Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]2=[N:7][CH:8]=1)[NH2:2].C(Cl)Cl.[C:25]([O:29][C:30]([NH:32][CH:33]1[CH2:37][CH:36]([C:38](O)=[O:39])[CH:35]([CH2:41][CH3:42])[CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O>[C:25]([O:29][C:30](=[O:31])[NH:32][CH:33]1[CH2:37][CH:36]([C:38]([NH:2][NH:1][C:3]2[N:4]=[C:5]3[CH:11]=[CH:10][N:9]([S:12]([C:15]4[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=4)(=[O:13])=[O:14])[C:6]3=[N:7][CH:8]=2)=[O:39])[CH:35]([CH2:41][CH3:42])[CH2:34]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CCC1CC(NC(=O)OC(C)(C)C)CC1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCC1CC(NC(=O)OC(C)(C)C)CC1C(=O)NNc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
A round-bottomed flask was charged with 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.0 g, 6.6 mmol, Step J) and DCM (40 mL) to give a brown suspension. 4-(tert-Butoxycarbonylamino)-2-ethylcyclopentanecarboxylic acid (2.0 g, 7.8 mmol, Step G), HATU (2.51 g, 6.59 mmol), and TEA (4.59 mL, 33.0 mmol) were added to the suspension and the resulting mixture was stirred at ambient temperature for about 24 h with dissolution occurring after about 2 h. Water (20 mL) was added and the layers were partitioned. The organic layer was washed with additional water (2×15 mL), brine (2×25 mL), dried over anhydrous MgSO4, filtered, and solvent was removed under reduced pressure to give a brown residue. The crude material was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH/DCM. The recovered impure material was re-purified by silica gel chromatography eluting with a gradient of 0-10% MeOH/DCM. The product-containing fractions from the two columns were combined and concentrated to give tert-butyl-3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentylcarbamate (2.45, 69%) as a brown solid: LC/MS (Table 2, Method d) Rt=1.47 min; MS m/z: 543 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([NH:5][N:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([C:25]([F:28])([F:27])[F:26])=[C:12]([N:17]3[CH:21]=[C:20]([C:22]([OH:24])=O)[N:19]=[CH:18]3)[CH:13]=2)[NH:8][C:7]1=[O:29])(=[O:4])=[O:3].Cl.[CH3:31][NH:32][CH3:33].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH3:31][N:32]([CH3:33])[C:22]([C:20]1[N:19]=[CH:18][N:17]([C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][C:11]=2[C:25]([F:26])([F:28])[F:27])[NH:8][C:7](=[O:29])[N:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:15]3=[O:16])[CH:21]=1)=[O:24]
Reactant: CNC
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(-n3cnc(C(=O)O)c3)cc2c1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1cn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)cn1
Temperature: 100 °C
Yield: 17.3 %

Procedure:
A solution of 1-(3-methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-yl)-1H-imidazole-4-carboxylic acid (120 mg, 0.277 mmol) in 10 ml of dimethylformamide is treated with dimethylamine hydrochloride (46 mg, 0.554 mmol), N-3-dimethylaminopropyl-N′-ethyl-carbodiimide hydrochloride (60 mg, 0.305 mmol), N-hydroxybenzotriazole (11 mg, 0.08 mmol) and triethylamine (0.1 ml, 0.72 mmol). The solution is heated to 100° C. for 1 hour, cooled to room temperature, evaporated in vacuo and the residue chromatographed over silica gel to give 22 mg (0.048 mmoles, 17%) of 1-(3-methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-yl)-1H -imidazole-4-carboxylic acid dimethylamide, m.p. 284 -286° C., ES-MS: m/z 461 [M+H]+.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2.[NH:19]1[C:23]2C=CC=C[C:22]=2[N:21]=[N:20]1.C(=O)C>CCCCCC>[N:19]1([CH:23]([NH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[CH:12]3)[CH3:22])[C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=2[N:21]=[N:20]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: Cc1ccccc1
Reactant: Nc1ccc2ncccc2c1
Agent: CC=O
Solvent: CCCCCC
Product: CC(Nc1ccc2ncccc2c1)n1nnc2ccccc21

Procedure:
[Step 1] 5 mL of a toluene suspension of 1.0 mg (3.5 mmol) of 6-aminoquinoline were added to 5 mL of a toluene suspension of 826 mg (3.5 mmol) of benzotriazole and stirred. 5 mL of a toluene solution containing 0.22 mL (3.8 mmol) of acetoaldehyde were dropped therein followed by stirring for 18 hours at room temperature. Following completion of the reaction, 15 mL of n-hexane were added followed by filtering out the solid. The solid was washed with n-hexane and dried under reduced pressure to obtain 20 g of N-[1-(1H-benzo[d][1,2,3]triazol-1-yl)ethyl]quinolin-6-amine in the form of a white solid (99%).
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:7][C:6]([Cl:18])=[N:5][C:4]=2[CH:3]=1.[CH:19]([C:21]1[O:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(O)C>[Cl:18][C:6]1[N:7]=[C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[N:10]=[CH:11][C:2]([C:24]3[O:25][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=3)=[CH:3][C:4]=2[N:5]=1
Reactant: Clc1nc(N2CCOCC2)c2ncc(Br)cc2n1
Reactant: O=Cc1ccc(B(O)O)o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Temperature: 95 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
To a 50 mL round bottom flask, 4-(7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine (0.5 g, 0.0015 mol—Preparation 3), 5-formyl-2-furanylboronic acid (0.21 g, 0.0015 mol), sodium carbonate (0.32 g, 0.003 mol), toluene (20 mL), ethanol (10 mL) and water (5 mL) were added. The reaction vessel was degassed with N2 for 5-10 minutes. To the same reaction mixture, Pd(PPh3)2Cl2 (0.053 g, 0.000075 mol) was added and again degassed with N2 for 5-10 minutes. The reaction mixture was stirred at 95° C. for 2 hours. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified by column chromatography (60-120 silica gel, 60% ethyl acetate in n-hexane) to yield the desired product (0.38 g, 72%). 1H NMR (300 MHz, CDCl3): δ 9.77 (s, 1H), 9.12 (d, J=2.1 Hz, 1H), 8.34 (d, J=2.1 Hz, 1H), 7.40 (d, J=3.6 Hz, 1H), 7.11 (d, J=3.6 Hz, 1H), 4.50 (br s, 4H), 3.91-3.88 (m, 4H): LC-MS (ESI): Calculated mass: 344.0; Observed mass [M+H]+: 345.0 (RT=1.39 min).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].C(=O)([O-])[O-].[K+].[K+].[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][C:25]([CH2:28]Br)=[CH:24][CH:23]=1)([O-:15])=[O:14].C(OCC)(=O)C>CN(C)C=O>[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][NH:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])=[CH:24][CH:23]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCNCc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Yield: 76.8 %

Procedure:
n-Amylamine (0.54 g) and potassium carbonate (0.98 g) were suspended in dimethylformamide (3.5 mL), and [[2′-nitro-1,1′-biphenyl-4-yl]methyl] bromide (0.51 g) was added in portions. Four hours later, ethyl acetate (20 mL) was added, and the resulting mixture was washed once with water (40 mL) and twice with brine (90 mL, each). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column (chloroform/ethyl acetate) to afford N-[(2′-nitro-1,1′-biphenyl-4-yl)methyl]-N-pentylamine as a yellow oil (0.40 g). Yield: 77%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Na+].CC(OC)(C)C.Cl>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: Cc1ccc(S(=O)O)cc1
Yield: 98.3 %

Procedure:
To a round bottom flask was added sodium 4-methylbenzenesulfinate (25 g, 140 mmol), MTBE (40 mL) and water (80 mL). To the reaction mixture was added concentrated HCl (12.7 mL, 154 mmol) dropwise via addition funnel over about 15 min. The resulting layers were separated and the aqueous layer extracted with MTBE (2×50 mL). The organic layers were combined and dried with MgSO4, filtered and concentrated in vacuo. The resulting solid was triturated with heptane, filtered, and dried under vacuum to provide the title compound (21.5 g, 98%). LC/MS (Table 1, Method a) Rt=1.12 min; MS m/z: 155.1 (M−H)−.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:10])([CH2:6][CH2:7][CH2:8][F:9])[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O1CCCC1.O>[C:4]([C:3]([NH:2][C:18](=[O:19])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH2:6][CH2:7][CH2:8][F:9])[CH3:10])#[N:5]
Reactant: CC(N)(C#N)CCCF
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C#N)(CCCF)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude rac-2-amino-5-fluoro-2-methylpentanonitrile hydrochloride product from Example 76A was initially charged in 185 ml of tetrahydrofuran/water (1:1), and 32.09 g (232.18 mmol) of potassium carbonate and 10.63 g (62.29 mmol) of benzyl chloroformate were added. The reaction mixture (biphasic mixture) was stirred at room temperature overnight. Another 1.93 g (11.33 mmol) of benzyl chloroformate were added to the reaction and the mixture was stirred at room temperature for a further 2 h. Subsequently, the biphasic system was separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution, and then dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue was purified by means of silica gel chromatography (eluent:cyclohexane/ethyl acetate gradient=20/1 to 5/1). 11.77 g of the target compound were obtained (72% of theory over two stages, 92% purity).
Reaction SMILES: [Na].[OH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]([OH:15])=[O:14].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>CS(C)=O>[OH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]([O:15][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)=[O:14]
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: COc1ccc(CCl)cc1
Agent: [Na]
Solvent: CS(C)=O
Product: COc1ccc(COC(=O)c2ccc3ccccc3c2O)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 66431.7 %

Procedure:
(This is a compound 15a of Scheme 1). A suspension of powdered sodium salt of 1-hydroxynaphthalene-2-carboxylic acid (1) (61.3 g, 0.29 mmol) in DMSO (205 mL) was treated with 4-methoxybenzyl chloride (98%, 46.7 g, 0.29 mmol) and then stirred at 70° C. for 1 h. After cooling, the mixture was poured into dilute aqueous KHCO3 (3.5 L) and the resulting precipitate was collected, washed with water and dried. The solid was extracted with boiling petroleum ether (bp 60-65° C., 1100 mL), treated with decolourising charcoal and the filtered solution was cooled for a prolonged period at 0° C. to provide crude 4-methoxybenzyl 1-hydroxynaphthalene-2-carboxylate (2) (59.4 g, 66%), suitable for further use. A sample was recrystallised from iPr2O/petroleum ether, mp 92-93° C. 1H NMR [(CD3)2SO] δ 11.91 (s, 1H, OH), 8.31 (d, J=8.2 Hz, 1H, H-3), 7.92 (d, J=8.1 Hz, 1H, H-4), 7.73 (d, J=8.8 Hz, 1H, ArH), 7.71 (brt, J=7.5 Hz, 1H, ArH), 7.61 (br t, J=1.6 Hz, 1H, ArH), 6.99 (d, J=8.6 Hz, 2H, H-3',5'), 5.40 (s, 2H, CH2), 3.34 (s, 3H, CH3). Anal. Calculated for C19H16O4): C, 74.0; H, 5.2. Found: C, 73.7; H, 5.2%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>ClCCl>[CH3:13][S:14]([NH:1][CH2:2][CH2:3][CH2:4][O:5][S:14]([CH3:13])(=[O:16])=[O:15])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: NCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCCOS(C)(=O)=O
Yield: 69.8 %

Procedure:
To a solution of 3-amino-1-propanol (11.47 ml, 150 mmoles) and triethylamine (46 ml, 330 mmoles) in dichloromethane (250 ml) was added methylsulfonyl chloride (25.5 ml, 330 mmoles) with stirring under ice-cooling and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed in turn with an aqueous sodium bicarbnonate and water and dried. After the solvent was distilled off, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 24.22 g of the desired product (69.8%, white crystals).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[CH2:6]1)=[O:4].[CH3:20][C:21]([O-])(C)[CH3:22].[K+].C(Br)C=C>C(O)(C)(C)C>[CH3:1][O:2][C:3]([C:5]1([CH2:22][CH:21]=[CH2:20])[C:10](=[O:11])[CH2:9][CH2:8][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CN(Cc2ccccc2Cl)CCC1=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C=CCBr
Product: C=CCC1(C(=O)OC)CN(Cc2ccccc2Cl)CCC1=O
Temperature: 30 °C
Reaction time: 0.25 h

Procedure:
14.60 g (51.8 mmol) of methyl-1-[(2-chlorophenyl)methyl]-4-oxo-3-piperidine carboxylate was dissolved in 40 ml of tertbutanol and warmed to 30° C. Within 2 minutes 6.57 g (58.4 mmol) of potassium tert-butylate in 45 ml of tert-butanol was added. After 15 minutes of stirring, 25 ml of tert-butanol was added once more. Then 6.34 g (51.4 mmol) of allylbromide was added within 10 minutes and stirred for 2 more hours at 30° to 35° C. The reaction mixture was concentrated by evaporation and 70 ml of water and 70 ml of ether were added to the residue. The organic phase was washed with 50 ml of sodium sulfate solution, dried on magnesium sulfate and concentrated by evaporation. The yield was 40.68 g of methyl1-[(2-chlorophenyl)methyl]-4-oxo-3-(2-propenyl)-3-piperidine carboxylate, which equals 88.1 percent. Data concerning the compound was:
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[CH:3]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)[O:4][C:5]1[C:6]([NH:15][S:16](=[O:28])(=[O:27])[NH:17][CH2:18][CH2:19][CH:20](OCC)[O:21]CC)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2.Cl.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C1COCC1>[F:36][C:2]([F:1])([F:35])[CH:3]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)[O:4][C:5]1[C:6]([NH:15][S:16](=[O:27])(=[O:28])[NH:17][CH2:18][CH2:19][CH:20]=[O:21])=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: CCOC(CCNS(=O)(=O)Nc1nc2ccccc2nc1OC(c1cccnc1)C(F)(F)F)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=CCCNS(=O)(=O)Nc1nc2ccccc2nc1OC(c1cccnc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.2 %

Procedure:
Compound 272 (72.0 mg, 0.136 mmol) obtained in Example 266 was dissolved in THF (1.50 mL). To this, a 1.00 mol/L aqueous hydrochloric acid solution (1.50 mL) was added and the mixture was stirred at room temperature for 1.5 hours. The reaction was stopped by addition of a saturated aqueous sodium bicarbonate solution to the reaction mixture, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 1/1) to give Compound 273 (41.6 mg, yield: 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[CH2:17]O.P(Br)(Br)[Br:20].C([O-])(O)=O.[Na+]>C1COCC1>[Br:20][CH2:17][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:4]=1[Cl:16]
Reactant: BrP(Br)Br
Reactant: OCc1c(Cl)cc(OCc2ccccc2)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cc(OCc2ccccc2)cc(Cl)c1CBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 222.1 %

Procedure:
Treat a 0° C. solution of (2,6-dichloro-4-benzyloxy-phenyl)-methanol (247 g, 0.872 mol) in THF (2.5 L) with phosphorous tribromide (94.45 g, 0.35 mol) and stir for 30 minutes at 0° C. under N2. Pour the reaction into saturated NaHCO3 and extract twice with ethyl acetate. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford 269 g (89%) of the titled product. ES MS (m/z): 346 (M+1).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.N1C=CC=CC=1.S(Cl)([Cl:19])=O>C(OCC)C>[CH3:1][C:2]1[S:3][C:4]([C:8]([Cl:19])=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(C(=O)O)s1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1nc(C)c(C(=O)Cl)s1
Yield: 41 %

Procedure:
15.7 g (0.1 mole) of 2,4-dimethylthiazole-5-carboxylic acid were suspended in 300 ml of ethyl ether and 8 g (0.1 mole) of pyridine, followed by the dropwise addition of 12 g (0.1 mole) of thionyl chloride at -3° C. for 45 minutes. After completion of the reaction, filtration and concentrating were conducted to obtain 7.2 g pf 2.4-dimethylthiazole-5-carboxylic acid chloride. Its purity and yield were 85% and 35%, respectively.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@H:7]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C@@H:6]1[CH2:19][CH2:20][C:21](=[O:23])[CH2:22][C@H:5]21.CC(C)([O-])C.[K+].[CH3:30][O:31][CH2:32]Cl.OC1C=CC([C@H:41]2[C@H]3C[C@@H](C(F)(F)F)C[C@H]3C3C=C(O)C=C[C:43]=3[O:42]2)=CC=1>C1COCC1>[CH3:30][O:31][CH2:32][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:41][O:42][CH3:43])=[CH:16][CH:17]=1)[CH:6]1[CH2:19][CH2:20][C:21](=[O:23])[CH2:22][CH:5]21
Reactant: Oc1ccc([C@@H]2Oc3ccc(O)cc3[C@@H]3C[C@H](C(F)(F)F)C[C@@H]32)cc1
Reactant: COCCl
Reactant: O=C1CC[C@@H]2[C@H](C1)c1cc(O)ccc1O[C@@H]2c1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(=O)CCC32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 0 C. solution of Example 19 (0.100 g, 0.32 mmol) in THF (3 mL) add potassium tert-butoxide (0.090 g, 0.81 mmol) followed by methoxymethyl chloride (MOM-Cl) (0.061 mL, 0.81 mmol). Remove the ice bath and stir for 1 h at room temperature. Pour the contents into ½ satd. NaHCO3 (50 mL) and extract with Et2O (2×25 mL) and EtOAc (2×25 mL). Wash the combine organic extracts with brine (50 mL), dry over Na2SO4, and concentrate to afford a brown residue. Purify the residue by MPLC (0% to 25% to 50% EtOAc/hexanes) to afford Preparation 35 (0.102 g, 80%). 1H NMR (CDCl3) δ 7.37 (d, J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz, 2H), 6.96 (d, J=2.4 Hz, 1H), 6.87 (dd, J=2.4, 8.8 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 5.28 (s, 1H), 5.20 (s, 2H), 5.13 (A of AB, JAB=7.0 Hz, 1H), 5.07 (B of AB, JAB=7.0 Hz, 1H), 3.87 (m, 1H), 3.50 (s, 3H), 3.48 (s, 3H), 3.04 (br d, J=14.4 Hz, 1H), 2.79 (dd, J=6.2, 14.4 Hz, 1H), 2.46 (m, 1H), 2.21 (m, 2H), 1.62-1.79 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.[Br:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26]Br)=[N:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][O:1][C:2]2[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=3)[C:4](=[O:18])[CH:3]=2)=[N:24][CH:25]=1
Reactant: BrCc1ccc(Br)cn1
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(OCc2ccc(Br)cn2)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1.23 g (5.00 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2b) in 8.0 mL DMF is added 1.26 g (5.00 mmol) 5-bromo-2-bromomethyl-pyridine and 2.07 g (15.0 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT, diluted with 80 mL of water, the formed precipitate is collected and dissolved in DMF. The solution is directly transferred to a reverse HPLC for purification (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [S:1]1[C:5]2[CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[N:3]=[C:2]1[NH2:13].C(=O)([O-])[O-].[K+].[K+].[CH3:20][N:21]1[C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=[N:22]1>O1CCCC1>[S:1]1[C:5]2[CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[N:3]=[C:2]1[NH:13][C:26]([C:25]1[N:21]([CH3:20])[N:22]=[CH:23][CH:24]=1)=[O:27]
Reactant: Cn1nccc1C(=O)Cl
Reactant: Nc1nc2c(s1)Cc1ccccc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1nccc1C(=O)Nc1nc2c(s1)Cc1ccccc1-2
Yield: 30.8 %

Procedure:
To a mixture 8H-Indeno[1,2-d]thiazol-2-ylamine 1b (Prepared in Example 1, Step 2, 320 mg; 1.70 mmol) and potassium carbonate (3.10 g; 22.4 mmol) in dry tetrahydrofuran (10 mL) under nitrogen was added 2-methyl-2H-pyrazole-3-carbonyl chloride (516 mg; 3.57 mmol). The slurry was then heated to reflux for 3 hr. The solvent was removed in vacuo, and the residue diluted with water and extracted with ethyl acetate. The organic layer was washed with 50 mL of 1N hydrochloric acid solution followed by brine solution and dried (sodium sulfate) filtered and concentrated in vacuo. The crude product was purified by trituration with diethyl ether to provide 155 mg of 2-Methyl-2H-pyrazole-3-carboxylic acid (8H-indeno[1,2-d]thiazol-2-yl)-amide 9. EI-HRMS m/e calcd for C15H12N4OS (M+) 296.0732, found 296.0731.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1)[CH2:8][C:9]1[CH:10]=[N:11][C:12]([CH3:18])=[C:13]([OH:17])[C:14]=1[CH2:15][OH:16])([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=1>>[C:1]([O:5][C:6](=[O:27])[N:7]([CH2:8][C:9]1[CH:10]=[N:11][C:12]([CH3:18])=[C:13]([O:17][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=2)[C:14]=1[CH2:15][OH:16])[C:19]1[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[CH:23][CH:24]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ncc(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)c(CO)c1O
Reactant: N#Cc1ccc(CBr)cc1
Product: Cc1ncc(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)c(CO)c1OCc1ccc(C#N)cc1
Yield: 70.3 %

Procedure:
The coupling of (4-cyano-phenyl)-(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (105) (137.0 g, 0.37 mole) and α-bromo-p-tolunitrile (72.7 g, 370 mmol), as described in Example 1, gave [5-(4-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl]-(4-cyano-phenyl)-carbamic acid tert-butyl ester (124) (126.0 g, 70% yield) as a colorless solid.