Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[C:14](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1/[CH:4]=[CH:5]/[C:6]([O:8][CH3:14])=[O:7]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C=Cc1ccc(F)cc1F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)/C=C/c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 7 h
Yield: 76.6 %

Procedure:
To a solution of 2,4-difluorocinnamic acid (20 g, 135 mmol) in N,N-dimethylformamide (500 mL) at room temperature under dry nitrogen was added potassium carbonate (90 g, 675 mmol) then iodomethane (21 mL, 337.5 mmol). The resulting mixture was stirred at room temperature under dry nitrogen for 7 hours before being quenched by the addition of water (1 L) and extracted with diethyl ether (3×200 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by an automated flash column chromatography system (CombiFlash® Separation System Sg 100c by Isco) using a pre-packed column (Redisep™ Disposable Columns for Flash Chromatography by Isco, 120 g column) eluting with 2% ethyl acetate in pentane increasing polarity in a linear gradient to 10% ethyl acetate in pentane over 1 hour to afford the title compound as a white solid (20.5 g, 77%). 1H NMR (400 MHz, CDCl3) δH 3.80 (3H, s), 6.50 (1H, d), 6.85 (1H, m), 7.50 (1H, m), 7.75 (1H, d); LRMS (APCI) 216 [MNH4+], 199 [MH+].
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:15]1([C:21]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:29]3[C@H:25]([CH2:26][NH:27][CH2:28]3)[C:24](=[O:30])[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[C:31]1([C:21]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C@H:29]3[C@H:25]([CH2:26][N:27]([C:10](=[O:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[N:2]([CH3:1])[CH3:13])[CH2:28]3)[C:24](=[O:30])[CH2:23][CH2:22]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Reactant: CN(C)c1ccccc1CC(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1ccccc1CC(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Reaction time: 1.5 h
Yield: 38.1 %

Procedure:
N,N'-Carbonyldiimidazole (2.43 g) is added to a solution of 2-dimethylaminophenylacetic acid (2.68 g) in dry dichloromethane (50 cc), cooled to +5° C. The mixture is stirred at +5° C. for 90 minutes and a solution of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (4.9 g) and triethylamine (4.2 cc) in dichloromethane (50 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (2×100 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 5 cm, height 50 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (40/60 by volume) and collecting 125 cc fractions. Fractions 5 to 20 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from a mixture of acetonitrile (40 cc) and isopropyl ether (200 cc). The crystals are drained, washed with isopropyl ether and dried. (3aR,7aR)-7,7-diphenyl-2-[2-(2-dimethylaminophenyl)acetyl]-4-perhydroisoindolone (2.58 g) is obtained in the form of white crystals, melting at 190° C.; [α]D20 =-242° (c=1.18, chloroform)
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[F:14].[CH3:16][OH:17]>>[CH3:2][O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:17][CH3:16])=[CH:7][C:6]=1[F:14]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1F
Reactant: CO
Agent: [Na]
Product: COC(=O)c1cc([N+](=O)[O-])c(OC)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 17 %

Procedure:
A mixture of sodium metal (1.27 g, 0.055 mol) and MeOH (250 mL) was stirred at 0° C. for 10 minutes. This solution was added to a solution of 2-fluoro-5-nitrobenzoic acid methyl ester (10.0 g, 0.046 mol) in MeOH (250 mL), and the mixture was stirred for 20 minutes at 0° C. to 5° C. The reaction mixture was then allowed to warm to room temperature and stir for 2 hours. The mixture was then filtered to give an off-white precipitate. Recrystallization with CHCl3 (70 ml) yielded an off-white crystalline solid, 1.825 g (0.008 mol, 17%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:10])[C:6](F)=[N:7][CH:8]=1)#[N:2].[CH3:11][CH:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:10][C:5]1[C:6]([N:13]2[CH2:14][CH2:15][CH2:16][CH:12]2[CH3:11])=[N:7][CH:8]=[C:3]([CH:4]=1)[C:1]#[N:2]
Reactant: CC1CCCN1
Reactant: Cc1cc(C#N)cnc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc(C#N)cnc1N1CCCC1C
Yield: 101.4 %

Procedure:
A solution of 5-cyano-2-fluoro-3-methylpyridine (Molekula, 400 mg; 2.94 mmol) in 1-butanol (1 mL), 2-methylpyrrolidine (Acros, 300 mg; 3.53 mmol) and DIEA (1.52 mL; 8.82 mmol) was heated at 90° C. for 18 hours. Reaction mixture was partitioned between EtOAc and water and washed with water to give the title compound as a yellow oil (600 mg, quantitative). HPLC (Method A) Rt 1.99 min (Purity: 96.1%). LC/MS (Method B): 202.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[Se:7])=[CH:4][CH:3]=1.Cl[CH:12]([CH:15]=O)[CH:13]=[O:14].C(=O)([O-])[O-].[Mg+2]>COCCOC>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[Se:7][C:12]([CH:13]=[O:14])=[CH:15][N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=[Se])c1ccc(Cl)cc1
Reactant: O=CC(Cl)C=O
Agent: O=C([O-])[O-]
Agent: [Mg+2]
Solvent: COCCOC
Product: O=Cc1cnc(-c2ccc(Cl)cc2)[se]1
Temperature: 60 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
To a suspension of 4-chloroselenobenzamide (219 mg, 1 mmol) and 2-chloromalonaldehyde (160 mg, 1.5 mmol) in 1,2-dimethoxyethane (1.5 ml) is added magnesium carbonate (42 mg, 0.5 mmol) and the resulting mixture is stirred at 60° C. under an atmosphere of nitrogen for 3 hours. The crude reaction mixture is then filtered through a plug of silica and washed with ethyl acetate, and filtrate is concentrated to give a brown solid. The crude product is purified by flash chromatography on silica gel to give 2-(4-chlorophenyl)selenazole-5-carbaldehyde (162 mg).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:6][C:5]=1[C:21]1[S:22][CH2:23][C@:24]([CH3:32])([C:26]([O:28]C(C)C)=[O:27])[N:25]=1>CO>[OH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:6][C:5]=1[C:21]1[S:22][CH2:23][C@:24]([CH3:32])([C:26]([OH:28])=[O:27])[N:25]=1
Reactant: COCCOCCOCCOc1ccc(O)c(C2=N[C@@](C)(C(=O)OC(C)C)CS2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCOCCOCCOc1ccc(O)c(C2=N[C@@](C)(C(=O)O)CS2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
A solution of 50% (w/w) NaOH (3.34 mL, 94 mmol) in CH3OH (34 mL) was added to 12 (2.14 g, 4.85 mmol) in CH3OH (70 mL) with ice bath cooling. The reaction mixture was stirred at room temperature for 18 h, and the bulk of the solvent was removed by rotary evaporation. The residue was treated with dilute NaCl (100 mL) and was extracted with ether (3×50 mL). The basic aqueous phase was cooled in ice, acidified with 2 N HCl to pH=2, and extracted with EtOAc (3×100 mL). After the EtOAc layers were washed with saturated NaCl (100 mL), glassware that was presoaked in 3 N HCl for 15 min was employed henceforth. After solvent removal by rotary evaporation, 1.88 g of 6 (97%) was obtained as an orange oil: [α]20 +40.0°; 1H NMR (D2O) δ 1.72 (s, 3H), 3.26 (d, 1H, J=11.2), 3.38 (s, 3H), 3.54-3.58 (m, 2H), 3.64-3.71 (m, 4H), 3.72-3.76 (m, 2H), 4.07-4.11 (m, 3H), 6.91-6.95 (m, 2H), 7.01 (dd, 1H, J=9.0, 3.0); 13C NMR δ 24.46, 40.04, 59.04, 68.40, 69.86, 70.48, 70.62, 70.80, 71.91, 83.44, 115.21, 115.65, 118.09, 121.63, 151.12, 153.69, 171.83, 176.18; HRMS m/z calcd for C18H26NO7S, 400.1429 (M+H). found, 400.1416.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH2:9])[NH:7][N:8]=2)[CH2:3][CH2:2]1.C([O:12][C:13](=O)[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])=O)C>CC(O)=O>[CH:1]1([C:4]2[CH:5]=[C:6]3[NH:9][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[F:23])=[CH:14][C:13](=[O:12])[N:7]3[N:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1cc(C2CC2)n[nH]1
Reactant: CCOC(=O)CC(=O)c1ccccc1F
Solvent: CC(=O)O
Product: O=c1cc(-c2ccccc2F)[nH]c2cc(C3CC3)nn12
Temperature: 25 °C

Procedure:
5-Cyclopropyl-2H-pyrazol-3-ylamine (2.9 g, 0.0235 mol) was suspended in AcOH (18 ml), 3-(2-fluorophenyl)-3-oxopropionic acid ethyl ester (4.67 ml, 1.1 eq) was added and the mixture heated at reflux for 3 h. The mixture was cooled to rt and concentrated underreduced pressure. The residue was stirred with EtOAc and the solid collected by filtration to give 2 g of 2-cyclopropyl-5-(2-fluorophenyl)-4H-pyrazolo[1,5-a]pyrimidin-7-one. Step B: The compound from step A (1 g, 0.00371 mol) was dissolved in POCl3 (12 ml) and cooled to 0° C. N,N-dimethylaniline (1.4 ml, 3 eq) was added and the mixture heated at 80° C. for 16 h. The mixture was cooled to rt and the volatiles removed. The resulting residue was dissolved in CH2Cl2, poured onto ice, and taken to pH 8 with NaHCO3 (s). The CH2Cl2 layer was removed, washed with water, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, hexane-EtOAc/hexane 1:9) to give 0.85 g of the title compound. LCMS: MH+=288.1.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=1>C(Cl)(Cl)Cl>[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N+:18]=1[O-:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccc(-c2ccco2)n1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(-c2ccco2)[n+]1[O-]
Temperature: 0 °C
Reaction time: 12 h
Yield: 52 %

Procedure:
4.90 g of metachioroperbenzoic acid are added in portions to a solution of 2.20 g of 2-furan-2-yl-6-methylpyridine (13.8 mmol) in 50 ml of chloroform cooled to 0° C. The mixture is stirred for 12 hours at room temperature and then the precipitate is removed by filtration and the filtrate is washed with a 5% aqueous solution of sodium bicarbonate. After drying over magnesium sulfate, filtration and evaporation, the title product is isolated by chromatography on a silica column (eluent: chloroform/methanol; 99:1). 1.25 g of a white powder are recovered.
Reaction SMILES: [S:1]1[C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][C:3]2[CH:10]=[CH:11][C:12]3[C:17]([C:2]1=2)=[CH:16][CH:15]=[C:14]([C:18](=[O:21])[CH2:19]Br)[CH:13]=3.[C:22]([O:26][C:27]([N:29]1[C@H:34]([C:35]([OH:37])=[O:36])[C@@H:33]2[CH2:38][C@H:30]1[CH2:31][CH2:32]2)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C@H:30]12[CH2:38][C@H:33]([CH2:32][CH2:31]1)[C@@H:34]([C:35]([O:37][CH2:19][C:18]([C:14]1[CH:13]=[C:12]3[C:17](=[CH:16][CH:15]=1)[C:2]1[S:1][C:5]([C:6](=[O:9])[CH2:7][O:37][C:35]([C@@H:34]4[C@@H:33]5[CH2:38][C@@H:30]([CH2:31][CH2:32]5)[N:29]4[C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])=[O:36])=[CH:4][C:3]=1[CH:10]=[CH:11]3)=[O:21])=[O:36])[N:29]2[C:27]([O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:28]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1C(=O)O
Reactant: O=C(CBr)c1ccc2c(ccc3cc(C(=O)CBr)sc32)c1
Product: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1C(=O)OCC(=O)c1ccc2c(ccc3cc(C(=O)COC(=O)[C@@H]4[C@H]5CC[C@H](C5)N4C(=O)OC(C)(C)C)sc32)c1

Procedure:
was synthesized from 1,1′-(naphtho[1,2-b]thiophene-2,7-diyl)bis(2-bromoethanone) (10c) and (1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (see, e.g., WO 2012/041227) by following an analogous procedure described in Step 5, Example 1. m/z 746.3 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][OH:29])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:39][C:40]#[C:41][C:42]([O:45][Si:46]([CH2:51][CH3:52])([CH2:49][CH3:50])[CH2:47][CH3:48])([CH3:44])[CH3:43].[H-].[Na+].C1OCCOCCOCCOCCOC1>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29][CH2:39][C:40]#[C:41][C:42]([O:45][Si:46]([CH2:47][CH3:48])([CH2:49][CH3:50])[CH2:51][CH3:52])([CH3:43])[CH3:44])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC[Si](CC)(CC)OC(C)(C)C#CCBr
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@H](CC[C@]4(C)C(CO)=CC[C@@H]34)[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)C#CCOCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 66 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene (200 mg, 0.367 mmol), 1-bromo-4-triethylsilyloxy-4-methyl-2-pentyne (216 mg, 0.741 mmol), sodium hydride (60% in oil, 44 mg, 1.10 mmol) 15-crown-5 (81 mg, 0.368 mmol) and tetrahydrofuran (1 ml) were subjected to reaction using a procedure similar to that of Example 5(1) (at room temperature 17 hours), worked up and purified by column chromatography (hexane:toluene=3:2) to give the titled compound (183 mg, 66%) as a pale yellow oil.
Reaction SMILES: C([O:4][C:5]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][Si](C)(C)C)=[CH:16][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:8])(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[C:20]([C:17]1[CH:18]=[CH:19][C:5]([OH:4])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)=[O:8])#[CH:21]
Reactant: CC(=O)Oc1ccc(C#C[Si](C)(C)C)cc1C(=O)c1ccc(C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc(O)c(C(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 100 mg (0.3 mmol) of 2-acetoxy-5-trimethylsilanylethynyl-4′-methylbenzophenone (Compound X) in 5 mL of tetrahydrofuran (under a blanket of argon) was added 0.86 mL (0.86 mmol) of tetrabutylammonium fluoride (1M in tetrahydrofuran). The resultant yellow solution was stirred at ambient temperature for 30 minutes, diluted with water (1 mL), extracted between ethyl ether and 10% HCl (aq.) solution, the layers separated and the aqueous phase washed with ethyl ether. The organic phases were combined, dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography (silica, 3% ethyl acetate in hexane) gave the title compound as an oil.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C(O)C>[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([N:19]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])=[CH:17][CH:16]=1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: COc1ccc(N)cc1
Solvent: CCO
Product: COc1ccc(N2CCC(C(=O)O)C2=O)cc1
Yield: 15.9 %

Procedure:
A mixture of 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.500 g; 2.94 mmol) and 4-methoxyaniline (1.09 g; 8.82 mmol) in ethanol (3 mL) was irradiated in a microwave oven for 3 minutes at 100° C. The mixture was concentrated under reduced pressure and the residue was dissolved in a solution of sodium hydroxide 6N, washed with dichloromethane, acidified with a solution of hydrochloric acid 6N to pH=2, extracted with ethyl acetate dried and concentrated under reduced pressure to yield 0.11 g (16%) of a pale pink solid which was used in the next step without further purification.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:28])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:14][C:13]=2[Cl:27])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH3:29][C:30]([NH2:34])([CH3:33])[C:31]#[CH:32]>>[NH2:34][C:30]([C:31]1[N:3]=[N:2][N:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:28])=[C:8]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])=[CH:14][C:13]=3[Cl:27])=[O:11])[CH:9]=2)[CH:32]=1)([CH3:33])[CH3:29]
Reactant: C#CC(C)(C)N
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Product: Cc1ccc(-n2cc(C(C)(C)N)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 434 (0.125 mmol) and 1,1-dimethyl-prop-2-ynylamine (0.125 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/DCM 0:100 to 5:95 as the eluent to afford the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6]3=[C:7]([CH2:12][CH2:13][N:5]3[CH:4]=[C:3]1[C:14]([OH:16])=O)[CH:8]=[CH:9][CH:10]=2.ClC(OCC(C)C)=O.[CH3:25][C:26]([O:28][CH2:29][C:30]1[CH2:49][S:48][C@@H:33]2[C@H:34]([NH:37][C:38]([C@H:40]([NH2:47])[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[O:39])[C:35](=[O:36])[N:32]2[C:31]=1[C:50]([OH:52])=[O:51])=[O:27].S([O-])([O-])(=O)=O>CN(C)C=O.C(N(CC)CC)C>[O:1]=[C:2]1[C:11]2[C:6]3=[C:7]([CH2:12][CH2:13][N:5]3[CH:4]=[C:3]1[C:14]([NH:47][CH:40]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:38]([NH:37][CH:34]1[C:35](=[O:36])[N:32]3[CH:33]1[S:48][CH2:49][C:30]([CH2:29][O:28][C:26](=[O:27])[CH3:25])=[C:31]3[C:50]([OH:52])=[O:51])=[O:39])=[O:16])[CH:8]=[CH:9][CH:10]=2
Reactant: O=C(O)c1cn2c3c(cccc3c1=O)CC2
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)[C@H](N)c3ccccc3)[C@H]2SC1
Agent: CC(C)COC(=O)Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(NC(=O)c3cn4c5c(cccc5c3=O)CC4)c3ccccc3)C2SC1
Reaction time: 0.25 h
Yield: 68 %

Procedure:
2.1 g of 6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid was added to 50 ml of anhydrous dimethylformamide and 1.66 ml of triethylamine was added to the mixture while ice-cooling and stirred for 15 minutes. Then, 1.6 ml of isobutyl chloroformate was added thereto dropwise and stirred for 45 minutes while ice-cooling. On the other hand, 4.5 g of cephaloglycine was suspended in 60 ml of anhydrous dimethylformamide and 2.8 ml of triethylamine and 1 g of anhydrous sulfate were added to the resulting mixture while ice-cooling followed by stirring the mixture for 30 minutes. Insoluble materials were removed by filtration and the filtrate was added at one time to the former reaction mixture and allowed to react for 2 hours while ice-cooling. After completion of the reaction, insoluble materials were removed by filtration and the filtrate was mixed with 10 ml of a 20% butanol solution of sodium 2-ethylhexanoate followed by the addition of 500 ml of diethyl ether to precipitate crystals. The crystals were collected by filtration and dissolved in 300 ml of water. The resulting solution was rendered acidic (pH=3) with dilute hydrochloric acid to precipitate solid materials, which were washed with water and dried under reduced pressure to obtain 4.0 g of 7-[2-(1,2-dihydro- 6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamido)-2-phenylacetamido]-3-(acetyloxymethyl)-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid as white amorphous crystals having a melting point of 245° to 248° C. (decomposition).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][O-:13].[Na+]>CO>[CH3:12][O:13][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ncccc1C(F)(F)F

Procedure:
Heat a mixture of 2-chloro-3-trifluoromethyl-pyridine (1.8 g, 10 mmol) and sodium methoxide (4M, 5 mL, 20 mmol) in MeOH (20 mL) at reflux for 18 hours. Cool the mixture and remove the volatiles by rotary evaporation. Dissolve the residue in EtOAc (50 mL) and wash with water (50 mL), saturated NaHCO3(aq) (50 mL) and brine (50 mL). Dry the organic extract over MgSO4 and remove the solvent under reduced pressure to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[CH3:11].[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>C(Cl)Cl>[CH3:11][C:5]1[CH:6]=[C:7]([N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)[CH:8]=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:12]
Reactant: COC(=O)c1ccc(F)cc1C
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(N2CCN(C)CC2)cc1C
Temperature: 110 °C
Yield: 37.8 %

Procedure:
In a cylindrical quartz tube were placed 4-fluoro-2-methyl-benzoic acid methyl ester (1.2 g, 7.14 mmol), N-methylpiperazine (0.95 ml, 8.5 mmol), K2CO3 (990 mg, 7.14 mmol) and DMSO (4 ml). The reaction was heated for 20 hours at 110° C. until HPLC revealed the disappearance of the starting-material. DCM (15 ml) was added and the solution was washed twice with water and the organic phase was dried over anhydrous Na2SO4. The crude was purified by flash chromatography (DCM/MeOH 95:5) affording the desired compound (670 mg, 38%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]3[N:28]=[C:27]([C:29]([O:31]C)=[O:30])[C:26]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:25][CH:24]=3)[CH:21]=2)[CH2:16][CH2:15][CH2:14]1)=[O:12].[Li+].[OH-]>CO.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]3[N:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:25][CH:24]=3)[CH:21]=2)[CH2:16][CH2:15][CH2:14]1)=[O:12]
Reactant: COC(=O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCC3)ccc1-c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCC3)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The title compound 6-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-phenylpicolinic acid (29) was prepared by the following procedure: To methyl 6-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-phenylpicolinate (29I) (23 mg, 0.044 mmol) in MeOH (0.55 mL) and water (0.11 mL) was added an aqueous solution of LiOH (0.066 mL of 2.0 M, ˜0.13 mmol). The reaction mixture was stirred at rt for 15 hours, concentrated under reduced pressure to remove MeOH and diluted with water. The pH was adjusted to ˜4 with 2 M HCl, and the resulting precipitate was isolated by filtration and washed with water. The crude material was purified by column chromatography on silica gel eluting with a gradient of DCM:MeOH 98:2-92:8, to provide the desired product 6-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-phenylpicolinic acid (29): MS (ESI(+)): m/z 507.1 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1)([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:18][C:14]2[CH:13]=[C:12]([N+:9]([O-:11])=[O:10])[CH:17]=[CH:16][CH:15]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: Cc1ccnc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccnc(Oc2cccc([N+](=O)[O-])c2)c1
Temperature: 130 °C
Reaction time: 24 h
Yield: 40.7 %

Procedure:
A suspension of 2-fluoro-4-methylpyridine (1.11 g), 3-nitrophenol (1.67 g) and potassium carbonate (1.80 g) in N,N-dimethylformamide (10 ml) was stirred at 130° C. for 24 hours. After cooling, the mixture was poured into water and stirred for 30 minutes. The precipitate was collected by filtration and dried to give 3-(4-methylpyridin-2-yloxy)-nitrobenzene (935 mg).