Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH:10]=O)=[CH:4][CH:3]=1.[CH:13]1[C:18]([NH:19][NH2:20])=[CH:17][CH:16]=[C:15]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:14]=1.Cl.C(O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:19]([C:18]3[CH:13]=[CH:14][C:15]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:16][CH:17]=3)[N:20]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=CCC(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)c1ccc(-n2nccc2-c2ccc(Cl)cc2)cc1
Yield: 75.5 %

Procedure:
A 250 mL one-necked round-bottomed flask equipped with reflux condenser, nitrogen inlet and provisions for magnetic stirring was charged with 3-(4-chlorophenyl)-3-ketopropionaldehyde (18.3 g, 0.1 mol), 4-sulfonamidophenylhydrazine hydrochloride (11.2 g, 0.05 mol) and 100 mL of absolute ethanol. The solution was heated to reflux for 15 hour and then diluted with 100 mL of water and allowed to stand whereupon a white solid formed that was isolated by filtration on a Buchner funnel and air dried to provide 12.6 g, 76% of 4-[5-(4-chlorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide, mp 185°-187° C. 1H nmr (CDCl3 /300 MHz) 7.89(d, J=8.7Hz, 2H), 7.76(d, J=1.8Hz, 1H), 7.43(d, J=8.7Hz, 2H), 7.34(d, J=8.7Hz, 2H), 7.17(d, J=8.7Hz, 2H), 6.53(d, J=1.8Hz, 1H), 4.93(brs, 2H), mass spectrum MH+ =334.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.C(=O)([O-])[O-].[K+].[K+].Br[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1.Cl>[Fe].O.C(O)C>[F:24][C:20]1[CH:19]=[C:18]([NH:1][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH2:6])[CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: Fc1cccc(Br)c1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: Nc1ccccc1Nc1cccc(F)c1

Procedure:
o-nitroaniline (2.8 g, 20.3 mmol), potassium carbonate (0.9 g, 6.5 mmol), cuprous iodide (0.78 g, 4.1 mmol) and 1-bromo-3-fluorobenzene (15.4 g, 88.0 mmol) were refluxed for 24 hours at 165° C. The reactant was subjected to steam distillation and the remainder was extracted with ethyl acetate. The ethyl acetate layer was washed, dried and concentrated in vacuo. The obtained residue was refined by a silica gel column chromatography (CHCl3). The eluent (1.2 g, 5.2 mmol) was refluxed for 1 hour together with powdered iron (2.9 g, 52 mmol), ethanol (4.2 ml), water (1 ml) and concd. hydrochloric acid (0.05 ml, 50 mmol), then the resultant was concentrated in vacuo.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([N:8]=[CH:9][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.S(C1C=CC(C)=CC=1)(O[CH2:15][CH:16]1[O:18][CH2:17]1)(=O)=O>>[N:8]1[N:4]2[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:15][CH:16]3[O:18][CH2:17]3)[C:3]2=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CO2)cc1
Reactant: Oc1cccn2nccc12
Product: c1cc(OCC2CO2)c2ccnn2c1

Procedure:
4-Hydroxypyrazolo[1,5-a]pyridine (5) as obtained by the above procedure is reacted, in the form of alkali metal salt, with glycidyl tosylate to give 3-(pyrazolo[1,5-a]pyrid-4-yloxy)-1,2-epoxypropane (6). The reaction is preferably carried out in a solvent such as dimethylformamide under an atmosphere of argon gas.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:13])[CH2:9][C:10]([CH3:12])=[O:11])([CH3:6])([CH3:5])[CH3:4].[Li]CCCC.CCCCCC.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl>O1CCCC1>[Cl:25][C:26]1[CH:27]=[C:28]([CH2:29][CH2:12][C:10](=[O:11])[CH2:9][C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:13])[CH:31]=[CH:32][CH:33]=1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: ClCc1cccc(Cl)c1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)CC(=O)CCc1cccc(Cl)c1
Yield: 86.6 %

Procedure:
Sodium hydride (5.43 g, 0.11 mol, 50% as an oil suspension) is placed in a 500 ml 3-neck flask (equipped with a thermometer, an addition funnel, and a rubber septum) under nitrogen and washed 2×100 ml hexanes to remove the oil. Then 230 ml dry THF (tetrahydrofuran) is introduced and the sodium hydride suspension is cooled to 4° and magnetically stirred. t-butylacetoacetate (16.5 ml, 0.1 mol) is added with a rate which is controlled so that the gas evolution is not too vigorous and the temperature is maintained at less than 10°. Stirring is continued until gas evolution ceases (1 hr). Then 62 ml of 1.7 M BuLi in hexane (0.105 mol) is added via syringe at a rate such that the temperature does not rise above 10°. The initial orange color becomes red during addition, but turns into pink after addition is complete. A fine solid also separates from solution. The resulting mixture is stirred for an additional 15 min. before 15.0 ml m-chlorobenzyl chloride (20.0 g, 0.125 mol) in 20 ml dry THF is added dropwise at a rate such that the temperature is maintained between 9° and 12°. When addition is complete, the cooling bath is removed and the reaction is stirred for an additional 1 hr. The reaction mixture is then poured into a 2 l Erlenmeyer flask and 300 ml diethyl ether is added followed by the addition of 130 ml cold 3 N aqueous HCl with stirring. The mixture is stirred for 15 min, and the layers are separated, and the acid layer is washed twice with 150 ml diethyl ether. The combined organic layers are then washed twice with 200 ml of water, 2×100 ml of aqueous 1% Citric acid (pH 4.5), and finally with 100 ml saturated aqueous brine. The organic layer is dried with anhydrous sodium sulfate and the solvent removed to give 24.5 g of t-butyl 5-(m-chlorophenyl)-3-oxo-pentanoate.
Reaction SMILES: [C:1]([C:3]1[CH:47]=[CH:46][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([C:10]([C:18]3[C:26]([O:27][CH3:28])=[CH:25][C:24]([CH3:29])=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4COCC[Si](C)(C)C)([CH3:17])[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(C3C(OC)=CC(C)=C4C=3C=CN4COCC[Si](C)(C)C)(C)CCC(OC)=O)N(COCC[Si](C)(C)C)C=2C=1)#N.Cl>CO>[C:1]([C:3]1[CH:47]=[CH:46][C:6]2[NH:7][C:8]([C:10]([C:18]3[C:26]([O:27][CH3:28])=[CH:25][C:24]([CH3:29])=[C:23]4[C:19]=3[CH:20]=[CH:21][NH:22]4)([CH3:17])[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: COC(=O)CCC(C)(c1c(OC)cc(C)c2c1ccn2COCC[Si](C)(C)C)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: COC(=O)CCC(C)(c1c(OC)cc(C)c2c1ccn2COCC[Si](C)(C)C)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)CCC(C)(c1nc2cc(C#N)ccc2[nH]1)c1c(OC)cc(C)c2[nH]ccc12
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
(±)-Methyl 4-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-4-(5-methoxy-7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-4-yl)pentanoate and (±)-methyl 4-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-4-(5-methoxy-7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-4-yl)pentanoate (Example 155-K) (28 mg, 0.041 mmol) was dissolved in MeOH (700 μl) and then added 1.25 M HCl in MeOH (0.662 ml, 0.827 mmol) and heated at 65° C. After 30 minutes, an additional aliquot of 1.25 M HCl in MeOH (0.993 ml, 1.241 mmol) was added along with MeOH (700 uL) and the reaction left stirring for 17 hours. At this point an additional aliquot of 1.25 M HCl in MeOH (1.5 ml, 1.875 mmol) was added the reaction was heated at 75° C. for 3 hours and after additional 1.25 M HCl in MeOH (1.5 ml, 1.875 mmol) was added, the temperature was increased 85° C. and the reaction stirred for further 4 hours. At this point, an additional aliquot of 1.25 M HCl in MeOH (3 ml, 3.75 mmol) was added and the reaction was heated at 90° C. for 2 h. The reaction was then cooled to 0° C. and quenched with saturated sodium bicarbonate until pH=7 and then diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were dried over sodium sulfate and then concentrated. The resulting residue was absorbed onto silica to purify via FCC (0-60% EtOAc:heptanes) to obtain the title compound. MS (ESI+) m/z 417.18 (M+H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17][CH:16]2[CH3:23])[CH:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17][CH:16]2[CH3:23])[CH:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: CC1CCC(C)N(c2cc(Cl)ncn2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(N2CCC(C)CCC2C)ncn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.2 %

Procedure:
0.08 g of sodium hydride (60% oil suspension) was suspended in 3 ml of tetrahydrofuran. 0.5 ml of tetrahydrofuran solution of 0.15 g of 2-butyn-1-ol was added dropwise at room temperature therein, and the mixture was stirred for 10 minutes. Into the mixture was added dropwise 0.5 ml of tetrahydrofuran solution of 0.33 g of 1-(6-chloropyrimidin-4-yl)-2,5-dimethyl hexahydro-1H-azepine at room temperature, and stirred for 4 hours at 60° C. After the reaction mixture was cooled to near room temperature, a saturated ammonium chloride aqueous solution was added therein, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.17 g of 1-(6-(2-butynyloxy)pyrimidin-4-yl)-2,5-dimethyl hexahydro-1H-azepine (hereinafter, referred to as Compound (34)).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[N+]=[N-])[CH:6]=[CH:7][CH:8]=1.[CH:24]([CH:26]=[CH2:27])=[O:25]>ClCCl.CCCCCCC.[O-2].[O-2].[Mn+4]>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[CH2:27][CH:26]2[CH:24]=[O:25])[CH:6]=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Reactant: C=CC=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCCCCCC
Product: O=CC1CC1(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Temperature: 55 °C

Procedure:
A solution of bis[3-(trifluoromethyl)phenyl]diazomethane, prepared as in Example 84 from 3,3'-(trifluoromethyl)benzophenone hydrazone (29.9 g) and activated manganese dioxide (30 g) in dichloromethane (150 mL) was added to a solution of acrolein (9.9 mL) in heptane (90 mL) over 15 minutes at 40° C. The solution was heated at 55° C. for 5.5 hours, then the dichloromethane was distilled off and replaced with heptane (100 mL). After the mixture was heated at 90° C. overnight, the solvent was removed in vacuo and the residue was purified by HPLC (dichloromethanehexane; 1:1). Evaporation of the appropriate fractions yielded 30.5 g of 2,2-bis[3-(trifluoromethyl)phenyl]cyclopropanecarboxaldehyde. Crystallization of a portion from hexane gave the analytical sample, 106°-108° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[N:18]([C:21]1[CH:22]=[CH:23][C:24]([N:28]([CH3:30])[CH3:29])=[N:25][C:26]=1[CH3:27])=[C:19]=[S:20]>O1CCCC1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:19](=[S:20])[NH:18][C:21]1[C:26]([CH3:27])=[N:25][C:24]([N:28]([CH3:29])[CH3:30])=[CH:23][CH:22]=1
Reactant: Cc1nc(N(C)C)ccc1N=C=S
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ccc(N(C)C)nc2C)c1NCCCO
Temperature: 65 °C
Reaction time: 72 h

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (1.13 g, 4.38 mmol) and 5-isothiocyanato-N,N,6-trimethylpyridin-2-amine (1.27 g, 6.57 mmol) in tetrahydrofuran (15 mL) was stirred at 65° C. for 3 days. The mixture was concentrated in vacuo, and the residue was washed with ethyl acetate/diisopropyl ether to give methyl 4-chloro-3-({[6-(dimethylamino)-2-methylpyridin-3-yl]carbamothioyl}amino)-2-[(3-hydroxypropyl)amino]benzoate as a brown amorphous (1.09 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[NH:6][C:7](=[S:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2].IC.[C:32](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:4]1[CH:5]([C:22]2[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[CH:28][CH:29]=2)[N:6]=[C:7]([S:21][CH3:32])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)NC1c1ccc(C#N)cc1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSC1=NC(c2ccc(C#N)cc2)C(C(C)=O)=C(C)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-{5-Acetyl-6-methyl-2-thioxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-4-pyrimidinyl}benzonitrile example 1; 100 mg, 0.24 mmol), 1-iodomethane (38.0 mg, 0.27 mmol) and potassium carbonate (34.1 mg, 0.25 mmol) are dissolved in 3 min acetone and stirred at room temperature overnight. The solvent is removed in vacuo and the crude product is purified via preparative HPLC (RP18-column; eluent: acetonitrile-water, gradient 10:90 to 90:10).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:13]([O-])=O.[H][H]>O1CCOCC1.[OH-].[Pd+2].[OH-]>[NH2:13][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:3]=1[NH:2][CH3:1])[C:7]([O:9][CH3:10])=[O:8]
Reactant: [H][H]
Reactant: CNc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1COCCO1
Product: CNc1ccc(C(=O)OC)cc1N
Yield: 61.1 %

Procedure:
The methyl 4-methylamino-3-nitrobenzoate (6.3 g) obtained above was suspended in 1,4-dioxane (125 ml). 20% Palladium hydroxide (6.3 g) was added thereto, and the mixture was stirred for 91 hours at room temperature in a hydrogen atmosphere. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluting solvent; ethyl acetate:n-hexane 1:4→2:3) to give methyl 3-amino-4-methylaminobenzoate (3.3 g, Y.:62%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=O)[CH:9]([CH2:13][CH:14]=O)[CH2:8][CH2:7]2.[C:16]([NH:19][CH2:20][CH2:21][NH2:22])(=[O:18])[CH3:17]>C(O)(=O)C>[Cl:1][C:2]1[C:11]2[C:10]3[N:22]([CH2:21][CH2:20][NH:19][C:16](=[O:18])[CH3:17])[CH:14]=[CH:13][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=CCC1CCc2cccc(Cl)c2C1=O
Reactant: CC(=O)NCCN
Solvent: CC(=O)O
Product: CC(=O)NCCn1ccc2c1-c1c(Cl)cccc1CC2
Yield: 45.1 %

Procedure:
325 mg of 8-chloro-2-(2-oxoethyl)-1-tetralone and 290 mg of N-acetylethylenediamine were heated to reflux in 14ml of acetic acid under argon for 1 hour. The solvent was removed in a vacuum and the residue was taken up in 10 ml of water and extracted several times with ethyl acetate. Chromatography on 20 g of silica gel with hexane/ethyl acetate 1:1 and then with ethyl acetate gave 190 mg (45%) of N-[2-(9-chloro-4,5-dihydro-1H-benz[g]indol-1-yl)ethyl]-acetamide as yellowish crystals with m.p. 146°-147°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C@H:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.O1[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1.Cl.N>O>[CH3:15][C@H:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]3[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]3)=[CH:3][CH:4]=2)=[N:13][NH:12][C:11](=[O:14])[CH2:10]1
Reactant: C[C@@H]1CC(=O)NN=C1c1ccc(N)cc1
Reactant: O=c1ccocc1
Agent: Cl
Agent: N
Solvent: O
Product: C[C@@H]1CC(=O)NN=C1c1ccc(-n2ccc(=O)cc2)cc1

Procedure:
A mixture of (R)-6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (100 mg), 4H-pyran-4-one (52 mg) and hydrochloric acid (0.1N, 1 ml) in water (1.3 ml) was stirred under reflux under nitrogen for 3 hours. Aqueous ammonia (880, 0.01 ml) was added to the cooled reaction mixture to afford the title compound which was collected, washed with water and dried, 91 mg, m.p. 257°-8° C. (softens 120° C.), [α]D25 =-369.5° (1.07% in dimethylformamide).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[F:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][O:49][C:50]2[CH:59]=[CH:58][C:57]([C:60]3[CH:61]=[N:62][N:63]([CH2:65][CH2:66][O:67][CH3:68])[CH:64]=3)=[CH:56][C:51]=2[C:52](OC)=[O:53])=[CH:44][CH:43]=1>CN(C)C=O>[F:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][O:49][C:50]2[CH:59]=[CH:58][C:57]([C:60]3[CH:61]=[N:62][N:63]([CH2:65][CH2:66][O:67][CH3:68])[CH:64]=3)=[CH:56][C:51]=2[C:52]([NH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:53])=[CH:44][CH:43]=1
Reactant: COCCn1cc(-c2ccc(OCc3ccc(F)cc3)c(C(=O)OC)c2)cn1
Reactant: Nc1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCn1cc(-c2ccc(OCc3ccc(F)cc3)c(C(=O)Nc3cccnc3)c2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Pyridinamine (49.0 mg, 0.52 mmol), HATU (148 mg, 0.39 mmol) and diisopropylethylamine (0.11 ml, 0.65 mmol) were added to a solution of methyl 2-{[(4-fluorophenyl)methyl]oxy}-5-{1-[2-(methyloxy)ethyl]-1H-pyrazol-4-yl}benzoate (may be prepared as described in Description 116; 100 mg, 0.26 mmol) in N,N-dimethylformamide (5 ml) and the mixture was stirred at room temperature overnight. The DMF was evaporated under reduced pressure on a buchi. Water (5 ml) and ethyl acetate (10 ml) were added to the residue. The organics were separated and the aqueous layer was further extracted with ethyl acetate (3×10 ml). The organics were combined and evaporated. The residue was purified using MDAP to yield the title compound. 36 mg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[C:19]([CH3:28])([CH3:27])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>CN(C)C=O>[CH3:8][O:7][C:5]([C:4]1[CH:3]=[C:2]([CH:11]=[CH:10][CH:9]=1)[O:1][C:19]([CH3:28])([CH3:27])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:6]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OC(C)(C)C(=O)OC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Methyl 3-hydroxybenzoate (17.05 g, 0.112 mol) was dissolved in dimethylformamide (100 mL). Subsequently, potassium carbonate (20.12 g, 0.145 mol) and then tert-butyl 2-bromoisobutyrate (50.00 g, 0.224 mol) were added thereto, and the mixture was stirred overnight at 80° C. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the concentrate. Washing was performed sequentially with water and saturated brine, followed by drying over sodium sulfate. The reaction mixture was subjected to filtration, concentration under reduced pressure, and purification by silica gel column chromatography (n-hexane/ethyl acetate=10/1), whereby a colorless oil was obtained (17.03 g, 57.80 mmol, 51.6%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=O)[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([NH2:48])[CH:43]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:48][C:44]3[CH:45]=[CH:46][CH:47]=[C:42]([O:41][CH3:40])[CH:43]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Reactant: COc1cccc(N)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(NC(=O)[C@H]2CCCN(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinecarboxylic acid (150 mg, 0.439 mmol), EDC (118 mg, 0.615 mmol), and HOBT (83 mg, 0.615 mmol) in DMF (3 mL) was added m-anisidine (54 mg, 0.44 mmol), and the mixture was stirred at room temperature for 4 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound (194 mg) as a yellow solid. LC-MS (ES) m/z=447 [M+H]+.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:5]=[C:6]([C:10](=[N:12]O)[CH3:11])[CH:7]=[N:8][CH:9]=1)[CH3:3]>CO.Cl.[Pd]>[CH:2]([C:4]1[CH:5]=[C:6]([CH:10]([NH2:12])[CH3:11])[CH:7]=[N:8][CH:9]=1)([CH3:3])[CH3:1]
Reactant: C=C(C)c1cncc(C(C)=NO)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)c1cncc(C(C)N)c1
Reaction time: 4 h
Yield: 41.6 %

Procedure:
To a stirred solution of 1-(5-(prop-1-en-2-yl)pyridin-3-yl)ethanone oxime (400 mg) in MeOH.HCl (1.25M, 8 mL) was added 10% Pd/C (40 mg) and stirred under hydrogen atmosphere for 4 h. The catalyst was filtered off and the residue was dissolved in 5 mL of 25% aqueous NH3 and extracted with CHCl3 and the organic layer was washed with brine, dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (10% MeOH/90% CHCl3 spiked with 0.25% of Et3N) to provide 155 mg of the product.
Reaction SMILES: [CH3:1][CH:2]([C:7](=[O:10])[CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[Li]CCCC.[CH2:18]([O:25][C:26]1[CH:38]=[CH:37][C:29]2[CH:30]=[C:31](C(OC)=O)[O:32][C:28]=2[CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>C1COCC1>[CH2:18]([O:25][C:26]1[CH:38]=[CH:37][C:29]2[CH:30]=[C:31]([C:6]3[O:5][C:3](=[O:4])[C:2]([CH3:1])=[C:7]([OH:10])[C:8]=3[CH3:9])[O:32][C:28]=2[CH:27]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCC(=O)C(C)C(=O)OC
Reactant: COC(=O)c1cc2ccc(OCc3ccccc3)cc2o1
Agent: [Cl-]
Agent: [H-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(-c2cc3ccc(OCc4ccccc4)cc3o2)oc(=O)c(C)c1O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of methyl 2-methyl-3-oxopentanoate (3.24 g) in THF (30 ml) was slowly added to a suspension of NaH (900 mg) in THF (50 ml) at 0° C., and after stirring for 10 minutes, the mixture was cooled to −78° C. and 1.58 M n-BuLi (14.2 ml) was slowly added dropwise. After stirring the reaction solution at −78° C. for 30 minutes, a solution of methyl 6-(benzyloxy)benzofuran-2-carboxylate (4.26 g) in THF (15 ml) was slowly added and the mixture was stirred at −78° C. for 4 hours. A saturated ammonium chloride aqueous solution was added to the reaction solution, and after bringing it to room temperature, extraction was performed with AcOEt and the organic layer was dried with MgSO4 and then filtered and concentrated. The residue was dissolved in MeOH (30 ml) and THF (10 ml), a 4 N lithium hydroxide aqueous solution (5 ml) and water (50 ml) were added, and after stirring at room temperature for 4 hours, a saturated KHSO4 aqueous solution (30 ml) was slowly added. The deposited yellow precipitate was filtered off and rinsed with AcOEt to obtain 6-(6-(benzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)CC>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Oc1ccnc2cc(Br)ccc12
Reactant: O=[N+]([O-])O
Solvent: CCC(=O)O
Product: O=[N+]([O-])c1cnc2cc(Br)ccc2c1O
Temperature: 60 °C

Procedure:
A solution of 7-bromoquinolin-4-ol (594 g, 2.65 mol) in propionic acid (5 L) was heated to 120° C., and nitric acid (215 mL of 16 molar (M)) was added dropwise over a period of 2.5 hours while maintaining the temperature in the range of 119° C. to 130° C. The reaction was then cooled to 60° C. and filtered to collect a solid, which was washed sequentially with water (3×500 mL), 2-propanol (500 mL), and diethyl ether (300 mL), and pulled dry with vacuum filtration to provide 447 g of 7-bromo-3-nitroquinolin-4-ol as a tan powder.