Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:21])[C:5](=[CH:11][NH:12][C:13]1[N:17]([CH2:18][CH3:19])[N:16]=[C:15]([CH3:20])[CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[C:4]([OH:21])=[C:14]2[C:15]([CH3:20])=[N:16][N:17]([CH2:18][CH3:19])[C:13]2=[N:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1cc(C)nn1CC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(c(C)nn2CC)c1O

Procedure:
14.8 g of [[(1-ethyl-3-methyl-5-pyrazolyl)amino]methylene]-malonic acid diethyl ester (0.05 mol) is dissolved in 50 g of diphenyl ether. The reaction mixture is heated to 235°-250° (bath temperature) and allowed to react at this temperature for 1 to 2 hours, while continuously distilling off the resulting ethanol. The last part of the alcohol is removed by means of a water aspirator. The diphenyl ether is separated by distillation with a fractionation column in vacuo. The 1-ethyl-4-hydroxy-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester is obtained at b.p.0.1-0.5 125°-129°, yield 10.7 g = 86% of theory, m.p. 91°-93°. The compound is recrystallized from ligroin (90°-100°), and has a melting point of 93°-94°. Hydrolysis of this product with aqueous sodium hydroxide yields 1-ethyl-4-hydroxy-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, m.p. 212°-213°.
Reaction SMILES: [CH3:1]OS(OC)(=O)=O.[CH3:8][S:9]([C:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][N:12]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+]>[OH-].[Na+]>[CH3:1][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:21])[C:11]([S:9]([CH3:8])=[O:10])=[N:12]1
Reactant: COS(=O)(=O)OC
Reactant: CS(=O)c1n[nH]c2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: Cn1nc(S(C)=O)c(=O)c2ccccc21
Reaction time: 0.25 h

Procedure:
Dimethylsulfate [12.5 g (0.1 mole)] was added gradually to a vigorously stirred solution of 6.5 g (0.0298 mole) of 3-(methylsulfinyl)-4(1H)-cinnolinone in 120 ml of 1N sodium hydroxide solution at 30°C. The temperature rose to 40° as the suspended dimethyl sulfate gradually went into solution over a period of 15 minutes. After an additional one-half hour of stirring, potassium carbonate excess was added to salt-out an oil. The product was extracted into 800 ml of methylene chloride, the solution was dried over K2CO3, charcoaled, filtered and concentrated. Wt 6.4 g (96.7%) mp. 187°-189°C. Recrystallization from 2-propanol-petroleum ether gave pure material, mp. 189°-191°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][O:7][C:6]=2[CH:13]=1.C1CCCCC1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])/[C:10](=[CH:22]/[N:23]([CH3:25])[CH3:24])/[CH2:9][CH2:8][O:7][C:6]=2[CH:13]=1
Reactant: COC(OC)N(C)C
Reactant: O=C1CCCOc2cc(Br)ccc21
Solvent: C1CCCCC1
Product: CN(C)/C=C1\CCOc2cc(Br)ccc2C1=O
Temperature: 25 °C
Yield: 86 %

Procedure:
8-Bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one (5.0 g, 20.7 mmol) in dimethylformamide dimethylacetal (15 mL) was heated at 110° C. for 18 h. The reaction was allowed to cool to room temperature and cyclohexane (20 mL) was added. The resulting solid precipitate was collected by filtration, washed with cyclohexane and then dried under vacuum at 40° C. to yield 8-Bromo-4-[1-dimethylamino-meth-(E)-ylidene]-3,4-dihydro-2H-benzo[b]-oxepin-5-one as yellow crystals (5.32 g, 86%). 1H NMR δ (ppm) (CDCl3): 7.73 (1 H, s), 7.61 (1 H, d, J=8.29 Hz), 7.29 (1 H, dd, J=8.29, 1.94 Hz), 7.18 (1 H, d, J=1.91 Hz), 4.28-4.21 (2 H, m), 3.14 (6 H, s), 2.77-2.70 (2 H, m).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([OH:9])[N:3]=1.[OH-].[Na+].[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15][NH2:16]>O>[NH2:1][C:2]1[NH:3][C:4](=[O:9])[N:5]=[C:6]([NH:16][CH2:15][CH:14]([O:17][CH3:18])[O:13][CH3:12])[N:7]=1
Reactant: COC(CN)OC
Reactant: Nc1nc(O)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(CNc1nc(N)[nH]c(=O)n1)OC
Temperature: 25 °C

Procedure:
A suspension of 2-amino-4-chloro-6-hydroxy-s-triazine (II) 15.0 g, 0.102 mol) in 250 mL of water was treated with sodium hydroxide (4.095 g, 0.102 mol), and the mixture was stirred to obtain a clear solution which was treated with aminoacetaldehyde dimethyl acetal (12.9 g, 0.12 mol). The mixture was heated under gentle reflux for 2.5 h. with stirring and then cooled to room temperature. The crystalline solid that separated was collected and washed with cold water (2×25 mL). Recrystallization from a large excess of water gave the compound as needles: 15.0 g (68.0%); mp 285° C. dec. Anal. (C7H13N5O3, 215.21) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.[NH:22]1[CH:26]=[C:25]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[N:24]=[CH:23]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([NH:31][C:30]3[CH:29]=[CH:28][C:27]([C:25]4[N:24]=[CH:23][NH:22][CH:26]=4)=[CH:33][CH:32]=3)=[O:17])[C:10](=[O:19])[CH:9]=2)[CH:7]=1
Reactant: Nc1ccc(-c2c[nH]cn2)cc1
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Product: CC(C(=O)Nc1ccc(-c2c[nH]cn2)cc1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
78 mg (0.25 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) (Example 2.2B) and 44 mg (0.28 mmol) of 4-(1H-imidazol-4-yl)aniline were reacted according to General Method 1. Yield: 40 mg (36% of theory)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.Cl.[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH2:29][NH2:30].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[C:5]([C:11]#[N:12])=[C:6]([NH:30][CH2:29][C:20]2[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:19]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Reactant: NCc1ccc2ccccc2n1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(NCc2ccc3ccccc3n2)nc(N)nc1-n1cccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, C-quinolin-2-yl-methylamine hydrochloride and DBU in DME. ES-MS m/e (%): 343 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:16])[C:10]#[C:11][C:12]([CH3:15])([OH:14])[CH3:13])=[CH:5][CH:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[OH:14][C:12]([CH3:15])([CH3:13])[C:11]#[C:10][C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[O:16]
Reactant: COc1ccc(C(O)C#CC(C)(C)O)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1ccc(C(=O)C#CC(C)(C)O)cc1
Reaction time: 3 h
Yield: 94.8 %

Procedure:
To a room temperature, stirred solution of 1-(4-methoxyphenyl)-4-methylpent-2-yne-1,4-diol (6.3 g, 0.029 mol) in DCM (50 mL), Dess Martin periodinane (31.2 g, 0.07 mol) was added and the reaction mixture was stirred for 3 h. The reaction mixture was then diluted with DCM (50 mL) and the combined organic layers were washed with a saturated NaHCO3 solution and water, dried over Na2SO4, filtered and then concentrated in vacuo to afford 4-hydroxy-1-(4-methoxyphenyl)-4-methylpent-2-yn-1-one (6 g, 96%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[CH:10]12[O:17][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2.Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH:5][C@@H:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:17]
Reactant: C1CCC2OC2CC1
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: O[C@@H]1CCCCC[C@H]1Nc1ccc(Cl)c(Cl)c1

Procedure:
A solution of 3,4-dichloroaniline, cycloheptene oxide, and concentrated HCl (2 ml.) is heated at reflux temperature for seven (7) days. The unreacted epoxide is evaporated and the residue is treated with excess ethereal HCl, and a syrup results. This is washed with ether. The residue is crystallized and recrystallized from methanol/ether (1/5.5, v/v) to give trans-3,4-dichloro-N-(2-hydroxycycloheptyl)aniline, hydrochloride salt.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[C:3]([O:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: COc1ccc(O)cc1
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2nc(Cl)ncc2Br)cc1
Reaction time: 24 h
Yield: 95.1 %

Procedure:
A mixture of 5-bromo-2,4-dichloropyrimidine (5.0 g, 22.0 mmol), 4-methoxyphenol (2.72 g, 22.0 mmol) and potassium carbonate (6.07 g, 44.0 mmol) in DMF (20 ml) was stirred for 24 hours. The mixture was added to water (100 ml) and the solid which separated out was collected by filtration, washed with water (50 ml) and dried under high vacuum to give the product (6.6 g, 96%). NMR: 3.8 (s, 3H), 7.0 (d, 2H), 7.2 (d, 2H), 8.8 (s, 11H).
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][CH:8]=[CH:7]3)[N:4]=[C:3]1[CH:15]([CH3:20])[CH2:16][C:17](O)=[O:18].CN(C=O)C.C(Cl)(=O)C([Cl:29])=O>C(Cl)Cl>[CH3:1][N:2]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][CH:8]=[CH:7]3)[N:4]=[C:3]1[CH:15]([CH3:20])[CH2:16][C:17]([Cl:29])=[O:18]
Reactant: CC(CC(=O)O)c1nc2c3cccnc3ccc2n1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(CC(=O)Cl)c1nc2c3cccnc3ccc2n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of 3-(3-methyl-3H-imidazo[4,5-f]quinolin-2-yl)butanoic acid (200 mg, 0.74 mmol) in oxalyl chloride (8 mL) and DCM (8 in L) was added DMF (5 mg). The mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness to give the product as a yellow solid (160 mg, 75% yield). See, e.g., Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 2000, 294-296; Tetrahedron Letters, 2000, 4165-4168.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].S(Cl)([Cl:13])=O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]([Cl:13])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=C(O)c1ccccc1O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Cl)c1ccccc1O

Procedure:
Into a clean, dry three necked round bottomed flask were charged one equivalent of salicylic acid, 50 mls is of anhydrous toluene and a few drops of pyridine catalyst. The flask was equipped with a stir bar, thermometer and an addition funnel. Into the addition funnel was charged one equivalent of thionyl chloride in a few mls of toluene. The contents of the reaction flask were heated to 40° C. under a nitrogen blanket before the thionyl chloride solution was added slowly. Once the addition was complete, the reaction proceeded at 40-45° C. for several hours or until the reaction mixture was homogeneous. Upon completion of the reaction, any unreacted thionyl chloride was removed under vacuum.
Reaction SMILES: C(O[CH:5]([O:9][C:10](=[O:12])[CH3:11])[C:6]([CH3:8])=[CH2:7])(=O)C.[C:13]1([O:19][CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C=CC>>[C:10]([O:9][CH:5]=[C:6]([CH3:7])[CH2:8][C:16]1[CH:17]=[CH:18][C:13]([O:19][CH3:20])=[CH:14][CH:15]=1)(=[O:12])[CH3:11]
Reactant: COc1ccccc1
Reactant: C=C(C)C(OC(C)=O)OC(C)=O
Solvent: C=CC
Product: COc1ccc(CC(C)=COC(C)=O)cc1
Temperature: 24.5 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
In an argon gas atmosphere, a four necked flask having a capacity of 200 ml was charged with 19.22 g (100 m moles) of 3,3-diacetoxy-2-methylpropene having a purity degree of 89.6% by mass and 108.14 g (1.0 mole) of anisol. Then, the resultant mixture was mixed with 1.42 g (10 m moles) of boron trifluoride-diethylether complex at an internal temperature of 24° C. for 2 minutes. The mixture was stirred at an internal temperature of 24 to 25° C. for one hour to cause the mixed propene compound and anisol to react with each other. After the reaction was completed, the resultant reaction liquid was washed two times with 20 ml of water and further with 20 ml of saturated aqueous sodium chloride solution. The resultant reaction liquid was subjected to a layer separation treatment, the resultant organic layer was removed by a distillation under reduced pressure (20 mmHg, 55 to 57° C.), the resultant residue was refined by a chromatography on silica gel using an eluting solvent:hexane/ethyl acetate mixture in a mixing volume ratio: 10/1. As a colorless liquid fraction, the target 1-acetoxy-2-methyl-3-(4-methoxyphenyl)propene was obtained in a yield of 93.4% in an amount of 20.58 g.
Reaction SMILES: CN(C)C([N:5]1[C:9]2=[N:10][CH:11]=[C:12]([Br:14])[CH:13]=[C:8]2[C:7]([C:15]2[O:19][CH:18]=[N:17][CH:16]=2)=[CH:6]1)=O.[OH-].[Na+]>CCO>[Br:14][C:12]1[CH:13]=[C:8]2[C:7]([C:15]3[O:19][CH:18]=[N:17][CH:16]=3)=[CH:6][NH:5][C:9]2=[N:10][CH:11]=1
Reactant: CN(C)C(=O)n1cc(-c2cnco2)c2cc(Br)cnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Brc1cnc2[nH]cc(-c3cnco3)c2c1
Temperature: 90 °C
Yield: 90.8 %

Procedure:
A mixture of 21 (667 mg, 1.99 mmol), EtOH (20 mL) and 10% aq. NaOH (10 mL) was heated at 90° C. for 40 min then cooled and poured onto water (50 mL). The aqueous layer was extracted with ethyl acetate (4×40 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4) and concentrated to give 22 as a white solid (477 mg, 91%); 1H NMR (400 MHz, CDCl3) δ 7.27 (d, J=2.5 Hz, 1H), 7.67 (d, J=2.5 Hz, 1H), 7.94 (s, 1H), 8.33 (d, J=2.1 Hz, 1H), 8.44 (d, J=2.1 Hz, 1H), 9.30-9.10 (bs, NH).
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:10](O)[CH2:11][OH:12].P(=O)(O)(O)O>[Cl-].[Zn+2].[Cl-].C1C=CC=CC=1>[O:9]1[CH2:10][CH2:11][O:12][CH:1]1[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: O=Cc1ccccc1O
Reactant: OCCO
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Product: Oc1ccccc1C1OCCO1

Procedure:
A mixture of 244 parts of salicylaldehyde, 125 parts of ethyleneglycol, 1 part of zinc chloride, 1 part by volume of concentrated phosphoric acid and 500 parts by volume of benzene was boiled in a circulating distillation apparatus until water was no longer being eliminated. The solution of the product was filtered and evaporated. The residue was distilled under a high vacuum. The product boiled at 88° to 91°C under 0.04 mm Hg pressure and melted at 67° to 70°C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH:8]=[C:7]([OH:13])[CH:6]=[CH:5]2.[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>>[F:12][C:10]1[CH:11]=[C:2]([C:17]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:15]([F:14])[CH:16]=2)[CH:3]=[C:4]2[C:9]=1[CH:8]=[C:7]([OH:13])[CH:6]=[CH:5]2
Reactant: COc1ccc(B(O)O)cc1F
Reactant: Oc1ccc2cc(Br)cc(F)c2c1
Product: COc1ccc(-c2cc(F)c3cc(O)ccc3c2)cc1F

Procedure:
The title compound was prepared by reacting 6-bromo-8-fluoro-2-naphthol (0.66 g, 2.74 mmol) with 3-fluoro-4-methoxyphenyl boronic acid (0.56 g, 3.3 mmol) according to method A to yield 0.67 g (85%) of a white solid: mp 138-140° C.; 1H NMR (DMSO-d6): δ 3.90 (3H, s), 7.17-7.30 (3H, m), 7.60-7.65 (2H, m), 7.71 (1H, dd, J=2.19 Hz), J=13.14 Hz), 7.90 (1H, d, J=8.37 Hz), 7.99 (1H, bs), 10.15 (1H, bs); MS (ESI) m/z285 (M−H)−.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[NH2:10][CH2:11][C:12]([OH:14])=[O:13].[OH-].[Na+]>O>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][N:10]([CH2:11][C:12]([OH:14])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: ClCc1ccccn1
Reactant: NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CN(Cc1ccccn1)Cc1ccccn1

Procedure:
2-Chloromethylpyridine hydrochloride (9.2 g, 8.53 mmol) and glycin (2 g, 26.6 mmol) were dissolved in water (30 mL) and stirred at room temperature for five days, with addition of 5 mol aqueous NaOH solution at intervals to maintain the pH at 8-10. The resulting dark red solution was extracted with ethyl acetate, neutralized with HCl and concentrated. The residue was dissolved in dichloromethane, and the insoluble sodium chloride was filtered. Pale yellow crystals formed from the filtrate, which were collected and dried under vacuum. Yield (2.87 g) (11.2 mmol, 42%). 1H NMR (CDCl3), 300 MHz): 3.39 (s, 2H), 3.98 (s, 4H), 7.06 (t, 2H), 7.30 (d, 2h), 7.56 (t, 2H), 8.36 (d, 2H). 13C NMR (CD3OD, 300 MHz): 57.36 (C, CH2), 59.77 (2C, PyCH2), 124.77 (2CH, Py), 125.15 (2CH, Py), 139.00 (C, CH2), 149.76 (2CH, Py), 156.10 (2C, Py), 173.05 (C, CO2H).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([NH:10][C@H:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][CH2:12]3)[O:8][CH2:9][C:4]=2[CH:3]=1.[C-:22]#[N:23].O>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C@H:11]1([NH:10][C:7]2[O:8][CH2:9][C:4]3[CH:3]=[C:2]([C:22]#[N:23])[CH:21]=[CH:20][C:5]=3[N:6]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1
Reactant: Brc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Reactant: [C-]#N
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Temperature: 160 °C
Yield: 41.1 %

Procedure:
A stirred mixture of (6-bromo-4H-benzo[d][1,3]oxazin-2-yl)-(R)-indan-1-yl-amine (Example 32) (2.0 g, 5.83 mmol), zink cyanide (1.03 mg, 8.77 mmol) and tetrakis-(triphenylphosphine)-palladium (673 mg, 0.58 mmol) in N,N-dimethylformamide (20 ml) was heated at 160° C. for 15 min in a microwave reactor. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2×70 ml). The combined organic layers were washed with brine (2×20 ml), dried (magnesium sulfate) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel to yield the title compound as light yellow foam (693 mg, 41%). MS (ISN): m/e=288.2 (M−H−).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:4][N:3]=1.[F-:19].[Cs+]>CS(C)=O>[F:19][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:4][N:3]=1
Reactant: COCCOc1cnc(Cl)c2ccc(OC)cc12
Reactant: [F-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COCCOc1cnc(F)c2ccc(OC)cc12
Temperature: 140 °C

Procedure:
To a solution of 1-chloro-6-methoxy-4-(2-methoxyethoxy)isoquinoline (560 mg, 2.092 mmol) in DMSO (5 mL) was added CsF (636 mg, 4.18 mmol) and heated to 140° C. for 2 hrs. LC/MS showed the desired product. The reaction was diluted with Ethylacteate and washed with water, and brine. The organic phase was collected, dried over MgSO4, and concentrated under vacuum to give the crude product as a reddish brown solid. The crude material was purified via silica gel chromatography (5-50% EtOAc:Hex) to give the product 1-fluoro-6-methoxy-4-(2-methoxyethoxy)isoquinoline (168 mg, 0.669 mmol, 32.0% yield) as a light yellow solid. MS: MS m/z 252.2(M++1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.O1CCN(CCN[S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])CC1>>[O:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[CH2:6][CH2:7]1
Reactant: O=S(=O)(NCCN1CCOCC1)C(F)(F)F
Reactant: NCCCN1CCOCC1
Product: O=S(=O)(NCCCN1CCOCC1)C(F)(F)F

Procedure:
In the manner described above, substituting N-(3-aminopropyl)morpholine (41.35 grams; 0.286 mole) for the N-(2-aminoethyl)morpholine and recrystallizing the crude product from methylcyclohexane, N-(3-morpholinopropyl)trifluoromethanesulfonamide is obtained, m.p. 95°-97° C.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:16]([C:18]2[N:22]=[C:21](C(Cl)(Cl)Cl)[O:20][N:19]=2)[CH:15]=[C:14]([CH3:27])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1.[CH3:28][NH2:29]>CN(C)C=O.O>[CH3:1][C:2]1[CH:17]=[C:16]([C:18]2[NH:22][C:21](=[N:29][CH3:28])[O:20][N:19]=2)[CH:15]=[C:14]([CH3:27])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1
Reactant: CN
Reactant: Cc1cc(CCCOc2c(C)cc(-c3noc(C(Cl)(Cl)Cl)n3)cc2C)on1
Solvent: O
Solvent: CN(C)C=O
Product: CN=c1[nH]c(-c2cc(C)c(OCCCc3cc(C)no3)c(C)c2)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.5 %

Procedure:
The product of Example 12 (1.00 g, 2.32 mmol) was added to 5 ml of 40% aqueous methylamine in dimethylformamide (3-5 mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic extracts were washed with water, brine, dried (MgSO4) and concentrated in vacuo. The crude residue (0.54 g) was purified by chromatography (Silica Gel 60, first with 2% methanol in methylene chloride and then with 50% ethyl acetate in hexanes) to give 300 mg (37.5%) of pure title compound as a yellow solid, mp 126.5°-127° C. (ethanol).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:38]([NH:42][C:43](=[O:51])[CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)([CH3:41])([CH3:40])[CH3:39]>>[C:38]([NH:42][C:43](=[O:51])[CH2:44][N:45]1[CH2:46][CH2:47][N:48]([C:32]([N:12]2[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=2[O:35][CH2:36][CH3:37])=[O:33])[CH2:49][CH2:50]1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)NC(=O)CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NC(C)(C)C)CC1

Procedure:
In a manner analogous to the method described in example 5, (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 4) was reacted with N-tert-butyl-2-piperazin-1-yl-acetamide (Enamine-BB) to give the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][N:9]([CH3:20])[C@@H:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[C:6]([CH3:21])[N:5]=[C:4]([C:22]2[C:27]([CH2:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:30][CH3:31])[N:3]=1.[C:32]1([OH:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CC([O-])(C)C.[K+].C([O-])(O)=O.[Na+]>CCOC(C)=O.CC(O)(C)C.CC(N(C)C)=O>[CH2:30]([C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([CH2:28][CH3:29])[C:22]=1[C:4]1[N:5]=[C:6]([CH3:21])[C:7]([CH2:8][N:9]([CH3:20])[C@@H:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[C:2]([O:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:3]=1)[CH3:31]
Reactant: Oc1ccccc1
Reactant: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Solvent: CC(=O)N(C)C
Product: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(Oc2ccccc2)n1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a vial containing [4-chloro-2-(2,6-diethyl-phenyl)-6-methyl-pyrimidin-5-ylmethyl]-methyl-(1S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine 9 (0.1 mL of a 0.2 M DMA solution, 0.02 mmol) is added phenol (0.1 mL of a 0.3 M DMA solution, 0.03 mmol) and KOtBu (0.1 mL of a 0.3 M solution in 7:3 DMA:tBuOH, 0.03 mmol) and allowed to stir at 70° C. for 16 h. EtOAc (50 mL) and sat. NaHCO3 (50 mL) are then added and the organic layer is washed with water.(100 mL), brine (100 mL) and dried over Na2SO4. The crude solution is filtered, concentrated and purified by SiO2 flash chromatography using hexanes:Et2O (5:1) affording (1S)—N-{[2-(2,6-diethylphenyl)-4-methyl-6-phenoxypyrimidin-5-yl]methyl}-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine as a colorless oil. [mass expected (491.67); mass found (491.42)].