Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:7]=[C:8]([C:12]2[C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][C:18]([C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=3)[CH:9]=[CH:10][CH:11]=1)([OH:5])=[O:4]>O.CO>[C:3]([C:6]1[CH:7]=[C:8]([C:12]2[C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][CH:16]=3)[CH:9]=[CH:10][CH:11]=1)([OH:5])=[O:4]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(-c3cccc(C(=O)O)c3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(-c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
A solution of NaOH (68.7 mg, 1.72 mmol, 5.00 equiv) in water (3 mL) was added dropwise with stirring to a solution of methyl 3-(3-carboxyphenyl)-2-phenylquinoxaline-6-carboxylate (131.9 mg, 0.33 mmol, 1.00 equiv. in methanol (10 mL). The resulting solution was stirred overnight at 50° C. in an oil bath. The mixture was concentrated by vacuum; the pH was adjusted to 3-4 with 1N hydrochloric acid, the solid precipitate was filtered and washed with ether, affording 60 mg (49%) of 3-(3-carboxyphenyl)-2-phenylquinoxaline-6-carboxylic acid as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][N:24]([CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[C:17]=23)[CH:12]=[CH:11][N:10]=1.C(N(CC)CC)C.[S:38](Cl)([CH3:41])(=[O:40])=[O:39]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][N:24]([CH:25]4[CH2:26][CH2:27][N:28]([S:38]([CH3:41])(=[O:40])=[O:39])[CH2:29][CH2:30]4)[C:17]=23)[CH:12]=[CH:11][N:10]=1
Reactant: Cc1ccc(F)c(-c2cc(Nc3ccnc4cnn(C5CCNCC5)c34)ccn2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(F)c(-c2cc(Nc3ccnc4cnn(C5CCN(S(C)(=O)=O)CC5)c34)ccn2)c1
Temperature: 25 °C
Yield: 19.8 %

Procedure:
N-(2-(2-Fluoro-5-methylphenyl)pyridin-4-yl)-1-(piperidin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine (17 mg, 0.042 mmol) and triethylamine (0.018 ml, 0.127 mmol) were combined in dichloromethane (3 mL) and cool in an ice bath. Mesyl chloride (3.61 μl, 0.046 mmol) was added and the reaction was briefly warmed to room temperature. The reaction mixture was concentrated and purified by silica column chromatography eluting with 0-5% methanol in dichloromethane to give to afford N-(2-(2-fluoro-5-methylphenyl)pyridin-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine (4 mg, 20%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.93 (d, J=10.61 Hz, 2H) 2.24-2.43 (m, 5H) 2.55-2.69 (m, 2H) 2.76 (s, 3H) 3.84 (d, J=12.63 Hz, 2H) 4.57 (t, J=10.74 Hz, 1H) 6.29 (br. s., 1H) 6.60 (dd, J=5.56, 2.02 Hz, 1H) 6.88-7.09 (m, 1H) 7.09-7.25 (m, 3H) 7.75 (dd, J=7.45, 2.15 Hz, 1H) 8.33 (s, 1H) 8.50 (d, J=5.56 Hz, 1H) 8.56 (d, J=4.55 Hz, 1H). MS [M+H] found 481.4.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([CH2:17][C:18](O)=[O:19])=[CH:10][C:11]2[O:15][CH2:14][O:13][C:12]=2[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:1]([C:8]1[C:9]([CH2:17][CH2:18][OH:19])=[CH:10][C:11]2[O:15][CH2:14][O:13][C:12]=2[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cc2c(cc1Cc1ccccc1)OCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1cc2c(cc1Cc1ccccc1)OCO2
Temperature: 25 °C
Yield: 82.3 %

Procedure:
A solution of 1.82 g of (6-benzyl-1,3-benzodioxol-5-yl)acetic acid in 22 ml of anhydrous tetrahydrofuran was dropwise added at 0° C. to a suspension of 0.38 g of lithium aluminum hydride in anhydrous tetrahydrofuran. The obtained mixture was warmed to a room temperature to carry out the reaction for 4 hours, followed by the addition of water. The mixture was filtered to remove the precipitate. The filtrate was concentrated in a vacuum to obtain a yellow oil residue. This residue was purified by silica gel column chromatography (ethyl acetate/hexane=2:8) to obtain 1.42 g of the title compound as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:14])([F:13])[F:12])[CH:5]=O.[CH3:15][C:16]([S@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17].C1COCC1>C(O[Ti](OCC)(OCC)OCC)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:14])([F:13])[F:12])/[CH:5]=[N:21]/[S@@:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20]
Reactant: O=Cc1ccc(OC(F)(F)F)c(Cl)c1
Reactant: CC(C)(C)[S@](N)=O
Agent: CCO[Ti](OCC)(OCC)OCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)/N=C/c1ccc(OC(F)(F)F)c(Cl)c1
Temperature: 65 °C
Yield: 96.6 %

Procedure:
To a solution of 3-chloro-4-(trifluoromethoxy)benzaldehyde (2.8 g, 12 mmol) and (R)-2-methylpropane-2-sulfinamide (2.7 g, 22 mmol) and THF (25 mL) at RT was added tetraethoxytitanium (9.3 mL, 45 mmol) and the reaction was heated to 65° C. for 12 h. The reaction was cooled to RT, water (100 mL) was added and the solids were filtered and discarded. The filtrate was extracted with EtOAc, the organic fraction was dried, filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (500:10) to afford 3.8 g (98%) of (R,E)-N-(3-chloro-4-(trifluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide (218).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.Cl[CH2:23][CH2:24][CH:25]([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]>O>[CH2:27]([O:26][CH:25]([O:29][CH2:30][CH3:31])[CH2:24][CH2:23][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1)[CH3:28]
Reactant: NC(=O)c1ccc(O)cc1
Reactant: CCOC(CCCl)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(CCOc1ccc(C(N)=O)cc1)OCC
Temperature: 100 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
500 mg of 4-hydroxybenzamide, 1.51 g of potassium carbonate, 10 mL of DMF and 730 mg of 3-chloro-1,1-diethoxypropane are added to a flask. The reaction mixture is stirred at 100° C. for 18 hours and then 5 mL of water are added. The aqueous phase is extracted with ethyl acetate, and then the organic phases are collected, washed with water and concentrated under reduced pressure. The product is obtained in the form of a powder in a yield of 89% and with a chemical purity of 95%.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Cl:16][C:17]1[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:8]2[O:7][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)=[CH:19][CH:18]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(c2ccc(Cl)cc2)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 10 mL of methyl acetoacetate, 3.9 g of NaH 60% dispersion in oil, 58 mL of 1.6M n-butyl lithium in hexane, 13.5 g of 4-chlorobenzaldehyde and 250 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 15 minutes at 0° C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 149°-150° C.). 'H NMR (CDCl3) δ2.83 (dd, 1H), 2.95 (dd, 1H), 3.60 (dd, 2H), 5.67 (dd, 1H), 7.33-7.44 (m, 4H).
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]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:26])[CH:3]=1.[CH3:27][N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:30]5[CH2:31][CH2:32][N:28]([CH3:27])[C:29]5=[O:33])=[CH:3][C:4]=4[F:26])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: CN1CCNC1=O
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCN(C)C3=O)cc2F)CC1
Yield: 47.6 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (209 mg) described in Preparation Example 121 and 1-methylimidazolidin-2-one (50 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (104 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:22](O)(=[O:26])[CH2:23][CH2:24][CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:22]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)(=[O:13])=[O:14])[CH:8]=[CH:7][C:5]=2[N:6]=1)(=[O:26])[CH2:23][CH2:24][CH3:25]
Reactant: Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Reactant: CCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Temperature: 60 °C
Reaction time: 8 h
Yield: 129.9 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-aminobenzothiazol-6-yl ester (intermediate 16) (359 mg, 1.107 mmol), butyric acid (146 mg, 1.66 mmol), HATU (631 mg, 1.66 mmol) and N,N-diisopropylethylamine (0.286 ml, 1.66 mmol) in 5.5 ml of dimethylformamide in a 20 ml round-bottomed flask, equipped with a magnetic bar, is stirred for 8 hours at 60° C. and then left overnight at room temperature. The reaction medium is extracted with ethyl acetate and washed with water and then with 0.1 N hydrochloric acid solution. The organic phase is dried over magnesium sulfate, filtered and then evaporated to dryness. The residue obtained (567 mg of pale yellow solid) is purified by chromatography on a 40 g Biotage silica cartridge, eluting with a 9/1 toluene/isopropanol mixture. After evaporating off the solvent, 239 mg of 4-fluorobenzenesulfonic acid 2-butyrylaminobenzothiazol-6-yl ester are obtained (white solid) in a yield of 55%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12](Cl)=[O:13])[CH:5]=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[NH3:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH2:22])=[O:13])[CH:5]=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19]
Reactant: O=C(Cl)c1cccc(Oc2ccc(C(F)(F)F)c(Cl)c2)c1
Reactant: N
Solvent: Cc1ccccc1
Product: NC(=O)c1cccc(Oc2ccc(C(F)(F)F)c(Cl)c2)c1
Temperature: 5 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
Into a 3 neck round bottom flask fitted with condenser and dropping funnel was added 3-(2-chloro-α,α,α-trifluoro-4-tolyloxy) benzoyl chloride (19.8 g 0.059 mol) and toluene (80 ml). The mixture was cooled in an ice bath to about 5° C. then ammonia solution 32% (15.6 g, 0.29 mol) was added dropwise. A yellow/orange precipitate formed and the mixture was stirred vigorously for 3 hours. The mixture was then extracted with toluene (200 ml) and washed with water (80 ml). The organic layer was separated, dried (MgSO4), filtered and the solvent removed in vacuo. The resulting solid was then triturated with hexane to afford the product as a white solid (16.5 g, 91%). IR 1652 cm-1 (amide C=O), 3376 and 3191 cm-1 (N--H str);
Reaction SMILES: [CH3:1][CH:2]([C:6](=[O:8])[CH3:7])[C:3](=[O:5])[CH3:4].[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11]>N12CCCN=C1CCCCC2.C(OCC)C>[CH2:14]([O:13][C:9](=[O:12])[CH2:10][CH2:11][C:2]([C:6](=[O:8])[CH3:7])([CH3:1])[C:3](=[O:5])[CH3:4])[CH3:15]
Reactant: C=CC(=O)OCC
Reactant: CC(=O)C(C)C(C)=O
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CCC(C)(C(C)=O)C(C)=O
Reaction time: 16 h
Yield: 59.3 %

Procedure:
30 g of 3-methyl-2,4-pentandione and 0.4 g of 1,8-diazabicyclo-[5.4.0]-undec-7-ene were mixed and 39.3 g of ethyl acrylate was added dropwise with the temperature being controlled by cooling with ice. Stirring was continued for 16 hours, the base was neutralized, 50 ml of diethyl ether was added, and the mixture was extracted with an aqueous sodium carbonate solution and water. Fractional distillation of the organic layer yielded 33.4 g of 4-acetyl-4-methyl-5-oxo-hexanoic acid ethyl ester (boiling point: 95° C./0.02 mbar; purity: 98%; colorless).
Reaction SMILES: [CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1.[Cl:6][SiH:7]([Cl:9])[Cl:8].C(O)(C)C>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH:1]1([Si:7]([Cl:9])([Cl:8])[Cl:6])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cl[SiH](Cl)Cl
Reactant: C1=CCCC1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: Cl[Si](Cl)(Cl)C1CCCC1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
In a 100 ml autoclave were charged 13.5 g (0.198 mole) of cyclopentene, 24.4 g (0.180 mole) of trichlorosilane and 25 μl of a 0.077 m mole/ml chloroplatinic acid solution in isopropyl alcohol (platinum content 1.92×10-6 mole), which were then stirred at 150° C. for 30 minutes. Cyclopentyl trichlorosilane was obtained quantitatively.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])=O.[NH2:12][C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[S:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:12]=[C:13]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[S:14][CH:2]=1
Reactant: O=C(CBr)c1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccccc3F)cs2)CC1
Yield: 26.4 %

Procedure:
A solution of 2-bromo-1-(2-fluorophenyl)ethanone (977 mg, 4.50 mmol), tert-butyl 4-(aminocarbonothioyl)piperidine-1-carboxylate (1.0 g, 4.09 mmol) and potassium carbonate (1.13 g, 8.18 mmol) in dimethylformamide (30 ml) was stirred at 110° C. for 1 hour. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the desired product (391 mg, 26.3%) as an oil.
Reaction SMILES: [CH3:1][C:2]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)(=[O:6])=[O:5])[CH3:3].[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25](B(O)O)[CH:24]=1.C(N(C(C)C)CC)(C)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O1CCCC1>[CH3:3][C:2]([CH:17]1[CH2:22][CH2:21][N:20]([C:25]2[CH:24]=[N:23][C:32]3[C:27]([CH:26]=2)=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:19][CH2:18]1)([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=1)(=[O:5])=[O:6])[CH3:1]
Reactant: CC(C)(C1CCNCC1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: OB(O)c1cnc2ccccc2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C1CCN(c2cnc3ccccc3c2)CC1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To a 10 ml vial was added 4-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperidine (30 mg, 0.089 mmol), quinolin-3-ylboronic acid (62 mg, 0.358 mmol), copper acetate (32.5 mg, 0.179 mmol), diisopropylethyl amine (0.049 ml, 0.358 mmol) and 1 ml tetrahydrofuran. The resulting reaction mixture was stirred at room temperature for one hour then 60° C. 3 hours. After aqueous work up, the crude product was purified on reverse phase column eluted with water/acetonitrile gradient solvent to give 24 mg desired product as fluffy white solid after lyophilizing.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](Cl)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:11][CH2:12][OH:13].CN1C(=O)CCC1.[H-].[Na+]>CCOC(C)=O>[NH2:1][C:2]1[CH:9]=[C:8]([O:13][CH2:12][CH3:11])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1Cl
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOc1cc(N)ncc1C#N
Temperature: 70 °C

Procedure:
6-Amino-4-chloronicotinonitrile (intermediate 16, 40 mg, 0.260 mmol) and EtOH (0.076 ml, 1.302 mmol) were charged into a sealed vial. NMP (1.5 ml) was added to the mixture at room temperature followed by NaH (60% dispersion in mineral oil, 62.5 mg, 1.56 mmol). The mixture was then heated at 70° C. for 2.5 days. The reaction mixture was diluted in EtOAc and washed with water (2×) and brine. The org. layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a beige solid. (UPLC-MS 1) tR 0.50 min; ESI-MS 164.0 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[C:6]([CH2:8][CH3:9])[NH:5][C:4]=1[C:10]([OH:12])=[O:11])#[N:2].[CH3:13][Si](C=[N+]=[N-])(C)C.CCOCC>C1COCC1>[CH3:13][O:11][C:10]([C:4]1[NH:5][C:6]([CH2:8][CH3:9])=[CH:7][C:3]=1[C:1]#[N:2])=[O:12]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCc1cc(C#N)c(C(=O)O)[nH]1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1cc(C#N)c(C(=O)OC)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Cyano-5-ethyl-1H-pyrrole-2-carboxylic acid (Intermediate 31) (500 mg) was dissolved in anhydrous THF (5 ml) and cooled to 0° C. (Trimethylsilyl)diazomethane/ether (2 ml) was added. The mixture was stirred at room temperature under nitrogen gas for 1 h. The solvent was removed in vacuo and MeOH was added. The mixture was stirred for a further 15 min, the solvent was removed in vacuo and the solid was dried under vacuum to give the title compound (580 mg).
Reaction SMILES: [N:1]1C=CC=CC=1.N.[NH2:8][C:9]1[C:10]([F:35])=[CH:11][C:12]([F:34])=[C:13]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([N+:27]([O-:29])=[O:28])=[C:22](F)[C:23]=3[CH3:25])[C:18](=[O:30])[C:17]([C:31]([OH:33])=[O:32])=[CH:16]2)[CH:14]=1>C(OCC)C>[NH2:1][C:22]1[C:23]([CH3:25])=[C:24]2[C:19]([C:18](=[O:30])[C:17]([C:31]([OH:33])=[O:32])=[CH:16][N:15]2[C:13]2[CH:14]=[C:9]([NH2:8])[C:10]([F:35])=[CH:11][C:12]=2[F:34])=[CH:20][C:21]=1[N+:27]([O-:29])=[O:28]
Reactant: c1ccncc1
Reactant: Cc1c(F)c([N+](=O)[O-])cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Agent: N
Solvent: CCOCC
Product: Cc1c(N)c([N+](=O)[O-])cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Temperature: 50 °C
Reaction time: 48 h

Procedure:
Pyridine (1.0 ml) and 28% aqueous ammonia (100 mg) were added to 1-(5-amino-2,4-difluorophenyl)-7-fluoro-8-methyl-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg), and the mixture was stirred at 50° C. for 2 days. Additional 28% aqueous ammonia (0.5 ml) was added, and the mixture was further stirred overnight at 50° C. Diethyl ether was added to the reaction mixture, followed by stirring. A supernatant liquid was removed, and ethanol was added to the residue. Solids deposited were collected by filtration and washed with ethanol to obtain the title compound (59 mg) as a yellow powder.
Reaction SMILES: [O:1]1[CH:6]2[C:7]([O:9][C:10](=[O:11])[CH:2]1[CH2:3][CH2:4][CH2:5]2)=O.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:19][CH2:18]1>C(Cl)Cl>[N:24]1[CH:25]=[CH:26][CH:27]=[N:28][C:23]=1[N:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[C:7](=[O:9])[CH:6]3[O:1][CH:2]([CH2:3][CH2:4][CH2:5]3)[C:10]2=[O:11])[CH2:18][CH2:19]1
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Reactant: O=C1OC(=O)C2CCCC1O2
Solvent: ClCCl
Product: O=C1C2CCCC(O2)C(=O)N1CCCCN1CCN(c2ncccn2)CC1
Reaction time: 0.5 h

Procedure:
Tetrahydropyran-2,6-dicarboxylic anhydride (3.0 g., 19 mmole) and 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine (4.98 g., 21 mmole) were combined and stirred for 30 minutes in 200 ml. of methylene chloride. The solvent was removed in vacuum and replaced with 300 ml. of xylene. The mixture was refluxed for 48 hours with water removal via a Dean-Stark trap. The solvent was again removed in vacuum and the residue was column chromatographed on 100 g. of silica with a gradient elution beginning with chloroform and ending with 5% ethanol in chloroform. The relevant fractions were combined and evaporated and the product crystallized from isopropanol with the addition of 4N isopropanolic HCl and ether. A second crystallization from isopropanol gave 1.9 g. of the title compound as the dihydrochloride, hemihydrate; m.p. 232°-233° C. (d).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([C:10](=O)[CH2:11][CH3:12])=[C:5](OC)[CH2:6][CH3:7].Cl.[Br:16][C:17]1[CH:18]=[C:19]([NH:23][NH2:24])[CH:20]=[CH:21][CH:22]=1.CCN(CC)CC>CO>[CH3:1][O:2][C:3]([C:4]1[C:10]([CH2:11][CH3:12])=[N:24][N:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Br:16])[CH:18]=2)[C:5]=1[CH2:6][CH3:7])=[O:14]
Reactant: NNc1cccc(Br)c1
Reactant: CCC(=O)C(C(=O)OC)=C(CC)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCc1nn(-c2cccc(Br)c2)c(CC)c1C(=O)OC
Temperature: -20 °C
Reaction time: 20 h

Procedure:
A solution of 7.10 g (35.5 mmol) of (E and/or Z)-3-methoxy-2-propionyl-pent-2-enoic acid methyl ester in 10 ml of MeOH was added to a solution of 8.09 g (35.5 mmol) of 3-bromophenylhydrazine hydrochloride in 150 ml of MeOH and the mixture was cooled to −20° C. To this mixture was added a solution of 3.79 g=5.22 ml (37.2 mmol) of Et3N in 40 ml of MeOH drop by drop and the reaction was then warmed up to RT. After 20 hours, it was poured into crashed ice and extracted twice with Et2O; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated to give 7.62 g of the title compound as light red oil. MS: 337.1 (MH+, 1 Br).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:13]=[C:12](Br)[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH2:15].[CH3:17][N:18](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:13]=[C:12]([C:17]#[N:18])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH2:15]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(Br)c(C(=O)OC)cc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1cc(C#N)c(C(=O)OC)cc1N
Temperature: 120 °C
Yield: 98 %

Procedure:
2-Amino-5-bromo-terephthalic acid dimethyl ester (15.0 g, 52.1 mmol), zinc (II) cyanide (6.11 g, 52.1 mmol) and tetrakis(triphenylphosphine)palladium (0) (3.0 g, 2.6 mmol) were suspended in DMF (50 ml) and the resultant reaction mixture degassed was purged with argon. The reaction mixture was heated at 120° C. for 30 minutes then concentrated in vacuo. The resultant residue was triturated with hot water (100 ml) and the product collected by filtration to yield the title compound as a dark grey solid (12.0 g, 98%). 1H NMR (d6-DMSO, 400 MHz) 8.11 (1H, s), 7.62 (2H, br s), 7.52 (1H, s), 3.89 (3H, s), 3.85 (3H, s).
Reaction SMILES: C(S[C:4]1[O:5][C:6]2[C:11]([C:12](=[O:14])[CH:13]=1)=[CH:10][CH:9]=[C:8]1[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=21)C.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CO>[N:19]1([C:4]2[O:5][C:6]3[C:11]([C:12](=[O:14])[CH:13]=2)=[CH:10][CH:9]=[C:8]2[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=32)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: C1CNCCN1
Reactant: CCSc1cc(=O)c2ccc3ccccc3c2o1
Solvent: CO
Product: O=c1cc(N2CCNCC2)oc2c1ccc1ccccc12
Yield: 28 %

Procedure:
Prepared from 2-ethylsulphanyl-benzo[h]chromen-4-one (0.384 g, 1.5 mmol) and piperazine (1.29 g, 15 mmol). Recrystallisation from ethyl acetate provided an off white solid. (0.121 g, 0.43 mmol, 28% yield) mp 208-209° C. UV λmax=317.0, 273.0, 255.0, 216.5 nm (Methanol). 1H NMR (200 MHz, CDCl3) δ 3.01 (4H, m); 3.55 (4H, m); 5.57 (1H, s); 7.56 (2H, m); 7.66 (1H, d); 7.85 (1H, m); 8.08 (1H, d); 8.21 (1H, m). EIMS m/z (EI+): 280 (M+), 261, 238, 225, 170, 139. Anal. Calcd for C17H16N2O2.0.3H2O: C, 71.46; H, 5.81; N, 9.80. Found: C, 71.88; H, 5.91; N, 9.33.