Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl>[O:1]=[C:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Reaction time: 168 h
Yield: 132.4 %

Procedure:
150 g of 1-tert-butyl 2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate, 264 g of pyridinium chlorochromate, and 75 g of celite were stirred in 2 L of chloroform at room temperature. During this stirring, another 100 g of pyridinium chlorochromate was added, and the reaction mixture was stirred for a total of 7 days. The reaction solution was filtered through celite (washed with 500 mL of chloroform), and the filtrate was concentrated under reduced pressure to obtain 197 g of black oil. The residue thus obtained was purified by column chromatography (silica gel 60, mobile phase: ethyl acetate/n-hexane=2/1; v/v) to obtain 119 g of the titled compound (yellow oily substance).
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:10]([O:12]C)=O)=[O:7])(C)(C)C.Br[CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CCCCCCC.CCOC(C)=O>[Si:26]([O:25][CH2:24][CH2:23][O:21][C:18]1[CH:17]=[CH:16][C:15]([C@@H:14]2[O:7][C:6](=[O:5])[NH:8][C@H:9]2[CH2:10][O:12][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH:20][CH:19]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: COC(=O)[C@@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc([C@@H]2OC(=O)N[C@H]2CO[Si](C)(C)C(C)(C)C)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for intermediate 11 starting with (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-hydroxyphenyl)propanoate and (2-bromoethoxy)(tert-butyl)dimethylsilane. TLC (heptane/EtOAc 1:1) Rf=0.51; tR=1.764 min (UPLC 1); LC-MS: [M+H] 482; Rt 1.57 min; (LCMS method 1); 1H NMR (400 MHz, CDCl3): 7.31 (d, 2H), 6.96 (d, 2H), 5.26 (br s, 1H), 5.22 (d, 1H), 4.13 (m, 2H), 4.00 (m, 2H), 3.79 (m, 1H), 3.67 (m, 2H), 0.93 (s, 9H), 0.92 (s, 9H), 0.11 (m, 12H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1.CN(C)C=O.[C:15]1([C:21]2[NH:30][C:24]3[N:25]=[CH:26][N:27]=[C:28]([SH:29])[C:23]=3[CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1C=CC=CC=1>O>[N+:7]([C:4]1[S:3][C:2]([S:29][C:28]2[C:23]3[CH:22]=[C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[NH:30][C:24]=3[N:25]=[CH:26][N:27]=2)=[N:6][CH:5]=1)([O-:9])=[O:8]
Reactant: Sc1ncnc2[nH]c(-c3ccccc3)cc12
Reactant: O=[N+]([O-])c1cnc(Br)s1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: O=[N+]([O-])c1cnc(Sc2ncnc3[nH]c(-c4ccccc4)cc23)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
After adding 1.06 g of 2-bromo-5-nitrothiazole and 15 ml of dimethylformamide to 6-phenyl-7H-pyrrolo[2,3-d]pyrimidine-4-thiol, the mixture was stirred at room temperature for 3 hours, and then 0.45 ml of pyridine was added and the mixture was stirred overnight. Water was added, and the precipitated crystals were filtered out, blow-dried and dried under reduced pressure to obtain 1.20 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][CH3:35])[CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH3:33])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[CH2:34]([N:27]([C:24]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:26][CH:25]=1)[CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH3:33])[CH3:35]
Reactant: CCCOCCN(CC)c1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(C=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCOCCN(CC)c1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
A mixture of methyl 7-bromo-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.25 g), 4-[N-ethyl-N-(2-propoxyethyl)amino]phenyl borate (0.3 g), 1M potassium carbonate solution (2.5 ml), ethanol (2.5 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.04 g), and the mixture was refluxed overnight under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-[N-ethyl-N-(2-propoxyethyl)amino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.31 g) as green oil.
Reaction SMILES: Br[C:2]([CH3:19])([CH3:18])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)=[O:4].[CH3:20][O-:21].[Na+]>CO>[CH3:20][O:21][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:6]=2)[C:2]([CH3:19])([CH3:18])[O:4]1
Reactant: C[O-]
Reactant: CC(C)(Br)C(=O)c1ccc(Sc2ccccc2)cc1
Agent: [Na+]
Solvent: CO
Product: COC1(c2ccc(Sc3ccccc3)cc2)OC1(C)C

Procedure:
3 g (0.0551 mol) of 2-bromo-2-methyl-1-(4-phenylsulphanyl-phenyl)-propan-1-one were dissolved in 30 ml of methanol. 1.79 ml of a 30% sodium methylate solution in methanol at room temperature were added. After 15′ the solution was evaporated and the product used without further purification in the following reaction.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C@@H:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:8][CH:9]=[CH2:10])=[O:6])C=C.[CH2:19](Cl)Cl>>[CH3:19][N:4]1[CH2:1][CH:10]=[CH:9][CH2:8][C@H:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])[C:5]1=[O:6]
Reactant: C=CCNC(=O)[C@H](CC=C)NC(=O)OC(C)(C)C
Reactant: ClCCl
Product: CN1CC=CC[C@H](NC(=O)OC(C)(C)C)C1=O
Temperature: 40 °C
Reaction time: 12 h
Yield: 63 %

Procedure:
1,1-Dimethylethyl {(1S)-1-[(2-propen-1-ylamino)carbonyl]-3-buten-1-yl}carbamate (0.94 g, 3.9 mmol) was dissolved in DCM (350 mL) and 1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium (0.3 g, 3.5 mmol) was added. The resulting solution was heated to 40° C. and stirred for 12 hours. The solvent was evaporated under reduced pressure and the crude product was purified by RP-HPLC yielding 1,1-dimethylethyl [(3S)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl]carbamate (0.6 g, 63%). LCMS: (M+H)+: 242.3.
Reaction SMILES: C(=O)=O.CC(C)=O.[NH2:8][C:9]1[S:10][C:11]2[C:16]([NH:17][C@H:18]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:19][OH:20])=[N:15][C:14]([S:25]CC3C=CC=CC=3)=[N:13][C:12]=2[N:33]=1.[Na].[NH4+].[Cl-]>N>[NH2:8][C:9]1[S:10][C:11]2[C:16]([NH:17][C@H:18]([CH2:21][CH:22]([CH3:23])[CH3:24])[CH2:19][OH:20])=[N:15][C:14]([SH:25])=[N:13][C:12]=2[N:33]=1
Reactant: CC(C)C[C@H](CO)Nc1nc(SCc2ccccc2)nc2nc(N)sc12
Agent: N
Agent: O=C=O
Agent: [Cl-]
Solvent: CC(C)=O
Product: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Reaction time: 0.01 h
Yield: 93 %

Procedure:
Liquid ammonia (140 mL) was condensed into a 250 mL flask (dry ice/acetone cooling) is and (R)-2-(2-amino-5-phenylmethylthio-thiazolo[4,5-d]pyrimidin-7-ylamino)-4-methyl-pentan-1-ol (WO 00/09511) (2.77 g, 7.11 mmol) was added in three portions. To the clear yellow solution was added an excess of sodium metal in small pieces, until a blue colour persisted. When the blue colour had remained for 25 seconds, solid NH4Cl was added to quench the reaction. The NH3 solvent was removed (N2), and the remains were dissolved in H2O (ca 70 mL), the mixture filtered, and the resulting clear solution neutralized to pH ca 7 with dilute HCl. The precipitated solid was filtered, washed with H2O and CH3CN, and dried at 40° C. under vacuum overnight to give 1.98 g (93%) of a light yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:31][Si](C)(C)C>CC(CC)=O>[ClH:31].[CH3:30][N:2]([CH3:1])[C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:11])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(CC(=O)NCCc2c[nH]c3ccccc23)CC1
Solvent: CCC(C)=O
Product: Cl
Reaction time: 1.5 h

Procedure:
2-(4-Dimethylamino-4-phenylcyclohexyl)-N-[2-(1H-indol-3-yl)ethyl]acetamide (141 mg, 0.35 mmol) was warmed gently in ethyl methyl ketone, and chlorotrimethylsilane (0.066 ml, 0.52 mmol) was added. After 1.5 h it was possible to filter off a beige-coloured, hygroscopic product with suction. The filtrate was reduced to a volume of 5 ml and ether was added. The hydrochloride thereby precipitated out as a colourless solid in a yield of 47% (72 mg). M.p.: 135-140° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 184.4 %

Procedure:
To a stirred solution of 4-Bromo-2-fluoro benzaldehyde (15 g, 79.36 mmol) in MeOH (100 mL) at −5° C. to 0° C. was added NaBH4 (6.0 g, 158.73 mmol) in equal portions and stirred at RT for 1 h until the starting material was completely consumed, as evidenced by TLC analysis. The reaction mixture was then diluted with ice cold water (100 mL) and concentrated under reduced pressure. The residue obtained on concentration was extracted with EtOAc (2×200 mL) and separated. The combined EtOAc layers were washed with brine solution (50 mL), dried over anhydrous NaSO4, filtered and concentrated to afford (4-bromo-2-fluorophenyl)methanol (30 g, 99% (from 2 batches))] as colorless oil (TLC solvent system: 30% EtOAc in PE; Rf: 0.3).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](Cl)[C:5]([Cl:10])=[CH:4][N:3]=1.[Cl-].[NH4+]>[Zn]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:10])=[CH:4][N:3]=1
Reactant: Clc1cnc(Cl)c(Cl)c1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Product: Clc1cnc(Cl)c(Cl)c1
Yield: 77.8 %

Procedure:
By the method described in Example 1, 11.0 g (0.05 mol) of 2,3,4,5-tetrachloropyridine, 4.4 g (0.065 gram atom) of zinc dust (96%) and 4.0 g (0.075 mol) of ammonium chloride are reacted to yield 7.1 g (78% of theory) of 2,3,5-trichloropyridine, m.p. 36°-40° C., which contains, according to gas-chromatographical analysis, 79.2% of 2,3,5-trichloropyridine, 11.8% of 2,3,4,5-tetrachloropyridine and 6.6% of unknown products.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:13].Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]([NH:23][CH3:24])=[O:22])[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[Cl:1][C:2]1[C:10]2[S:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:13][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]([NH:23][CH3:24])=[O:22])[CH:16]=1
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: CSc1nc2ccc(O)c(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cc(Oc2ccc3nc(SC)sc3c2Cl)ccn1
Temperature: 85 °C
Yield: 50.6 %

Procedure:
To the solution of 7-chloro-2-(methylthio)benzo[d]thiazol-6-ol (80 mg, 0.346 mmol, 1.0 eq) in 1 mL of NMP was added 4-chloro-N-methylpicolinamide (88 mg, 0.519 mmol, 1.5 eq) and cesium carbonate (281 mg, 0.865 mmol, 2.5 eq) at room temperature. The reaction mixture was stirred at 85° C. for >48 hours till ca. 75%-80% completion, thereafter the mixture was diluted with water (ca. 50 mL) and aqueous layer extracted with ethyl acetate (ca. 50 mL×3). Combined organic layers were dried over sodium sulfate, filtered and condensed under reduced pressure to give crude product which was purified on ISCO using gradient 0%-100% ethyl acetate-hexane mixture to give 64 mg of product in 50% yield. LC/MS (m/z) [366.0] (MH+)
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH:19]([C:21]1[C:30]([CH3:31])=[C:29]([O:32][C:33](=[O:35])[CH3:34])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1)=[O:20].Cl>CCCCCC.O1CCCC1.O>[OH:20][CH:19]([C:21]1[C:30]([CH3:31])=[C:29]([O:32][C:33](=[O:35])[CH3:34])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1)/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC(=O)Oc1c(C)c(C=O)nc2ccccc12
Reactant: C#CCCCCCC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCCCCC/C=C/C(O)c1nc2ccccc2c(OC(C)=O)c1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 398.2 %

Procedure:
13.9 ml of an n-hexane solution of 13.9 mmols of diisobutylaluminium hydride was added to a solution of 1.68 g (1.53 mmols) of 1-octyne in 20 ml of n-hexane in an atmosphere of nitrogen at 0° C. and stirred at 50° C. for 2 hours. After removal of the solvent by distillation under reduced pressure, 20 ml of tetrahydrofuran was added, followed by further addition of a solution, in 15 ml of tetrahydrofuran, of 2.66 g (11.6 mmols) of 2-formyl-3-methyl 4-acetoxyquinoline at -78° C. The reaction temperature was raised from -78° C. to room temperature and the reaction solution was stirred at room temperature for 15 minutes. The solution was added to a solution of 15 ml of 1N hydrochloric acid and 100 ml of water and filtered through Celite, followed by extraction with ethyl acetate, washing with water and then with a saturated sodium chloride aqueous solution, and drying with sodium sulfate. The solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (solvent: n-hexane : ethyl acetate=15:1) to obtain 2.08 g (yield 52%) of 2-(trans-1-hydroxy-2-nonenyl)-3-methyl-4-acetoxyquinoline.
Reaction SMILES: [OH-].[Na+].[CH2:3]([OH:9])[CH2:4][O:5][CH2:6][CH2:7][OH:8].[C:10](#[N:13])[CH:11]=[CH2:12]>ClCCl>[C:10]([CH2:11][CH2:12][O:9][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:12][CH2:11][C:10]#[N:13])#[N:13]
Reactant: C=CC#N
Reactant: OCCOCCO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: N#CCCOCCOCCOCCC#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2% (w/v) sodium hydroxide (5 mL) and diethylene glycol (5.3 g, 50 mmol) was added acrylonitrile (7.95 g, 150 mmol). The mixture was stirred at room temperature overnight and additioned with 50 mL dichloromethane. The organic layer was washed 2× with brine and dried (MgSO4). The solvent was removed by rotary evaporation. The oily residue was treated with 200 proof ethanol, and the solvent was removed by rotary evaporation. This was repeated 2× to remove excess unreacted acrylonitrile. The product was used without further purification
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[CH:31]=[CH:30][C:10]2[N:11]([CH2:28][CH3:29])[C:12]([CH2:14][C:15]3[N:16]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[F:27])[N:17]=[CH:18][CH:19]=3)=[N:13][C:9]=2[CH:8]=1)=[O:6])[C:2]#[CH:3]>C(O)(=O)C.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[CH2:28]([N:11]1[C:10]2[CH:30]=[CH:31][C:7]([C:5]3[O:6][C:2]([CH3:3])=[CH:1][N:4]=3)=[CH:8][C:9]=2[N:13]=[C:12]1[CH2:14][C:15]1[N:16]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[N:17]=[CH:18][CH:19]=1)[CH3:29]
Reactant: C#CCNC(=O)c1ccc2c(c1)nc(Cc1ccnn1-c1cc(F)ccc1F)n2CC
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: CC(=O)O
Product: CCn1c(Cc2ccnn2-c2cc(F)ccc2F)nc2cc(-c3ncc(C)o3)ccc21

Procedure:
A mixture of crude N-propargyl 1-ethyl-2-{[2-(2,5-difluorophenyl)-pyrazol-3-yl]methyl}-1H-benzimidazole-5-carboxamide (450 mg) and mercury(II) acetate (1 eq) is heated at reflux in acetic acid (15 mL) for 6 h. The mixture is concentrated, saturated aqueous potassium carbonate added and extracted with ethyl acetate (3×). The combined organic layers were washed with water then with saturated aqueous sodium chloride, dried (MgSO4), concentrated, and triturated with ether to give 1-ethyl-2-{[2-(2,5-difluorophenyl)-pyrazol-3-yl]methyl}-5-(5-methyl-oxazol-2-yl)-1H-benzimidazole, which is converted to the hydrochloride salt in ethyl acetate. 1H NMR (d6 DMSO): δ 8.16(s,1H), 8.09-9.01m.(2H), 7.78(m,1H), 7.62(m,1H), 7.49-7.45(m,3H), 7.04(m,1H), 6.56(s,1H), 4.70(s,2H), 4.36(q,2H), 2.41(s,3H), 1.21(t,3H). LCMS MH+ 420.5.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].C(O)(=O)C.[CH3:9][C:10]1[CH:15]=[C:14]([NH:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=2)[N:13]=[C:12]([C:27]2[CH:28]=[N:29][C:30]([NH:33][CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[CH:31][CH:32]=2)[CH:11]=1>C1COCC1>[CH3:9][C:10]1[CH:15]=[C:14]([NH:16][C:17]2[CH:22]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:20]=[CH:19][N:18]=2)[N:13]=[C:12]([C:27]2[CH:28]=[N:29][C:30]([NH:33][CH:34]3[CH2:39][CH2:38][N:37]([C:2]([NH2:3])=[O:1])[CH2:36][CH2:35]3)=[CH:31][CH:32]=2)[CH:11]=1
Reactant: N#C[O-]
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2ccc(NC3CCNCC3)nc2)c1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2ccc(NC3CCN(C(N)=O)CC3)nc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium cyanate (9.47 mg, 0.117 mmol), acetic acid (0.017 mL, 0.292 mmol), 4-methyl-N6′-(piperidin-4-yl)-N6-(4-(trifluoromethyl)pyridin-2-yl)-2,3′-bipyridine-6,6′-diamine (25 mg, 0.058 mmol), and THF (1 mL) were combined. The mixture was stirred at room temperature for 16 hours. The crude solution was purified via reverse phase high pressure liquid chromatography to afford 4-(4-methyl-6-(4-(trifluoromethyl)pyridin-2-ylamino)-2,3′-bipyridin-6′-ylamino)piperidine-1-carboxamide. MS ESI calcd. for C23H25F3N7O [M+H]+ 472. found 472. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.53-8.49 (m, 3H), 8.28 (s, 1H), 8.24 (d, J=6.5 Hz, 1H), 7.44 (s, 1H), 7.39 (s, 1H), 7.22-7.16 (m, 2H), 4.42 (m, 1H), 3.80 (m, 1H), 3.72-3.65 (m, 2H), 3.45 (dd, J=11.0, 4.0 Hz, 1H), 2.36 (s, 3H), 2.22 (m, 1H), 2.00 (m, 1H), 1.82 (s, 3H). rhSyk IC50=4 nM.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([OH:11])=[O:10])[NH:7][N:8]=1)([O-:3])=[O:2].[C:12](=O)(O)[O-].[Na+]>CO.S(=O)(=O)(O)O>[CH3:12][O:10][C:9]([C:6]1[NH:7][N:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:11]
Reactant: O=C(O)c1cc([N+](=O)[O-])n[nH]1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])n[nH]1
Temperature: 25 °C

Procedure:
A solution of 5-Nitro-2H-pyrazole-3-carboxylic acid (5 gm, 32 mmol) in 100 ml of 2% sulfuric acid methanol was refluxed for 20 hours. The mixture was cooled to room temperature and added to saturated sodium bicarbonate. The mixture was extracted with ethyl acetate three times to obtain 3.59 gm of title product after drying over magnesium sulfate, filtering and evaporating to dryness. ESI M+1=171.
Reaction SMILES: [C:1]([N:8]([CH3:27])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[F:23])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=1>>[C:4]([O:3][C:1](=[O:2])[N:8]([CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19]([C:29]3[CH:34]=[CH:33][C:32]([C:35](=[O:40])[C:36]([F:38])([F:39])[F:37])=[CH:31][CH:30]=3)[CH:20]=[CH:21][C:22]=2[F:23])[CH2:11][CH2:10]1)[CH3:27])([CH3:7])([CH3:6])[CH3:5]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(NCc2cc(B(O)O)ccc2F)CC1
Reactant: O=C(c1ccc(Br)cc1)C(F)(F)F
Product: CN(C(=O)OC(C)(C)C)C1CCC(NCc2cc(-c3ccc(C(=O)C(F)(F)F)cc3)ccc2F)CC1

Procedure:
The title compound was prepared from boronic acid (247) (300 mg, 0.79 mmol) and 1-(4-bromophenyl)-2,2,2-trifluoroethanone (240 mg, 0.95 mmol) in accordance with Method B.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH2:25][CH3:26])[N:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[Cl:27].[Li+].[OH-]>O.C1COCC1>[NH2:24][C:21]1[N:20]=[CH:19][C:18]([C:17]#[C:16][C:15]2[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[C:5]([Cl:27])[CH:6]=3)=[N:11][CH:12]=[N:13][C:14]=2[CH2:25][CH3:26])=[CH:23][CH:22]=1
Reactant: CCc1ncnc(-c2ccc(C(=O)OC)c(Cl)c2)c1C#Cc1ccc(N)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ncnc(-c2ccc(C(=O)O)c(Cl)c2)c1C#Cc1ccc(N)nc1
Temperature: 50 °C

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 3.3 g (8.4 mmol) 4-[5-(6-amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-chloro-benzoic acid methyl ester using 1.06 g (25.2 mmoL) LiOH in 20 mL water and 100 mL THF. The reaction mixture is stirred over night at 50° C. The solvent is removed under reduced pressure and the residue is taken up in water. Aqueous 1 M HCl is added until pH 5-6 is reached. The precipitated product is filtered off and washed with water and MeOH. After drying 2.5 g (89%) of the desired product are obtained as solid material.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[O-])=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[Cl:31])[NH2:27]>C(#N)C>[Cl:31][C:30]1[CH:29]=[CH:28][C:26]([NH:27][C:19](=[O:21])[NH:18][C:15]2[CH:14]=[CH:13][C:12]([O:11][C:9]3[CH:8]=[CH:7][N:6]=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[CH:10]=3)=[CH:17][CH:16]=2)=[CH:25][C:24]=1[C:23]([F:22])([F:32])[F:33]
Reactant: CNC(=O)c1cc(Oc2ccc(NC(=O)[O-])cc2)ccn1
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CC#N
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Temperature: 25 °C
Yield: 87.7 %

Procedure:
A mixture of 4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenylcarbamate (25 g, 0.06871 mol) and 3-trifluoromethyl-4-chloroaniline (13.4 g, 0.06871 mol) in acetonitrile (250 ml) was refluxed for 24 hours when product precipitated out of reaction mass. The reaction mass was cooled to room temperature and obtained product was filtered, washed with acetonitrile till a clear filtrate was obtained. It was then vacuum dried to obtain 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide (sorafenib base) (28 g).