Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[Br:10]N1C(=O)CCC1=O>C(#N)C.C(Cl)(Cl)(Cl)Cl>[Br:10][C:8]1[CH:9]=[C:3]([S:2][CH3:1])[CH:4]=[CH:5][C:6]=1[NH2:7]
Reactant: CSc1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: CSc1ccc(N)c(Br)c1
Temperature: 25 °C

Procedure:
To a solution containing 1.0 mL (8.0 mmol) of 4-(methylthio)aniline in 40 mL of a 3:1 solution mixture of acetonitrile/carbon tetrachloride was added 1.6 g (8.8 mmol) of N-bromosuccinimide. The reaction mixture was heated to reflux for 30 min, then cooled to ambient temperature and concentrated in vacuo. To the residue was added 100 mL of ethyl acetate and the organic solution was washed sequentially with saturated aqueous sodium bicarbonate solution and saturated aqueous brine (100 mL each), dried over sodium sulfate, filtered and evaporated in vacuo to yield a viscous oil. The crude material was purified by flash chromatography on a Biotage Horizon® system (silica gel, 0 to 30% ethyl acetate/hexanes gradient) to give the title compound. 1H NMR (CDCl3): δ 7.45 (s, 1H), 7.15 (dd, J=8.3, 2.0 Hz, 1H), 6.72 (d, 8.5 Hz, 1H), 4.08 (bs, NH2), 2.44 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8]C2([Si](C)(C)C)C#N.Cl[Sn]Cl.O.Cl.[CH3:23][C:24]([OH:26])=[O:25]>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH:23]2[C:24]([OH:26])=[O:25]
Reactant: CC(=O)O
Reactant: C[Si](C)(C)C1(C#N)CCOc2c(Br)cccc21
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: O=C(O)C1CCOc2c(Br)cccc21

Procedure:
A solution of 8-bromo-4-(trimethylsilyl)-3,4-dihydro-2H-chromene-4-carbonitrile (9.6 g, 29.45 mmol) in a mixture of conc. HCl/HOAc (50 mL/40 mL) was added SnCl2.H2O (26.57 g, 117.8 mmol) and the miture was refluxed for 48 hours. The reaction solution was concentrated and the residue was partitioned between water and EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to afford 8-bromo-3,4-dihydro-2H-chromene-4-carboxylic acid. 1H-NMR (300 MHz, CDCl3) δ ppm 7.15˜7.46 (m, 2H), 6.75˜6.92 (m, 1H), 4.24˜4.4 (m, 2H), 3.78˜3.84 (m, 1H), 2.1˜2.39 (m, 2H).
Reaction SMILES: [Cl-].[CH3:2][Mg]I.[C:5](=[C:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:17])([CH3:7])[CH3:6].[Cl-].[NH4+]>O1CCCC1>[C:5]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:17])([CH3:2])([CH3:7])[CH3:6]
Reactant: C[Mg]I
Reactant: CC(C)=C1Cc2ccccc2C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)C1Cc2ccccc2C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To the cupurous chloride (0.258 g, 2.61 mmol) inside 250 mL round bottom flask was added 22 mL of methylmagnesium iodide (3.0 M solution in diethyl ether, 66 mmol) at 0° C. under nitrogen. Diethyl ether was removed in vacuo. Tetrahydrofuran (65 mL) was then introduced. To this resulting suspension was added a solution of 2-isopropylidene-1-indanone (5.00 g, 29 mmol) in Tetrahydrofuran (25 mL) through a dropping funnel dropwise at 0° C. The mixture was stirred at the same temperature for another 1 h and then at ambient temperature overnight (16 h). The slurry was poured into ice (32 g) containing ammonium chloride (6.44 g). The solution was extracted with diethyl ether (5*80 mL). All ethereal layers were combined, washed with water (20 mL), dried over anhydrous magnesium sulfate and concentrated to yield 5.29 g (97%) of 2-t-butyl-1-indanone. H-NMR (CDCL3) δ 0.95 (s, 9H), 2.38 (dd, J=4.3, 8.0 Hz, 1 H), 2.90 (dd, J=4.3, 17.4 Hz, 1H), 3.08 (dd, J=8.0, 17.4 Hz, 1H) 7.23 (br t, J=7.4 Hz, 1H), 7.35 (br d, J=7.6 Hz, 1H), 7.46 (br t, J=7.6 Hz, 1H), 7.61 (br d, J=7.4 Hz, 1H):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:15]1[N:16]([CH2:23][C@@H:24]2[CH2:26][O:25]2)[CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[N:19]=1.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:26][C@@H:24]3[O:25][C:15]4=[N:19][C:18]([N+:20]([O-:22])=[O:21])=[CH:17][N:16]4[CH2:23]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cn(C[C@@H]2CO2)c(Cl)n1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cn2c(n1)O[C@@H](CN1CCN(c3ccc(Cl)cc3)CC1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
Then, a mixture of 1-(4-chlorophenyl)-piperazine obtained, (R)-2-chloro-1-(oxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 9 (763 mg, 3.75 mmol) and DMF (5 ml) was stirred at 70° C. for 6 hours. To the solution, sodium hydride (219 mg, 5.48 mmol) was added with cooling on ice-bath followed by stirring at room temperature for 2 hours. To the reaction mixture, ice-water was added, and precipitates were filtered off. The resulting solids were recrystallized from acetone/water to afford (S)-2-[4-(4-chlorophenyl)piperazin-1-ylmethyl]-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (250 mg, yield 18%) as a light yellow powder.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]1([SH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O[K])(C)(C)C>C1COCC1>[C:1]1([C:7]([S:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][C:9]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C(#Cc1ccccc1)C(=Nc1ccccc1)Sc1ccccc1
Reactant: Sc1ccccc1
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: C(=C(Sc1ccccc1)c1ccccc1)C(=Nc1ccccc1)Sc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 201 mg of phenyl 3,N-diphenylpropynimidothioate in 5 ml of THF was added 0.08 ml of thiophenol and tert-butoxy potassium (a catalytic amount). The mixture was stirred at room temperature for 2 hours and then refluxed for 2 hours. The reaction mixture was concentrated under vacuum. The residue was purified by medium pressure preparative HPLC to obtain 269 mg of phenyl 3,N-diphenyl-3-(phenylthio)-2-propenimidothioate (hereinafter referred to as the present compound 42) as a yellow oil.
Reaction SMILES: C([O:8][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:24](=[O:25])[C:23]2[CH2:26][CH2:27][CH:28]=[CH:29][C:22]=2[O:21][C:20]2[CH:30]=[CH:31][CH:32]=[CH:33][C:19]1=2)[CH:10]=[O:11])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:24](=[O:25])[C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[O:21][C:20]2[CH:30]=[CH:31][CH:32]=[CH:33][C:19]1=2)[CH:10]=[O:11]
Reactant: O=CN(CCCCCCN1C(=O)C2=C(C=CCC2)Oc2ccccc21)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=CN(O)CCCCCCN1C(=O)c2ccccc2Oc2ccccc21
Yield: 6.5 %

Procedure:
Title compound 403 (348 mg, 0.783 mmol) was dissolved in methanol (10 mL). The 10% palladium on charcoal (120 mg, 33% by wt) was added. The reaction mixture was stirred for 3 hours under 1 atmosphere of hydrogen at room temperature. The reaction mixture was filtered to remove the catalyst and the filtrate was evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and evaporated to afford title compound 404 (18 mg, 6%) as a white solid. 1H NMR (CD3OD) δ (ppm): 8.24, 7.89 (2s, rotamers, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.54-7.46 (m, 2H), 7.33 (dt, J=7.4, 2.0 Hz, 1H), 7.28-7.21 (m, 4H), 4.19 (br s, 2H), 3.50 (t, J=6.8 Hz, 1H), 3.44 (t, J=6.8 Hz, 1H), 1.70-1.55 (m, 4H), 1.44-1.29 (m, 4H). MS (m/z): 355.2 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:43]([N:45]([CH2:60][CH3:61])[C:46]([C@@H:48]1[CH2:53][CH2:52][CH2:51][N:50]([CH:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:49]1)=[O:47])[CH3:44]>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([N:57]3[CH2:56][CH2:55][CH:54]([N:50]4[CH2:51][CH2:52][CH2:53][C@@H:48]([C:46](=[O:47])[N:45]([CH2:60][CH3:61])[CH2:43][CH3:44])[CH2:49]4)[CH2:59][CH2:58]3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: CCN(CC)C(=O)[C@@H]1CCCN(C2CCNCC2)C1
Product: CCN(CC)C(=O)[C@@H]1CCCN(C2CCN(C(=O)C34CCC(N(CC(=O)N5C[C@@H](F)C[C@H]5C#N)C(=O)OCc5ccccc5)(CC3)CC4)CC2)C1
Yield: 77.8 %

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (74.9 mg) and (3R)—N,N-diethyl-1-(piperidin-4-yl)piperidine-3-carboxamide (61.0 mg) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-[4-[(3R)-3-(N,N-diethylcarbamoyl)piperidin-1-yl]piperidin-1-yl]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (71.7 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2.[F:13][C:14]([F:29])([F:28])[C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:13][C:14]([F:28])([F:29])[C:15]1[CH:16]=[C:17]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]3)[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC1Cc2cccc(Br)c2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC1Cc2cccc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2C1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
Using a method similar to Example 15 a), 6.75 g (0.03 mol) of (2), 8.5 g (0.033 mol) of 3,5-bis(trifluoromethyl)phenylboronic acid and 7.0 g (0.066 mol) of sodium carbonate were placed in 120 ml of dimethoxyethane and 36 ml of water in the reaction vessel, the mixture was degassed a number of times and saturated with argon. 120 mg (0.5 mmol) of palladium acetate and 282 mg (1.1 mmol) of TPP were added and the reaction mixture was stirred for 2 hours at 80° C. After addition of 150 ml of water, the mixture was extracted 3 times with 150 ml each time of diethyl ether, the combined ether phases were washed 3 times with 150 ml each time of water and dried over magnesium sulfate. Removal of the solvent gave 9.93 g of (18) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][CH:11]=[CH:10]2)=[O:4].C([Mg]Br)C.[CH3:18][C:19]1([CH3:27])[C:21]([CH3:23])([CH3:22])[CH:20]1[C:24](Cl)=[O:25]>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][CH:11]=[C:10]2[C:24]([CH:20]1[C:21]([CH3:23])([CH3:22])[C:19]1([CH3:27])[CH3:18])=[O:25])=[O:4]
Reactant: COC(=O)c1cccc2cc[nH]c12
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: COC(=O)c1cccc2c(C(=O)C3C(C)(C)C3(C)C)c[nH]c12
Yield: 63.2 %

Procedure:
A mixture of methyl-indole-7-carboxylate (Maybridge, 1.0 g, 5.7 mmol), ethylmagnesium bromide (1.0 M solution in THF, 6.9 mL, 6.9 mmol), zinc chloride (1.0 M solution in Et2O, 6.9 mL, 6.9 mmol) and the product of Example 1A (7.4 mmol) in 25 mL of dichloromethane was processed as described in Example 1B to provide the title compound (1.1 g, 3.6 mmol, 63% yield). MS (DCI/NH3) m/z 300 (M+H)+.
Reaction SMILES: CN1CCCC1.[NH2:7][C:8]1[N:13]=[C:12]([N:14]2[C:23]3[C:18](=[CH:19][C:20]([F:26])=[C:21](F)[C:22]=3[Cl:24])[C:17](=[O:27])[C:16]([C:28]([OH:30])=[O:29])=[CH:15]2)[C:11]([F:31])=[CH:10][C:9]=1[F:32].C(OC([NH:40][C@@:41]12[CH2:48][CH2:47][CH2:46][C@:45]1([F:49])[CH2:44][NH:43][CH2:42]2)=O)(C)(C)C>C(#N)C>[NH2:40][C@@:41]12[CH2:48][CH2:47][CH2:46][C@:45]1([F:49])[CH2:44][N:43]([C:21]1[C:22]([Cl:24])=[C:23]3[C:18]([C:17](=[O:27])[C:16]([C:28]([OH:30])=[O:29])=[CH:15][N:14]3[C:12]3[C:11]([F:31])=[CH:10][C:9]([F:32])=[C:8]([NH2:7])[N:13]=3)=[CH:19][C:20]=1[F:26])[CH2:42]2
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: CC(C)(C)OC(=O)N[C@@]12CCC[C@]1(F)CNC2
Agent: CN1CCCC1
Solvent: CC#N
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4C[C@]5(N)CCC[C@]5(F)C4)c(Cl)c32)c(F)cc1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 11.6 %

Procedure:
N-methylpyrrolidine (0.246 mL, 2.37 mmol) and 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (306 mg, 0.79 mmol) were added to a solution of (1R,5S)-1-(tert-butoxycarbonylamino)-5-fluoro-3-azabicyclo[3.3.0]octane (193 mg, 0.79 mmol) in acetonitrile (10.0 mL), and the mixture was heated to reflux for 10 hours. 1-(6-Amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (92 mg, 0.24 mmol) was added again to the reaction solution, and the mixture was further heated to reflux for 4.5 hours. The solvent was evaporated under reduced pressure, and then the residue was extracted with a 10% citric acid solution and ethyl acetate. Then, the organic layer was washed with water twice and brine, dried over anhydrous sodium sulfate, and filtered. Thereafter, the solvent was evaporated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (dichloromethane:methanol=99:1). The resulting oil (409 mg) was dissolved in concentrated hydrochloric acid (3.0 mL) under ice-cooling, and the solution was stirred at room temperature for 2.5 hours. The reaction solution was washed with chloroform twice, and then the aqueous layer was adjusted to pH 12 with a saturated sodium hydroxide solution. The basic solution was adjusted to pH 7.4 with hydrochloric acid, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the solvent was evaporated under reduced pressure. Chloroform was added to the residue, and the insoluble material was removed by filtration. Then, the filtrate was evaporated under reduced pressure, and the resulting residue was purified by recrystallization from ethanol to give 47 mg of the title compound as a pale yellow solid.
Reaction SMILES: B.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]#[N:13])=[C:6]2[C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[F:21].Cl.N>O1CCCC1>[NH2:13][CH2:12][C:7]1[NH:8][C:9]2[C:5]([C:6]=1[C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[F:21])=[CH:4][C:3]([Cl:2])=[CH:11][CH:10]=2
Reactant: N#Cc1[nH]c2ccc(Cl)cc2c1-c1c(F)cccc1F
Agent: B
Agent: Cl
Agent: N
Solvent: C1CCOC1
Product: NCc1[nH]c2ccc(Cl)cc2c1-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Borane in tetrahydrofuran (7 ml of a 1M solution) is added to a solution of 1 g (3.46 mmol) of 5-chloro-3-(2,6-difluorophenyl)indole-2-carbonitrile in 15 ml of dry tetrahydrofuran. The solution is stirred at room temperature for 2 hours and then refluxed for half an hour and cooled to room temperature. 5 ml of 5N aqueous HCl is added dropwise and the mixture is refluxed for 20 minutes. The mixture is then poured onto a mixture of ice and aqueous 10 percent ammonia, and the precipitate is extracted with chloroform. The chloroform layer is washed with water and dried over magnesium sulfate, filtered and evaporated to dryness. Recrystallization from chloroform (charcoal) affords colorless crystals; m.p. 212°-214° .
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19]CC)=[O:18])[CH:15]=3)[N:10]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[Li+].[OH-]>C1COCC1>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=3)[N:10]([C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1ccc2c(c1)c(-c1ccnc(C)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To the solution of ethyl 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylate (260 mg, 0.5 mmol) in THF (5 mL) was added LiOH (1M, 2 mL). The reaction mixture was stirred at room temperature for overnight. HCL was added to adjust the pH to 4-5 and ethyl acetated was added. The extract was washed with water (10 mL0 and dry over sodium sulfate and concentrated to give the desired product in 95% yield.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[C:11](=O)(O)[O-].[Na+]>CO.S(=O)(=O)(O)O>[CH3:11][O:9][C:8]([C@H:5]1[CH2:6][CH2:7][C@H:2]([NH2:1])[CH2:3][CH2:4]1)=[O:10]
Reactant: O=C([O-])O
Reactant: N[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](N)CC1

Procedure:
A solution of trans 4-amino-cyclohexanecarboxylic acid (12.5 g, 87.0 mmol) in methanol (400 mL) and conc. sulphuric acid (9.0 mL) was stirred at room temperature for one week. The mixture was then neutralised with sodium bicarbonate and the solvent was concentrated under vacuum. The residue was taken into water and continuously extracted with DCM for 18 hours. The organic phase was dried over sodium sulphate and concentrated under vacuum to afford 9.20 g (67%) of trans 4-amino-cyclohexanecarboxylic acid methyl ester as an oil. 1H NMR (400 MHz, CDCl3): δ 3.67 (s, 3H), 2.67 (tt, 1H), 2.24 (tt, 1H), 2.02-1.90 (m, 4H), 1.55-1.41 (m, 2H), 1.19-1.10 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([C:14]([O:16]CC)=[O:15])=[CH:12][N:13]=2)=[CH:5][CH:4]=1.[Li+].[OH-].Cl>C1COCC1.O>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][C:11]([C:14]([OH:16])=[O:15])=[CH:12][N:13]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(-c2ccc(C(F)(F)F)cc2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.5 %

Procedure:
Ethyl 2-[4-(trifluoromethyl)phenyl]thiazole-5-carboxylate (28 mg, 0.09 mmol.) and LiOH (5.0 mg, 0.12 mmol) were diluted with THF/H2O=1:1 (1 mL), and then stirred for 3 hrs at room temperature. The mixture was acidified with 1N HCl, concentrated under reduced pressure, and diluted with EtOAc and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to yield the crude title compound as a yellow solid (23 mg, 91%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](C(O)=O)=[CH:7][C:6]=2[CH:13]=1.C(=O)(O)[O-].[Na+].[B-](F)(F)(F)[F:20].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(Cl)(Cl)(Cl)Cl.O.ClCCl.[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([F:20])=[CH:7][C:6]=2[CH:13]=1
Reactant: O=C(O)c1cc2cc(Br)ccc2o1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Fc1cc2cc(Br)ccc2o1
Reaction time: 20 h

Procedure:
5-Bromobenzofuran-2-carboxylic acid (4.68 g) was suspended in carbon tetrachloride (150 ml) and water (50 ml). To this was added sodium bicarbonate (3.36 g), followed by Selectflor (7.1 g) and the reaction mixture was stirred rapidly for 20 hours. The reaction mixture was diluted with dichloromethane and 2N sodium hydroxide solution. The organic phase was separated, washed with brine and dried over anhydrous MgSO4. The solvent was evaporated under reduced pressure at room temperature. The residue was applied to a silica cartridge (20 g) and eluted with diethyl ether. This gave 5-bromo-2-fluoro-1-benzofuran (1.4 g).
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].C1CCN2C(=NCCC2)CC1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.[Br:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][N:33]=1>C(#N)C>[Br:31][C:32]1[N:33]=[C:34]2[CH:5]=[CH:4][C:2]([CH3:3])([CH3:1])[O:6][C:35]2=[CH:36][CH:37]=1
Reactant: Oc1ccc(Br)nc1
Reactant: C#CC(C)(C)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC1(C)C=Cc2nc(Br)ccc2O1
Reaction time: 0.5 h

Procedure:
To a solution 2-methyl-3-butyn-2-ol (21) in acetonitrile (6 mL) was added DBU (0.80 mL, 6.61 mmol) at 0° C., then TFAA was added dropwise, also at 0° C. The reaction was stirred for 30 min. In another round bottom flask, DBU (0.80 mL, 6.61 mmol) was added to a solution of 2-bromo-5-hydroxy pyridine (1 g, 5.75 mmol) in 6 mL of acetonitrile at 0° C. Then 2-methyl-3-butyn-2-ol was added dropwise into this reaction, which was stirred for 30 additional min. The solvent was removed by rotary evaporation, and the residue was diluted with DCM. After separation, the organic layer was washed with 1M HCl, 1M NaOH, sat NaHCO3 and brine, was dried over MgSO4 and concentrated in vacuum. The crude product was dissolved in 2 ml of xylene and subjected to microwave irradiation (130° C., 220 W) for 30 min. The solvent was removed by rotary evaporation and the product concentrated in vacuum. The crude product was purified by column chromatography (silica gel) (10:1 Hx/EtOAc) to give 300 mg of a yellow solid (23% over the two steps). 1H NMR (CDCl3): 1.45 (s, 6H), 5.86 (d, 1H, J=10.4), 6.44 (d, 1H, J=10), 6.90 (d, 1H, J=8.8), 7.14 ppm (s, 1H, J=8.4). HRMS (ESI) m/z calcd for C10H11NOBr [(M+H)+] 240.0024. found: 240.0026.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5]CC)=O.CC(C)([O-])C.[K+].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][C:30](=[O:32])[CH3:31])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>C(O)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:28]2[CH2:29][C:30](=[O:32])[CH2:31][C:3](=[O:5])[CH:2]2[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1ccc(C=CC(C)=O)cc1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C1C(=O)CC(=O)CC1c1ccc(OC)c(OC)c1
Yield: 871.4 %

Procedure:
Diethyl malonate (73. 7 g) was dissolved in ethanol (700 ml), and then potassium tert-butoxide (51.6 g) was gradually added thereto. A solution of 4-(3,4-dimethoxyphenyl)-3-buten-2-one (79.1 g) in ethanol (500 ml) was added dropwise, and the mixture was refluxed for 1.5 hours. After distilling off the reaction solvent under reduced pressure, ice water was poured over it and it was adjusted to pH4 with concentrated hydrochloric acid. The deposited crystals were filtered by suction, washed with water and then air-dried to give 122 g of ethyl 2-(3,4-dimethoxyphenyl)-4,6-dioxocyclohexane carboxylate (99.6%).
Reaction SMILES: C([S:4][CH2:5][CH:6]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][S:8]C(=O)C)(=O)C.[OH-].[Na+].II>C(O)C.ClCCl>[C:16]([O:15][C:13](=[O:14])[NH:12][CH:6]1[CH2:7][S:8][S:4][CH2:5]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(=O)SCC(CSC(C)=O)NC(=O)OC(C)(C)C
Agent: II
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CSSC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
A solution of thioacetic acid S-(3-acetylsulfanyl-2-tert-butoxycarbonylamino-propyl) ester (330 mg) in ethanol (5 ml) was treated with 2.5 ml of 1N sodium hydroxide for 1 hour at room temperature. The yellow solid turned green-brown. The reaction mixture was diluted with dichloromethane (25 ml) and then an aqueous solution of 0.1M iodine (10 ml) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour and quenched by addition of 1M sodium bisulfite solution. The organic layer was separated, washed with water, dried over sodium sulfate and the solvent evaporated in vacuo to afford the title product (170 mg). 1H-NMR (CDCl3, 400 MHz): 5.00 (br s, 1H), 4.90 (m, 1H), 3.15 (d, 2H), 3.05 (d, 2H), 1.40 (s, 9H).