Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([OH:21])=[O:20])=[C:8]([CH2:11][S:12][C:13]3[S:14][C:15]([CH3:18])=[N:16][N:17]=3)[CH2:9][S:10][C@H:5]12)=[O:2].[C:24]1([C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N+]=[N-])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1.C(O)(=O)C>[CH:1]([NH:3][C@@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([O:21][CH:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:20])=[C:8]([CH2:11][S:12][C:13]3[S:14][C:15]([CH3:18])=[N:16][N:17]=3)[CH2:9][S:10][C@H:5]12)=[O:2]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC=O)[C@H]3SC2)s1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC=O)[C@H]3SC2)s1
Reaction time: 16 h

Procedure:
A solution of 7β-formamido-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethylceph-3-em-4-carboxylic acid (8.5 g) in tetrahydrofuran (300 ml) was treated with an excess of a solution of diphenyldiazomethane in petroleum (300 ml) and the mixture was kept at 20° for 16 hours. A few drops of acetic acid were added and solvents were removed under reduced pressure. The resulting yellow syrup was dissolved in ethyl acetate and washed with sodium bicarbonate solution. A solid (7.5 g) precipitated and was dried in vacuo. A sample (5.77g) of the wet solid was dissolved in methylene chloride, and the solution was dried and concentrated under reduced pressure. The residue was crystallised from methanol to give the title ester (5.08 g),m.p. 108° (decomp.), λmax. (EtOH) 268nm (ε 12,400), τ (CDCl3 + a little DMSO-d6) values include 1.50 (d, J 9 Hz; NH), 1.72 (s; HCO), 6.30 (singlet; C-2 CH2) and 7.31 (singlet;CH3).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[C:21]([F:25])=[CH:22][CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C:21]1[C:13]2[N:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:10]([C@@H:8]([NH2:7])[CH3:9])=[N:11][C:12]=2[CH:24]=[CH:23][CH:22]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(F)c2n1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc2cccc(F)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
To a solution of [(S)-1-(7-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester (625 mg) in DCM (3 mL) was added TFA (3 mL) and the resulting mixture was stirred at RT for 3 h. The crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo affording (S)-1-(7-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine as a pale orange oil (372 mg, 83%). LCMS: RT 1.97 and 2.11 min [M+H]+ 255.9.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:11]([N:12]2[C:15](=[O:17])[CH3:16])=[C:10]2[CH:18]=[CH:19][CH:20]=[CH:21][C:9]2=[CH:8][CH:7]=3)=[CH:4][CH:3]=1.[C:22]1([N:28]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[N:30]=[C:29]2C2C=CC(B(O)O)=CC=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:52](O)[CH3:53]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:15]([N:12]1[C:13]2[CH:14]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[CH:7]=[CH:8][C:9]3[CH:21]=[C:20]([C:53]4[CH:52]=[CH:4][C:3]([C:29]5[N:28]([C:22]6[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=6)[C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=6[N:30]=5)=[CH:2][CH:14]=4)[CH:19]=[CH:18][C:10]=3[C:11]1=2)(=[O:17])[CH3:16]
Reactant: CCO
Reactant: OB(O)c1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Reactant: CC(=O)n1c2cc(Br)ccc2c2ccc3ccccc3c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(=O)n1c2ccccc2c2ccc3cc(-c4ccc(-c5nc6ccccc6n5-c5ccccc5)cc4)ccc3c21

Procedure:
Following the above procedure, Suzuki coupling of 6.7 g of 9-bromo-11-acetyl-11H-benzo[a]carbazole and 14.0 g of 4-(1-phenyl-1H-benzo [d]imidazol-2-yl) phenylboronic acid were stirred together in 30 ml of toluene. To this was added 0.02 g of tetrakis(triphenylphosphine)palladium, 6.9 g of potassium carbonate and 10 ml of aqueous ethanol were added and refluxed under nitrogen for 6 h. The reaction was quenched with water and the toluene layer was removed and passed through a celite column. The organic layers were combined and then evaporated in a rotary evaporator under vacuum to yield 9.5 g of 11-acetyl-3-[4-(1-phenyl-1H-benzo[d] imidazol-2-yl) phenyl]-11H-benzocarbazole as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2[O:12][C:11](C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:39]=[CH:38][CH:37]=[CH:36][C:26]=1[CH2:27][S:28]([N:31]1[CH2:34][CH:33]([OH:35])[CH2:32]1)(=[O:30])=[O:29]>>[CH:11]([OH:12])=[O:29].[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:39]=[CH:38][CH:37]=[CH:36][C:26]=3[CH2:27][S:28]([N:31]3[CH2:32][CH:33]([OH:35])[CH2:34]3)(=[O:29])=[O:30])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: O=S(=O)(Cc1ccccc1Br)N1CC(O)C1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3CS(=O)(=O)N3CC(O)C3)cc2F)cn1
Product: O=CO

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 1-((2-bromobenzyl)sulfonyl)azetidin-3-ol. MS (ESI): mass calcd. for C20H19FN4O3S, 414.12; m/z found, 414.9 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.43-8.38 (m, 1H), 8.08 (d, J=1.5, 1H), 7.95 (m, 1H), 7.68-7.60 (m, 1H), 7.49-7.41 (m, 2H), 7.39-7.28 (m, 3H), 4.45-4.36 (m, 3H), 3.79-3.70 (m, 2H), 3.67-3.59 (m, 2H).
Reaction SMILES: [CH2:1]([Si:4]([CH2:29][CH:30]=[CH2:31])([CH2:26][CH:27]=[CH2:28])[CH2:5][CH2:6][CH2:7][Si:8]([CH2:13][CH2:14][CH2:15][Si:16]([CH2:23][CH:24]=[CH2:25])([CH2:20][CH:21]=[CH2:22])[CH2:17][CH:18]=[CH2:19])([O:11][CH3:12])OC)[CH:2]=[CH2:3].[C:32]([Li])([CH3:35])([CH3:34])[CH3:33]>CCCCC>[CH2:1]([Si:4]([CH2:29][CH:30]=[CH2:31])([CH2:26][CH:27]=[CH2:28])[CH2:5][CH2:6][CH2:7][Si:8]([CH2:13][CH2:14][CH2:15][Si:16]([CH2:17][CH:18]=[CH2:19])([CH2:20][CH:21]=[CH2:22])[CH2:23][CH:24]=[CH2:25])([C:32]([CH3:35])([CH3:34])[CH3:33])[O:11][CH3:12])[CH:2]=[CH2:3]
Reactant: C=CC[Si](CC=C)(CC=C)CCC[Si](CCC[Si](CC=C)(CC=C)CC=C)(OC)OC
Reactant: [Li]C(C)(C)C
Solvent: CCCCC
Product: C=CC[Si](CC=C)(CC=C)CCC[Si](CCC[Si](CC=C)(CC=C)CC=C)(OC)C(C)(C)C
Temperature: -78 °C
Reaction time: 17 h
Yield: 85 %

Procedure:
Under a nitrogen atmosphere, bis{3-(triallylsilyl)propyl}dimethoxysilane (29′) (1.0 g, 2.097 mmol) was cooled down to −78° C., then n-pentane solution of 1.61M t-butyllithium 1.954 mL (3.145 mmol) was added dropwise, then stirred at −78° C. for 17 hours. The reacted mixture was cooled down to 0° C., quenched with water, saturated ammonium chloride aqueous solution was added. The obtained organic layer was separated. The obtained water layer was extracted with diethyl ether and the collected organic layer was each washed with saturated sodium bicarbonate aqueous solution and saturated saline solution in this order, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, obtaining a crude product. The crude product was purified through short silica gel column chromatography (eluent: hexane/ethyl acetate=20/1), obtaining bis({3-(triallylsilyl)propyl}(tert-butyl)methoxysilane (30) (yield: 0.902 g, yield (%): 85%).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[NH2:9])=O)=[CH:4][CH:3]=1.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][C:15]([CH3:17])=O>C(O)C>[F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]2[N:8]([CH3:10])[N:9]=[C:15]([CH3:17])[C:14]=2[C:13]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=1
Reactant: CN(N)C(=O)c1ccc(F)cc1
Reactant: CCOC(=O)CC(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(C)c1-c1ccc(F)cc1
Reaction time: 14 h
Yield: 43.7 %

Procedure:
A mixture of 4-fluoro-N-methylbenzohydrazide (5.0 g), ethyl acetoacetate (4.84 g) and ethanol (140 ml) was stirred for 14 hrs. with heating under reflux. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give an oil from a fraction eluted with hexane-ethyl acetate (4:1-1:1, v/v). This oil was dissolved in ethanol (50 ml), 1,8-diazabicyclo[5.4.0]-7-undecene (0.5 ml) was added, and the mixture was stirred for 4 hrs. with heating under reflux. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give ethyl 5-(4-fluorophenyl)-1,3-dimethyl-1H-pyrazole-4-carboxylate (3.41 g, yield 44%) as colorless crystals.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][OH:4].[H-].[Na+].Br[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1>CN(C)C=O.O>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([O:4][CH2:3][CH:2]([F:5])[F:1])=[N:10][CH:11]=1
Reactant: OCC(F)F
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)COc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
2,2-Difluoroethanol (0.40 ml) was added dropwise to a suspension of sodium hydride (0.270 g) in dimethylformamide (5 ml) cooled in an ice-bath under argon. The mixture was stirred at room temperature for 40 minutes, then re-cooled in an ice-bath. A solution of 2,5-dibromopyridine (1 g) in dimethylformamide (5 ml) was added. The solution was then heated at 65° C. under argon for 18 h, allowed to cool and diluted with water (50 ml). The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed with water, brine, dried over magnesium sulphate, filtered and evaporated. The product was purified by column chromatography eluting with hexane to give a colourless oil (0.946 g).
Reaction SMILES: I[C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[C:22]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)#[CH:23]>>[O:11]=[C:9]1[CH2:8][C:7]([C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])=[N:6][C:5]2[CH:20]=[CH:21][C:2]([C:23]#[C:22][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[CH:3][C:4]=2[NH:10]1
Reactant: C#Cc1cccs1
Reactant: N#Cc1cccc(C2=Nc3ccc(I)cc3NC(=O)C2)c1
Product: N#Cc1cccc(C2=Nc3ccc(C#Cc4cccs4)cc3NC(=O)C2)c1
Yield: 82.8 %

Procedure:
Prepared from 3-(7-iodo-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile (Example 50) (185 mg, 0.48 mmol) and 2-ethynylthiophene (78 mg, 0.72 mmol) [prepared from 2-thiophenecarboxaldehyde according to J. Org. Chem. 1982, 47, 2201-2204] according to the general procedure F. Obtained as a light yellow solid (146 mg).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12]([N+:19]([O-:21])=O)=[C:13]([NH:15][C:16](=O)[CH3:17])[CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S1C=CC=C1.[ClH:27].[H][H]>CO.[Pt].CC(O)C>[ClH:27].[OH:21][N:19]1[C:12]2[CH:11]=[CH:10][C:9]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])=[CH:14][C:13]=2[N:15]=[C:16]1[CH3:17]
Reactant: [H][H]
Reactant: CC(=O)Nc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pt]
Agent: Cl
Solvent: c1ccsc1
Solvent: CO
Solvent: CC(C)O
Product: Cc1nc2cc(C(=O)c3ccccc3)ccc2n1O
Yield: 73 %

Procedure:
(a-2) A mixture of 5.6 parts of N-(5-benzoyl-2-nitrophenyl)acetamide, 2 parts of a solution of thiophene in methanol 4%, 200 parts of methanol and 7 parts of 2-propanol, saturated with hydrogen chloride was hydrogenated at normal pressure and at room temperature with 1 part of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was washed with 2-propanone and dried, yielding 4.2 parts (73%) of (1-hydroxy-2-methyl-1H-benzimidazol-5-yl) phenylmethanone monohydrochloride as a residue (int. 49).
Reaction SMILES: [CH3:1]N(C)CCO.[Li+].CCC[CH2-].[Si:12]([O:19][CH2:20][C@H:21]1[O:25][C:24]([CH3:27])([CH3:26])[N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:22]1[CH2:35][C:36]1[CH:41]=[CH:40][N:39]=[C:38]([Cl:42])[CH:37]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].CI>C1COCC1>[Si:12]([O:19][CH2:20][C@H:21]1[O:25][C:24]([CH3:27])([CH3:26])[N:23]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C@H:22]1[CH2:35][C:36]1[CH:41]=[C:40]([CH3:1])[N:39]=[C:38]([Cl:42])[CH:37]=1)([C:15]([CH3:16])([CH3:17])[CH3:18])([CH3:13])[CH3:14]
Reactant: CN(C)CCO
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccnc(Cl)c2)[C@@H](CO[Si](C)(C)C(C)(C)C)OC1(C)C
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc(C[C@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)cc(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Dimethylethanolamine (0.128 ml, 1.27 mmol) was added to anhydrous hexanes (1.4 L) and cooled to 0° C. N-BUTYLLITHIUM (2.5 M in hexanes)(1.02 ml, 2.55 mmol) was added dropwise and stirred for 30 minutes before being cooled to −78° C. (4S,5S)-Tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-4-((2-chloropyridin-4-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate (0.200 g, 0.425 mmol) in hexanes (1 mL) was added dropwise and the solution was stirred for 1 hour at −78° C. to give a dark orange solution. MeI (0.106 ml, 1.70 mmol) in THF (3.2 mL) was added dropwise and the reaction was allowed to slowly warm to 0° C. and was quenched with saturated aqueous ammonium chloride. The reaction was diluted with ethyl acetate and water and separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water, brine, dried over sodium sulfate, and concentrated to give the titled compound which was used directly for the next step without purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[N:16]1([C:2]2[N:7]=[CH:6][C:5]([C:8]3([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)C1(c2ccc(Cl)nc2)CC1
Reactant: C1CCNC1
Product: CCOC(=O)C1(c2ccc(N3CCCC3)nc2)CC1
Temperature: 100 °C

Procedure:
A mixture of ethyl 1-(6-chloropyridin-3-yl)cyclopropanecarboxylate (69.8 mg, 0.309 mmol) and pyrrolidine (250.0 μL, 3.0 mmol) in a sealed tube was heated at 100° C. for 4 hours. Then the excess pyrrolidine in the mixture was removed under reduced pressure. The residue was purified by flash chromatography column to afford ethyl 1-(6-pyrrolidin-1-ylpyridin-3-yl)cyclopropanecarboxylate.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=O.C(N(CC)CC)C.ClC(OCC)=O.[NH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31]>ClCCl>[OH:31][CH2:30][C:29]([NH:28][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:2]([I:1])[CH:3]=1)([CH3:33])[CH3:32]
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1cc(I)cc(C(F)(F)F)c1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CO)NC(=O)c1cc(I)cc(C(F)(F)F)c1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
To a solution of 3-iodo-5-(trifluoromethyl)benzoic acid (2.32 g) and triethylamine (1.13 ml) in dichloromethane (20 ml) was added dropwise a solution of ethyl chloroformate (1.4 ml) in dichloromethane (2.0 ml) over 10 minutes at −30° C., and the mixture was stirred at −30° C. for 1 hour. 2-Amino-2-methyl-1-propanol was added dropwise to the mixture over 5 minutes at −30° C., and the mixture was stirred at −30° C. for 30 minutes and then at room temperature for 1 hour. The mixture was quenched with aqueous ammonium chloride solution at 0° C., and extracted with dichloromethane (X2). The combined organic extracts were washed successively with saturated aqueous sodium hydrogen carbonate solution, 1N hydrochloric acid and brine, and then dried over magnesium sulfate, evaporated, and purified with column chromatography (silica gel, ethyl acetate:hexane=20:80) to give N-(2-hydroxy-1,1-dimethylethyl)-3-iodo-5-(trifluoromethyl)benzamide (2.10 g) as an oil.
Reaction SMILES: [Br:1][CH:2]1[CH2:8][CH:7]([Br:9])[C:6](=[O:10])[O:5][C:3]1=[O:4].[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[Br:9][CH:7]([CH2:8][CH:2]([Br:1])[C:3]([O:5][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4])[C:6]([O:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]
Reactant: OCc1ccccc1
Reactant: O=C1OC(=O)C(Br)CC1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C(OCc1ccccc1)C(Br)CC(Br)C(=O)OCc1ccccc1
Yield: 100.2 %

Procedure:
2.18g (8 mmol) of 2,4-dibromoglutaric anhydride, 2.1 ml (20 mmol) of benzyl alcohol, and 2 ml of benzene are stirred for 1 5 hours at room temperature 76 mg (0.4 mmol) of p-toluenesulfonic acid monohydrate and 8 ml of benzene are added, and the solution is refluxed under a Dean-Stark trap for 2 hours. Filtration over silica gel and evaporation yields 3.77g (100%) of dibenzyl 2,4-dibromoglutarate as a colourless oil. 1H NMR (CDCl3): δ7.37 (br. s., 10H), 5.21 (narrow AB system, 4H, J=12.5); dl isomer: δ4.55 (dd, 2H, J=6.5, 7.5), 2.69 (dd, 2H, J=6.5, 7.5); meso isomer: δ 4.42 (t, 2H, J=7.5), 2.90 (dt, 1H, J=7.5 (t), 14.5 (d)), 2.66 (dt, 1H, J=7.5 (t), 14.5 (d)); dl/meso=6:1. IR (neat): 3034, 1740, 1499, 1456, 1385, 1273, 1154, 750, 696 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].N1C=CC=CC=1.Cl.[NH2:20][OH:21]>CO.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:20][OH:21])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: NO
Reactant: O=Cc1ccc(Br)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=[N+]([O-])c1cc(C=NO)ccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
To a solution of 4-bromo-3-nitro-benzaldehyde (commercially available) (10 g, 43.5 mmol) in methanol (28 ml) under a nitrogen atmosphere was added pyridine (7.74 g, 97.8 mmol) and hydroxylamine hydrochloride (6.04 g, 86.94 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with a mixture of ethyl acetate and aqueous sodium hydrogen carbonate (saturated). The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/cyclohexane 1:3) to give 4-bromo-3-nitro-benzaldehyde oxime (5.34 g, 67% yield). 1H-NMR (CDCl3, 400 MHz): 8.11 (s, 1H), 8.05 (d, 1H), 7.75 (d, 1H), 7.62 (m, 2H).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][CH3:10])[N:3]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][CH3:10])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCc1nccc(O)n1
Product: COCc1nccc(Cl)n1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
47 g (335.7 mmol) of 4-hydroxy-2-methoxymethylpyrimidine (from stage a) are mixed with 210 ml of phosphorus oxychloride and stirred at 70° C. for 2 h and subsequently heated to boiling for 2.5 h. The excess phosphorus oxychloride is removed by distillation in vacuo, the residue is hydrolyzed with ice, and solid potassium bicarbonate is added to eliminate excess acid. Several extractions with methylene chloride are carried out, and the organic phase is evaporated in vacuo. The black residue is filtered through silica gel (n-heptane/ethyl acetate 1:1). 15.7 g of oil are obtained.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:23])([F:22])[C:5]1[CH:6]=[C:7]([C:11]2[C:15]([NH2:16])=[C:14]([C:17](OCC)=[O:18])[S:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1>CO>[CH3:1][NH:2][C:17]([C:14]1[S:13][N:12]=[C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:4]([F:23])([F:22])[F:3])[CH:6]=2)[C:15]=1[NH2:16])=[O:18]
Reactant: CN
Reactant: CCOC(=O)c1snc(-c2cccc(C(F)(F)F)c2)c1N
Solvent: CO
Product: CNC(=O)c1snc(-c2cccc(C(F)(F)F)c2)c1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
One hundred ml. of methanol were saturated with gaseous methyl amine. Two grams of ethyl 3-(3-trifluoromethylphenyl)-4-amino-5-isothiazolecarboxylate were added. The reaction mixture was stirred at ambient temperature for about 30 minutes and was then heated to refluxing temperature for about 30 minutes. TLC indicated some amide had formed. Gaseous methylamine was bubbled through the refluxing reaction mixture for about 4 additional hours, at which time TLC indicated starting material was no longer present. The reaction mixture was poured into an ice-water mixture. N-methyl 3-(3-trifluoromethylphenyl)-4-amino-5-isothiazolecarboxamide formed in the above reaction precipitated and the precipitate collected by filtration. M.P. 113° C. (after vacuum drying). Yield 1.4 g.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH2:15]1[CH:17](N)[CH2:16]1>>[CH:17]1([C:10]2[CH:5]=[C:4]([NH:1][C:8]3[CH:7]=[CH:6][C:5]4[C:4]([NH2:1])=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]=3)[CH:13]=[CH:12][CH:11]=2)[CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: NC1CC1
Product: Nc1cccc2nc(Nc3cccc(C4CC4)c3)ccc12

Procedure:
The title compound, MS: m/e=276.4 (M+H+), was prepared in accordance with the general method of example 1 from 5-nitro-2-chloroquinoline and 3-cyclopropylamine.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.Cl.[CH3:23][C:24]1[N:25]=[N:26][N:27]([CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)[CH:28]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:31]2[CH2:32][CH2:33][CH:29]([N:27]3[CH:28]=[C:24]([CH3:23])[N:25]=[N:26]3)[CH2:30]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: Cc1cn(C2CCNC2)nn1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1cn(C2CCN(c3c(F)c(N)c4c(=O)c(C(=O)O)cn(C5CC5)c4c3F)C2)nn1
Yield: 46.5 %

Procedure:
5-Amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (298 mg, 1 mmol) was reacted with 470 mg (2.5 mmol) of 3-(4-methyl-1,2,3-triazol-1-yl)pyrrolidine hydrochloride in the presence of 380 mg (2.5 mmol) of DBU in 20 ml of dry acetonitrile for two days under reflux conditions and the atmosphere of nitrogen. The yellow suspension was then evaporated to dryness and to the residue water was added. The yellow solid was filtered and crystallized repeatedly (3x) with acetonitrile to free the product from the unreacted starting material. After drying, 200 mg of the desired product was obtained, m.p. 271°-272.5° C. 1H NMR (TFA) δ: 9.15 (s, 1H), 8.4 (s, 1H), 5.8-5.6 (m, 1H), 4.8-4.05 (m, 5H), 3.0-2.7 (m, 2H), 2.67 (s, 3H), 1.65-1.2 (m, 4H). Anal. calcd. for C20H20F2N6O3.1/2 H2O: C, 54.67; H, 4.82; N, 19.12. Found: C, 54.91; H, 4.69; N, 18.76.