:21]=1)[C:6]2=[O:23])[CH3:2].[C:24]1(O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl.C(OCC)(=O)C>[C:24]1([O:15][C:14]([C:8]2[O:9][C:10]3[C:5]([C:6](=[O:23])[C:7]=2[C:17]2[S:18][CH:19]=[C:20]([CH3:22])[N:21]=2)=[CH:4][C:3]([CH2:1][CH3:2])=[C:12]([OH:13])[CH:11]=3)=[O:16])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCc1cc2c(=O)c(-c3nc(C)cs3)c(C(=O)[O-])oc2cc1O
Reactant: Oc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)c(-c3nc(C)cs3)c(C(=O)Oc3ccccc3)oc2cc1O
Reaction time: 20 h
Yield: 40.9 %

Procedure:
In a 5 mL Schlenk tube 18 mg (0.054 mmol) 6-ethyl-7-hydroxy-3-[(4-methyl)-1,3-thiazol-2-yl]-4-oxo-4H-chromene-2-carboxylate 10 (Aldrich, no. R66,464-2) were suspended in 0.5 mL methylene chloride. Then 51 mg (0.54 mmol) phenol and 18 μl (0.108 mmol) triflate anhydride were added at ambient temperature. The resulting mixture was stirred for 20 hours, diluted in 10 mL of ethyl acetate and washed with water and saturated solutions of sodium bicarbonate and sodium chloride. The organic layer was separated, dried over magnesium sulfate and filtered. Evaporation of the solvent on a rotavapor yielded 9 mg of a yellow solid. This crude product was used without further purification.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([NH:22][CH3:23])[CH:14]=1)=[O:12].C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)C>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]([O:10][CH3:9])=[O:12])=[CH:14][C:15]=1[NH:22][CH3:23]
Reactant: CNc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CNc1cc(C(=O)OC)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
Add an aqueous solution of sodium hydrosulfite (17.4 g, 100 mmol in 80 mL of water) to methyl-3-(methylamino)-4-nitrobenzene carboxylate (855 mg, 4.75 mmol) in tetrahydrofuran (70 mL) and ethanol (30 mL) at 0° C. The orange solution turned to an orange suspension upon addition. Stir the mixture at room temperature for 2 hours. The orange suspension turned to a yellow suspension over this time. Add saturated sodium bicarbonate (100 mL) then the yellow suspension turned colorless. Extract the mixture with ethyl acetate (2×100 mL). Wash the combined organics with brine (30 mL). Dry over magnesium sulfate, filter, concentrate, and dry under high vacuum to yield methyl 4-amino-3-(methylamino)benzoate (586 mg, 68%) as a yellow oil. The resulting oil began to crystallize upon standing after 10 minutes. 1H NMR (400 MHz, CDCl3) δ ppm 2.89 (s, 3H), 3.37-3.81 (m, 2H), 3.85 (s, 3H), 6.67 (d, J=8.01 Hz, 1H), 7.33 (d, J=1.37 Hz, 1H), 7.44 (dd, J=8.11, 1.66 Hz, 1H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:14]([CH2:15][C@@H:16]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][C:12]([Br:28])=[C:11]2[C:7]=1[CH:8]=[N:9][NH:10]2)(=[O:3])[CH3:2].[Br:29]N1C(=O)CCC1=O>ClCCl>[C:1]([O:4][CH2:5][C:6]1[C:14]([CH2:15][C@@H:16]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][C:12]([Br:28])=[C:11]2[C:7]=1[C:8]([Br:29])=[N:9][NH:10]2)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C[C@H](Cc1cc(Br)c2[nH]ncc2c1COC(C)=O)C(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)C[C@H](Cc1cc(Br)c2[nH]nc(Br)c2c1COC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
(S)-Diethyl 2-((4-(acetoxymethyl)-7-bromo-1H-indazol-5-yl)methyl)succinate (555 mg, 1.219 mmol) was dissolved in dichloromethane (20 mL). N-Bromosuccinimide (250 mg, 1.405 mmol) was added to the mixture followed by a small amount of silica gel. Reaction stirred at room temperature for 1 hour. Mixture was concentrated some by roto-vap. Silica gel chromatography eluting ethyl acetate-hexanes afforded the title compound as clear colorless oil in 84% yield. MS (M−H)−=533.1, 531.2, 535.1.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[CH:9]=2)=[CH:6][CH:7]=1.[NH2:14][NH2:15]>C(O)(CC)C.O>[CH3:13][C:10]1[CH:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([NH:14][NH2:15])=[CH:7][CH:6]=2)[S:12][N:11]=1
Reactant: NN
Reactant: Cc1cc(-c2ccc(Cl)nn2)sn1
Solvent: O
Solvent: CCC(C)O
Product: Cc1cc(-c2ccc(NN)nn2)sn1
Temperature: 130 °C

Procedure:
A mixture of 3-chloro-6-(3-methylisothiazol-5-yl)pyridazine (0.85 g, 4.0 mmol) and anhydrous hydrazine (3.8 ml, 120 mmol) in 30 mL of sec-BuOH was heated at 130° C. for 3 hours. The mixture was cooled to 23° C. and diluted with 5 mL of water. The solid was collected by filtration and was washed by 2 mL of water to produce a yellow solid. MS (ESI pos. ion) m/z: 208 (MH+). Calc'd exact mass for C8H6ClN3S: 207.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([SnH:13]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12].Cl[C:23]1[N:28]=[C:27]([Cl:29])[CH:26]=[CH:25][N:24]=1>>[Cl:29][C:27]1[CH:26]=[CH:25][N:24]=[C:23]([Sn:13]([CH2:9][CH2:10][CH2:11][CH3:12])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:18][CH2:19][CH2:20][CH3:21])[N:28]=1
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: Clc1ccnc(Cl)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCCC[Sn](CCCC)(CCCC)c1nccc(Cl)n1
Yield: 44.7 %

Procedure:
Using the procedure described in Example 1, Step 1, use LDA, tributyltin hydride (10.8 g, 37.2 mmol) and 2,4-dichloropyrimidine (5.2 g, 34.9 mmol)) to obtain the desired compound (6.3 g). 1H NMR (CDCl3) δ8.52 (d, 1H), 7.18 (d, 1H), 1.58 (m, 6H), 1.30 (q, 6H), 1.18 (t, 6H), 0.86 (t, 9H).
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)/[CH:7]=[CH:8]/[CH3:9])[OH:3]>O.C(O)C>[OH:3][C:2]1[CH:4]=[CH:5][C:6]([C:7]2[O:3][C:2]3[C:1]([O:11][CH3:12])=[CH:10][C:6](/[CH:7]=[CH:8]/[CH3:9])=[CH:5][C:4]=3[C:8]=2[CH3:9])=[CH:10][C:1]=1[O:11][CH3:12]
Reactant: C/C=C/c1ccc(O)c(OC)c1
Solvent: O
Solvent: CCO
Product: C/C=C/c1cc(OC)c2oc(-c3ccc(O)c(OC)c3)c(C)c2c1
Reaction time: 24 h

Procedure:
150 g ferric chloride in 400 ml water are added to a solution of 100 g (E)-isoeugenol in 1.3 liter 75 percent ethanol and allowed to stand for 24 hours at 0° C. The resulting sediment is filtered off and recrystallized from ethanol, resulting in 53 g trans-2,3-dihydro-2-(4-hydroxy-3-methoxyphenyl-7-methoxy3-methyl-5-(E)-propenylbenzofuran ("dehydrodiisoeugenol") as colorless crystals; melting point 132°-133° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:25]2[C:26]([CH3:39])=[CH:27][C:28]([O:31][CH2:32][C:33]([CH3:38])([CH3:37])[C:34]([OH:36])=[O:35])=[N:29][CH:30]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[N:9](COCC[Si](C)(C)C)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=1.[OH-].[Na+]>FC(F)(F)C(O)=O.O>[F:1][C:2]1[CH:3]=[C:4]([C:25]2[C:26]([CH3:39])=[CH:27][C:28]([O:31][CH2:32][C:33]([CH3:37])([CH3:38])[C:34]([OH:36])=[O:35])=[N:29][CH:30]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[NH:12][C:11]([C:13]([F:14])([F:16])[F:15])=[CH:10][N:9]=1
Reactant: Cc1cc(OCC(C)(C)C(=O)O)ncc1-c1ccc(-c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(OCC(C)(C)C(=O)O)ncc1-c1ccc(-c2ncc(C(F)(F)F)[nH]2)c(F)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 87.6 %

Procedure:
In trifluoroacetic acid (2.0 mL) and water (0.1 mL) was dissolved 3-[(5-{3-fluoro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoic acid (640 mg), and the solution was stirred at room temperature for 10 hours. The solution was neutralized by adding 2N aqueous sodium hydroxide solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated brine, the organic layer was separated and concentrated under reduced pressure. Ether was added to the obtained residue, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 3-[(5-{3-fluoro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoic acid (432 mg).
Reaction SMILES: C(O[C@H]1C2C(=CC(Br)=CC=2)[C@@H](NC[C@@H](O)[C@@H](N)CC2C=C(F)C=C(F)C=2)C1)C=C.Br[C:31]1[CH:32]=[CH:33][C:34]2[C@H:35]3[CH2:52][C@@H:49]([C:50]=2[CH:51]=1)[NH:48][CH2:47][C@@H:46]([OH:53])[C@H:45]([CH2:54][C:55]1[CH:60]=[C:59]([F:61])[CH:58]=[C:57]([F:62])[CH:56]=1)[NH:44][C:43](=[O:63])[CH2:42][CH2:41][CH2:40][CH:39]=[CH:38][CH2:37][O:36]3.[CH3:64][N:65]1[CH2:72][CH:71]2[CH:67]([CH2:68][NH:69][CH2:70]2)[CH2:66]1>>[F:62][C:57]1[CH:56]=[C:55]([CH:60]=[C:59]([F:61])[CH:58]=1)[CH2:54][C@@H:45]1[NH:44][C:43](=[O:63])[CH2:42][CH2:41][CH2:40][CH:39]=[CH:38][CH2:37][O:36][C@@H:35]2[CH2:52][C@@H:49]([C:50]3[CH:51]=[C:31]([N:69]4[CH2:70][CH:71]5[CH:67]([CH2:66][N:65]([CH3:64])[CH2:72]5)[CH2:68]4)[CH:32]=[CH:33][C:34]=32)[NH:48][CH2:47][C@H:46]1[OH:53]
Reactant: CN1CC2CNCC2C1
Reactant: O=C1CCCC=CCO[C@@H]2C[C@H](NC[C@@H](O)[C@H](Cc3cc(F)cc(F)c3)N1)c1cc(Br)ccc12
Agent: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c2cc(Br)ccc21
Product: CN1CC2CN(c3ccc4c(c3)[C@@H]3C[C@H]4OCC=CCCCC(=O)N[C@@H](Cc4cc(F)cc(F)c4)[C@H](O)CN3)CC2C1
Yield: 46 %

Procedure:
Step FG (1): The title compound (80 mg) was prepared in 46% yield via Ullman type coupling of (1S,4R,5S,15R)-19-bromo-5-(3,5-difluoro-benzyl)-4-hydroxy-14-oxa-2,6-diaza-tricyclo[13.6.1.016,21]docosa-11,16(21),17,19-tetraen-7-one (TFA salt of Example 68) and 2-methyloctahydropyrrolo[3,4-c]pyrrole by following a procedure analogous to Step FF (1). LC/MS (M+H)+ 581.43. 1H NMR (400 MHz, CD3OD) δ ppm 1.27 (s, 2H) 1.49 (s, 1H) 1.98-2.06 (m, 2H) 2.23-2.35 (m, 5H) 2.38 (s, 2H) 2.54 (s, 1H) 2.58-2.69 (m, 2H) 2.75 (s, 1H) 2.92 (d, J=12.09 Hz, 4H) 2.99-3.11 (m, 2H) 3.18 (s, 1H) 3.55 (d, J=10.83 Hz, 1H) 3.83 (m, 2H) 3.88-3.98 (m, 2H) 4.05 (d, J=14.10 Hz, 1H) 4.30 (m, 1H) 4.65 (m, 1H) 5.42-5.54 (m, 2H) 6.70-6.77 (m, 5H) 7.19 (t, J=7.43 Hz, 2H). CD3OD
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[S:12]1[CH2:16][C:15](=S)[NH:14][C:13]1=[O:18]>CO>[CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:15]1[CH2:16][S:12][C:13](=[O:18])[N:14]=1
Reactant: Cc1nc[nH]c1CSCCN
Reactant: O=C1NC(=S)CS1
Solvent: CO
Product: Cc1nc[nH]c1CSCCNC1=NC(=O)SC1
Yield: 37 %

Procedure:
A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (1.71 g.) and thiazolidine-2-one-4-thione (1.33 g.) in methanol (30 ml.) was heated under reflux for one hour. Concentration, followed by successive recrystallisation of the residue from methanol, ethanol and aqueous ethanol afforded 4-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]thiazoline-2-one (1.0 g.) m.p. 195°-197°.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[N:11]=[C:10]3[CH:13]=[C:14]([N:18]4[CH2:23][CH2:22][NH:21][CH:20]([CH3:24])[CH2:19]4)[C:15]([F:17])=[CH:16][C:9]3=[CH:8][C:7]=2[C:6](=[O:25])[C:5]([C:26]([OH:28])=[O:27])=[CH:4]1)[CH3:2].[CH2:29]=O>C(O)=O>[CH3:24][CH:20]1[N:21]([CH3:29])[CH2:22][CH2:23][N:18]([C:14]2[C:15]([F:17])=[CH:16][C:9]3[C:10]([CH:13]=2)=[N:11][C:12]2[N:3]([CH2:1][CH3:2])[CH:4]=[C:5]([C:26]([OH:28])=[O:27])[C:6](=[O:25])[C:7]=2[CH:8]=3)[CH2:19]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(C)C4)cc3nc21
Reactant: C=O
Solvent: O=CO
Product: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(C)C(C)C4)cc3nc21

Procedure:
8-(3,4-Dimethyl-1-piperazinyl)-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Reference Example 21 but starting from 2.3 g of 1-ethyl-7-fluoro-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid, 2.26 cm3 of 98% formic acid and 5.6 cm3 of a 30% aqueous solution of formaldehyde. 1.75 g of 8-(3,4-dimethyl-1-piperazinyl)-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 293°-294° C.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21](Cl)(=[O:23])[CH3:22]>>[C:21]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])(=[O:23])[CH3:22]
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: CC(=O)Cl
Product: CCOC(=NC(C)=O)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and acetyl chloride, there is obtained ethyl N-acetyl-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: M+ 308 (2), 279 (25), 194 (100);
Reaction SMILES: O=S(Cl)Cl.[N+:5]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[C:13]2[C:18]([OH:20])=[O:19])([O-:7])=[O:6].[CH3:21]O>>[CH3:21][O:19][C:18]([C:13]1[C:12]2[C:17](=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=[CH:10][CH:11]=2)[N:16]=[CH:15][CH:14]=1)=[O:20]
Reactant: O=C(O)c1ccnc2c([N+](=O)[O-])cccc12
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccnc2c([N+](=O)[O-])cccc12
Temperature: 70 °C
Yield: 22 %

Procedure:
SOCl2 (10 ml, 137 mmol) was added slowly to 8-nitro-quinoline-4-carboxylic acid 473 (3.0 g, 13.8 mmol) in MeOH (40 ml) and the mixture was heated at 70° C. for 7 h. After cooling, the solvent was removed in vacuo and the residue was diluted with EtOAc. The organic phase was washed with sat. NaHCO3 solution and brine, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with n-hexane/EtOAc (95:5) as the eluent to give the title compound (0.70 g, 22%).