Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[CH:13][CH:12]=[CH:11]3)[CH2:7][CH2:6]1)=O.O.[NH2:19][NH2:20]>CO>[N:14]1[C:15]2[C:10](=[CH:9][C:8]([C:5]3([C:3]([NH:19][NH2:20])=[O:2])[CH2:7][CH2:6]3)=[CH:17][CH:16]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)C1(c2ccc3ncccc3c2)CC1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)C1(c2ccc3ncccc3c2)CC1
Yield: 99.9 %

Procedure:
A solution of 1-quinolin-6-yl-cyclopropanecarboxylic acid methyl ester (513 mg, 2.26 mmol) and hydrazine monohydrate (3.39 g, 67.7 mmol) in methanol (5 mL) was heated under reflux overnight. After cooling, the solvent was removed in vacuo to afford 513 mg (100%) of the title compound and used without further purification. LCMS (method A): [MH]+=228, tR=2.88 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][N:13]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Li+].CC([N-]C(C)C)C.CN([CH:34]=[O:35])C>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH:34]=[O:35])[N:13]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc([N+](=O)[O-])cc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: C[Si](C)(C)CCOCn1cc(-c2ccc([N+](=O)[O-])cc2)nc1C=O
Yield: 29.9 %

Procedure:
Reaction of 4-(4-nitro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (170 mg, 0.53 mmol), 0.53 M LDA (1 mL, 0.53 mmol), and DMF (232 uL, 1.60 mmol) for 4 h at −40° C. followed by column chromatography on silica gel (EtOAc/hexane 9:1) gave the title compound (55 mg, 30%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ0.00 (s, 9H), 0.95 (t, 2H, J=9.0 Hz), 3.63 (t, 2H, J=9.0 Hz), 5.82 (s, 2H), 7.79 (s, 1H), 7.98 (d, 2H, J=9.0 Hz), 8.27 (d, 2H, J=9 Hz), 9.89 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13](=[O:15])[NH2:14])=[CH:8][C:7]=1[CH3:16].CS(C)=O.OO.C(=O)([O-])[O-].[K+].[K+]>O>[C:21]([O:20][C:18]([NH:17][CH:4]([CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13](=[O:15])[NH2:14])=[CH:8][C:7]=1[CH3:16])[C:3]([OH:25])=[O:2])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)C(Cc1c(C)cc(C(N)=O)cc1C)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C(N)=O)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 43.5 °C
Reaction time: 3 h

Procedure:
2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionic acid methyl ester (250 g, 0.713 mol), DMSO (750 mL) and 30% H2O2 (250 mL), were added to a 5 L three-necked round bottom flask equipped with addition funnel, mechanical stirrer, heating mantel, reflux condenser, thermocouple and nitrogen inlet. Potassium carbonate (158 g, 1.14 mol, 1.6 eq) was dissolved in water (750 mL) and added dropwise over 30 minutes. During the addition, a temperature increase was observed (from 23° C. to 34° C.). The resulting mixture was warmed up to about 42-45° C. and the progress of the reaction monitored by HPLC. After 3 hours, to the warm mixture was added activated carbon (ECOSORB-941) (37.5 g, 15% by weight). The resulting slurry was refluxed for 1 hour, and then filtered hot through CELITE®. The CELITE® pad was rinsed with H2O (1.5 L). The resulting mixture was cooled to about 10° C. and quenched with 2.0N HCl (pH 2, 1.22 L), to yield a mixture comprising a white solid precipitated. The mixture was aged under agitation for a period of about 4 hours in an ice bath and then filtered and dried for 48 hours in a vacuum oven to yield the title compound as a white crystalline solid.
Reaction SMILES: [CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6]2.N1C=CC=CC=1.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>ClCCl>[CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH:23][S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])[CH:20]=[CH:21][CH:22]=2)[CH:3]2[CH:7]1[CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4]2
Reactant: CCS(=O)(=O)Cl
Reactant: CC1(c2cccc(N)c2)C2CN(CCCc3ccccc3)CC21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cccc(C2(C)C3CN(CCCc4ccccc4)CC32)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.5 %

Procedure:
To a solution of 3-[6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine (Preparation 8, 110 mg, 0.36 mmol) in dichloromethane (4 ml), at 0° C. under nitrogen was added pyridine (56 μl, 0.72 mmol) then dropwise over 5 minutes ethanesulfonylchloride (67 μl, 92 mg , 0.72 mmol). The mixture was allowed to warm to room temperature and was stirred for 16 hours. Further pyridine (56 μl, 0.72 mmol) and ethanesulfonylchloride (67 μl, 92 mg , 0.72 mmol) were added and the mixture was stirred for 2 hours. The crude mixture was purified by silica (40 g) column chromatography eluting with 80:20:1 ethyl acetate:hexane:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless oil (48 mg, 34%).
Reaction SMILES: [NH2:1][C:2]1[N:11]2[CH2:12][CH2:13][N:14]=[C:10]2[C:9]2[CH:8]=[CH:7][C:6]([O:15][CH2:16][CH2:17][CH2:18][S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[C:5]([O:25][CH3:26])[C:4]=2[N:3]=1.[NH2:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][N:29]=1>>[NH2:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([NH:1][C:2]2[N:11]3[CH2:12][CH2:13][N:14]=[C:10]3[C:9]3[CH:8]=[CH:7][C:6]([O:15][CH2:16][CH2:17][CH2:18][S:19]([N:22]([CH3:24])[CH3:23])(=[O:20])=[O:21])=[C:5]([O:25][CH3:26])[C:4]=3[N:3]=2)=[O:33])=[CH:30][N:29]=1
Reactant: COc1c(OCCCS(=O)(=O)N(C)C)ccc2c1N=C(N)N1CCN=C21
Reactant: Nc1ccc(C(=O)O)cn1
Product: COc1c(OCCCS(=O)(=O)N(C)C)ccc2c1N=C(NC(=O)c1ccc(N)nc1)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 16, Step 2 was used to prepare the title compound from 3-[(5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl)oxy]-N,N-dimethylpropane-1-sulfonamide (Example 17 Step 1) and 6-aminonicotinic acid. High vacuum drying gave the title compound (117 mg, 59%): HPLC MS RT=1.60 min, MH+=502.2; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.19-2.24 (2H, m), 2.78 (6H, s), 3.19-3.24 (2H, m), 3.99 (3H, s), 4.20-4.26 (2H, m), 4.37 (2H, t), 4.47-4.54 (2H, m), 7.04 (1H, d), 7.46 (1H, d), 8.03 (1H, d), 8.48 (1H, dd), 8.77 (1H, d).
Reaction SMILES: [Mg].Cl[Si:3]([O:10][CH2:11][CH3:12])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].Br[C:14]1[CH:27]=[CH:26][C:25]2[S:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[S:17][C:16]=2[CH:15]=1>C1COCC1>[CH2:5]([O:4][Si:3]([O:10][CH2:11][CH3:12])([O:7][CH2:8][CH3:9])[C:14]1[CH:27]=[CH:26][C:25]2[S:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[S:17][C:16]=2[CH:15]=1)[CH3:6]
Reactant: CCO[Si](Cl)(OCC)OCC
Reactant: Brc1ccc2c(c1)Sc1ccccc1S2
Agent: [Mg]
Solvent: C1CCOC1
Product: CCO[Si](OCC)(OCC)c1ccc2c(c1)Sc1ccccc1S2
Yield: 69.8 %

Procedure:
A 3-neck 3 L flask was filled with magnesium turnings (20 g), THF (650 g) and chlorotriethoxysilane (146 g), and heated to reflux. 2-Bromothianthrene from Example 3A was added to the flask in small portions. Grignard started instantly. The reaction was allowed to cool for 1 hour, after which magnesium salts were precipitated with hexanes (500 mL). The solution was filtered, followed by evaporation of volatiles by rotary evaporator. The material was distilled twice at 190 . . . 200° C./<1 mbar, giving colorless 2-(triethoxysilyl)thianthrene (125.9 g, 69.8% overall yield based on thianthrene, purity >99% by GC/MS).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.Cl.[NH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:12]=1.[BH3-]C#N.[Na+]>C(O)(=O)C.CO>[C:15]([OH:17])(=[O:16])[CH3:14].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:12]=2)[CH:2]=1
Reactant: O=Cc1cccnc1
Reactant: Nc1ccc(C(=O)O)c(-c2ccccc2)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)c1ccc(NCc2cccnc2)cc1-c1ccccc1
Reaction time: 0.17 h
Yield: 186.5 %

Procedure:
3-Pyridinecarboxaldehyde (1.2 mL, 12.8 mmol) and 4-amino-2-phenylbenzoic acid hydrochloride (3.2 g, 12.8 mmol), prepared in Example 190A, were dissolved in 100 mL 1% acetic acid in methanol. After stirring for 10 minutes, NaBH3CN was added, and stirring was continued for 18 hours. The reaction was evaporated to dryness under reduced pressure and partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The organic extracts were combined, washed with brine, and dried over Na2SO4 to give 4-(3-Pyridylmethylamino)-2-phenylbenzoic acid acetic acid salt (4.35 g, 90%) of the title compound. MS m/e 305 (M+H)+. 1H NMR (d6-DMSO, 300 MHz) δ 4.41 (s, 2H), 6.45 (d, J=3 Hz, 1H), 6.60 (m, 1H), 7.15-7.90 (m, 10H), 8.48 (m, 1H), 8.60 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH3:26])[CH2:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].[CH2:27]([Sn](CCCC)(CCCC)C(C)=C)[CH2:28][CH2:29]C>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([C:28]([CH3:29])=[CH2:27])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH3:26])[CH2:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10]
Reactant: C=C(C)[Sn](CCCC)(CCCC)CCCC
Reactant: CCCN1CC[C@@H](c2ccc(NS(=O)(=O)c3ccc(Br)cc3F)cc2)C1
Solvent: C1CCOC1
Product: C=C(C)c1ccc(S(=O)(=O)Nc2ccc([C@@H]3CCN(CCC)C3)cc2)c(F)c1
Temperature: 150 °C
Reaction time: 0.67 h
Yield: 97.2 %

Procedure:
0.2 g of 2-fluoro-4-bromo-N-[4-((S)-1-propyl-pyrrolidin-3-yl)-phenyl]-benzenesulfonamide (0.45 mmol), 1.05 g of tributyl-isopropenyl-stannane (3.17 mmol) and 0.026 g of tetrakistriphenylphosphinpalladium(0) (0.02 mmol) were dissolved in 3 ml of tetrahydrofuran and stirred for 40 minutes at 150° C. in the microwave (CEM). The reaction mixture was filtered over celite, washed with methanol, and the filtrate evaporated to dryness under reduced pressure. The residue was purified via silica gel chromatography with cyclohexane/ethyl acetate (20%), ethyl acetate, and ethyl acetate/methanol (15%). Fractions containing the product were combined, the solvent evaporated to yield 0.176 g of the title product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][C:26]1[O:27][C:28]([CH3:34])=[C:29]([C:31](Cl)=[O:32])[N:30]=1.O>CN(C)C(=O)C>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([F:24])=[C:2]([NH:1][C:31]([C:29]5[N:30]=[C:26]([CH3:25])[O:27][C:28]=5[CH3:34])=[O:32])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: Cc1nc(C(=O)Cl)c(C)o1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1nc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)c(C)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a solution of N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.61 mmol) in N,N-dimethylacetamide (4.0 mL) was added 2,5-dimethyl-1,3-oxazole-4-carbonyl chloride (127 mg, 0.79 mmol), 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, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was washed with ethanol to give the title compound (198 mg, 72%) as a white powder.
Reaction SMILES: N#N.[C:3]1([CH3:11])[C:4]([CH:9]=O)=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])#[N:13]>C(O)(C)C.N1CCOCC1>[C:12]([C:14](=[CH:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:11])[C:15]([O:17][CH3:18])=[O:16])#[N:13]
Reactant: Cc1ccccc1C=O
Reactant: COC(=O)CC#N
Agent: N#N
Solvent: CC(C)O
Solvent: C1COCCN1
Product: COC(=O)C(C#N)=Cc1ccccc1C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
A 100-mL, 1-necked round bottom flask (with magnetic stir-bar and dry N2 adaptor) was charged with 11.6 mL (12.0 g, 100 mmol) of o-tolualdehyde, 8.8 mL (9.9 g, 100 mmol) of methyl cyanoacetate, and 50 mL of isopropanol. Morpholine (0.50 mL, 0.55 g, 6.3 mmol, 6.3 mol %) was added and the mixture was stirred at 20–33° C. for 60 minutes. This mixture was diluted with 25 mL of isopropanol. The precipitate was filtered, washed with 10 mL of isopropanol, and dried to afford 17.37 g (86.3%) of methyl 2-cyano-3-(2-mehtylphenyl)-2-propenoate as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH:12]1([C:18]2[NH:19][CH:20]=[C:21]([CH3:23])[N:22]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(#N)C>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:19]2[CH:20]=[C:21]([CH3:23])[N:22]=[C:18]2[CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: Cc1c[nH]c(C2CCCCC2)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cn(-c2cc(Cl)ccc2[N+](=O)[O-])c(C2CCCCC2)n1

Procedure:
3.75 g 4-Chloro-2-fluoro-nitrobenzene, 3.4 g 2-Cyclohexyl-4-methyl-imidazole, 50 ml acetonitrile and 5 ml triethylamine were heated 6 hours at 60° C. The solvent was distilled off followed by extraction with 100 ml ethylacetate and 2 times 50 ml water. The organic layer was distilled off and the residue chromatographed on silica gel with 5% MeOH/CH2Cl2.
Reaction SMILES: [ClH:1].O1CCOCC1.[CH2:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([NH:21]C(=O)OC(C)(C)C)[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1>[ClH:1].[ClH:1].[CH2:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([NH2:21])[CH2:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NC1CCCN(Cc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: NC1CCCN(Cc2ccccc2)C1
Reaction time: 8 h
Yield: 95 %

Procedure:
A 4N-hydrochloric acid/1,4-dioxane solution (4 ml) was added to a solution of tert-butyl 1-benzyl-3-piperidinylcarbamate (0.448 g, 1.54 mmol) in tetrahydrofuran (4 ml) and stirred overnight. After the solvent was distilled off under reduced pressure, diethyl ether was added to the residue to precipitate a solid, and the supernatant was decanted and then dried under reduced pressure to obtain 1-benzyl-3-piperidinamine dihydrochloride (0.384 g, 95%).
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.[OH:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>N1C=CC=CC=1>[CH:19]1([N:9]2[C:8]3[N:7]=[C:6]4[CH:22]=[C:2]([N:30]5[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][OH:24])[CH2:28][CH2:29]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: OCCN1CCNCC1
Reactant: O=C(O)c1cn(C2CC2)c2nc3cc(Cl)c(F)cc3cc2c1=O
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2nc3cc(N4CCN(CCO)CC4)c(F)cc3cc2c1=O
Yield: 18.3 %

Procedure:
The reaction is carried out under conditions analogous to Reference Example 5 but starting from 4 g of 8-chloro-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 6.2 g of 1-(2-hydroxyethyl)-piperazine in 40 cm3 of pyridine The reaction mixture is heated for 22 hours at a temperature close to 115° C. The pure product is isolated after recrystallizing 3 times from 3 times 200 cm3 of ethanol containing 10% of dimethylformamide each time. 0.94 g of 1-cyclopropyl-7-fluoro-8-[4-(2-hydroxyethyl)-1-piperazinyl]-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid melting at 255° C.
Reaction SMILES: [NH3:1].[O:2]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH:7]2[NH:12][C:13](=[N:16][C:17]2[C:21]([CH3:22])=[CH:20][S:19][CH:18]=2)SC)[O:5][CH2:4][CH2:3]1>CO>[O:2]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH:7]2[NH:12][C:13]([NH:16][C:17]2[C:21]([CH3:22])=[CH:20][S:19][CH:18]=2)=[NH:1])[O:5][CH2:4][CH2:3]1
Reactant: N
Reactant: CSC(=Nc1cscc1C)NC1CCCCC12OCCO2
Solvent: CO
Product: Cc1cscc1NC(=N)NC1CCCCC12OCCO2
Temperature: 100 °C

Procedure:
In a ReactiVial, a 7 M solution of ammonia in methanol (2 ml) was added to 1-(1,4-dioxaspiro[4.5]dec-6-yl)-2-methyl-3-(4-methylthiophen-3-yl)isothiourea (58.8 mg), and the mixture was heated in a sand bath at about 100° C. for 16 hours. Removal of the solvent gave a residue of 51 mg of an oily product which was directly reacted further.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27]Cl.C(OCC)(=O)C>CN1C(=O)CCC1>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc2ccn(Cc3ccccn3)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere: to a solution of 1H-indole-6-carboxylic acid methyl ester (for synthesis see example 2a), 2.47 g, 14.1 mmol) in NMP (140 mL) was added Cs2CO3 (10.1 mg, 31 mmol) at 0° C. After stirring for 15 min 2-picolyl chloride hydrochloride (2.77 g, 16.9 mmol) was added and the mixture was stirred at room temperature for 18 h. Ethyl acetate (200 mL) was added and the mixture was washed with saturated aqueous ammonium chloride (3×150 mL) and brine (200 mL). The organic phase was dried (Na2SO4) and concentrated. The crude product was purified using column chromatography (ethyl acetate/heptane 1:3) to give the title compound as a colourless oil, which slowly crystallised on standing (2.72 g, 10.2 mmol, 72%).
Reaction SMILES: [SH:1][CH:2]([CH2:5][SH:6])[CH2:3][OH:4].N1C=CN=C1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[Cl-].[NH4+]>C1COCC1>[Si:12]([O:4][CH2:3][CH:2]([SH:1])[CH2:5][SH:6])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: OCC(S)CS
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(S)CS
Temperature: 0 °C
Reaction time: 18 h
Yield: 94.6 %

Procedure:
To a solution of 2,3-dimercapto-1-propanol (15.0 ml, 150 mmol) and imidazole (15.3 g, 224 mmol, 1.5 eq) in THF (300 mL) was added t-butyldimethylsilyl chloride (21.4 g, 142 mmol, 0.95 eq) at 0° C. The mixture was stirred at 0° C. for 1 hr and at room temperature for 18 hr. A saturated solution of ammonium chloride was added and the aqueous phase was extracted with dichloromethane. The organic layer was dried with anhydrous sodium sulphate and the solvent was evaporated under reduced pressure. The crude material was purified by flash chromatography with a mixture of hexane and ethyl acetate (90:10) to give the pure compound (32.04 g) in 94.5% yield.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:37]=[CH:36][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)\[C:25]([O:27]CC)=[O:26])=[CH:19][CH:18]=1.CO.Cl>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:37]=[CH:36][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)\[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=1
Reactant: CCOC(=O)/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\C(=O)O)c2cccnc2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of ethyl Z-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(3-pyridyl)acetate (520 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at 40° C. for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate to obtain Z-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(3-pyridyl)acetic acid (321 mg, yield 66%) as colorless crystals. m.p. 156-157° C. (decomposition)
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][S:8][CH:7]2[CH2:10][CH:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:12](=[O:13])[N:6]12)=O.[NH3:22].CO>>[C:18]([O:17][C:15](=[O:16])[NH:14][CH:11]1[C:12](=[O:13])[N:6]2[CH:7]([S:8][CH2:9][CH:5]2[C:3](=[O:2])[NH2:22])[CH2:10]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: N
Reactant: COC(=O)C1CSC2CC(NC(=O)OC(C)(C)C)C(=O)N21
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CC2SCC(C(N)=O)N2C1=O
Reaction time: 8 h

Procedure:
Compound 4 (0.5 g, 1.58 mmol) was treated with NH3/MeOH (20 mL) at room temperature and stirred overnight. The crude product was obtained by evaporation and used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1.[CH3:12][C:13]1[C:18]2[NH:19][C:20](=[O:22])[O:21][C:17]=2[CH:16]=[CH:15][CH:14]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([C:15]2[CH:14]=[C:13]([CH3:12])[C:18]3[NH:19][C:20](=[O:22])[O:21][C:17]=3[CH:16]=2)=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: Cc1cccc2oc(=O)[nH]c12
Reactant: O=C(Cl)c1cc(Cl)nc(Cl)n1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C(=O)c2cc(Cl)nc(Cl)n2)cc2oc(=O)[nH]c12
Temperature: 0 °C

Procedure:
2.75 g (13.0 mmol) 2,6-dichloro-pyrimidine-4-carboxylic acid chloride, 1.94 g (13.0 mmol) 4-methyl-3H-benzoxazol-2-one and 6.93 g (52.0 mmol) aluminium trichloride were heated to 125° C. for 1.5 h with stirring. The mixture combined with ice water and the product precipitated as a solid was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [Na].C(O)C.[Cl:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C@@H:15]([CH3:23])[C@H:16]([OH:22])[C:17](OCC)=[O:18])=[CH:9][NH:10]2.Br.[CH3:25][NH:26][C:27](NC)=[NH:28]>O>[Cl:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([CH:15]([CH:16]1[O:22][C:27]([NH:26][CH3:25])=[N:28][C:17]1=[O:18])[CH3:23])=[CH:9][NH:10]2
Reactant: CCOC(=O)[C@@H](O)[C@H](C)c1c[nH]c2cccc(Cl)c12
Reactant: CNC(=N)NC
Agent: Br
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CNC1=NC(=O)C(C(C)c2c[nH]c3cccc(Cl)c23)O1
Yield: 12.1 %

Procedure:
Sodium (100 mg) was dissolved into ethanol (5 ml). Ethyl (2S*,3R*)-3-(4-chloroindol-3-yl)-2-hydroxybutyrate (200 mg) and N,N′-dimethyl guanidine hydrogen bromide (143 mg) were added. The whole was refluxed for 16 hours. To the reaction mixture was added water and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. Concentration of the solution gave a residue, which was subjected to silica gel chromatography. Elution with hexane-acetone (1:1) provided the titled compound (25 mg).
Reaction SMILES: [N:1]1([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Br:18]N1C(=O)CCC1=O.O>O1CCOCC1>[Br:18][C:2]1[N:1]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccccc1-n1cnc2ccccc21
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccccc1-n1c(Br)nc2ccccc21

Procedure:
Compound 1 (25.75 grams, 117.5 mmol) was dissolved in dioxane (400 mL). To this was added N-bromosuccinimide (20.91 grams, 117.5 mmol). This was stirred at reflux for 3 hours after which time the mixture was poured into water and the product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated in vacuo and chromatographed (silica gel) using a mobile phase of dichloromethane-ethyl acetate 5:1 (v/v) to provide the title compound. Mass spectral and NMR data confirm the structure. Also synthesized analogously was the 5,6-dimethylbenzimidazole analog.