Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:14]([O:16][CH2:17]C)=[O:15])[NH:7]2.[Mg].ClCCl.[NH4+].[Cl-]>CO>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH:6]([C:14]([O:16][CH3:17])=[O:15])[NH:7]2
Reactant: CCOC(=O)c1cc2c(OC)c(OC)ccc2[nH]1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1Cc2c(ccc(OC)c2OC)N1
Temperature: 25 °C

Procedure:
Ethyl 4,5-dimethoxyindole-2-carboxylate (0.500 g, 2 mmol) was dissolved in methanol (10 ml) and magnesium shavings (0.2431 g, 10 mmol) were then added, with stirring, at room temperature under a nitrogen atmosphere. After the reaction started, a water bath was used to maintain the reaction temperature between 5-15° C. At the end of the reaction, dichloromethane (200 ml) was added to the mixture, followed by NH4Cl solution (200 ml). The organic phase was separated out and the aqueous phase was extracted with dichloromethane (3×50 ml). The combined organic phases were dried over magnesium sulphate and the solvent was removed to give a brown oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][C:6]1[CH:15]=[C:14]2[C:9]([N:10]=[CH:11][C:12]([O:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([NH:25][C:26]([C:28]4[CH:29]=[CH:30][C:31]5[S:36][CH2:35][C:34](=[O:37])[NH:33][C:32]=5[CH:38]=4)=[O:27])[CH2:21][CH2:20]3)=[N:13]2)=[CH:8][CH:7]=1.C(N(CC)CC)C>CN(C)C=O>[O:37]=[C:34]1[NH:33][C:32]2[CH:38]=[C:28]([C:26]([NH:25][CH:22]3[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][O:16][C:12]4[CH:11]=[N:10][C:9]5[C:14]([N:13]=4)=[CH:15][C:6]([O:5][C:1](=[O:3])[CH3:2])=[CH:7][CH:8]=5)[CH2:20][CH2:21]3)=[O:27])[CH:29]=[CH:30][C:31]=2[S:36][CH2:35]1
Reactant: O=C1CSc2ccc(C(=O)NC3CCN(CCOc4cnc5ccc(O)cc5n4)CC3)cc2N1
Reactant: CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc2ncc(OCCN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
Acetyl chloride (11.4 μL, 0.16 mmol, 1.1 eq) is added at room temperature to a stirred solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-hydroxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide (70 mg, 0.15 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), followed by triethylamine (40.7 μL, 0.29 mmol, 2.0 eq). After 1 hour stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×5 mL) and water (5 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford acetic acid 3-(2-{4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-piperidin-1-yl}-ethoxy)-quinoxalin-6-yl ester as a white powder (35 mg, 41% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([CH:24]([F:26])[F:25])([C:14]2[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:15]=2[F:23])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C1COCC1.[Pd]>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:14]2[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=2[F:23])([CH:24]([F:26])[F:25])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC1=NC(c2cc([N+](=O)[O-])ccc2F)(C(F)F)COC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1=NC(c2cc(N)ccc2F)(C(F)F)COC1
Yield: 94.9 %

Procedure:
[5-Difluoromethyl-5-(2-fluoro-5-nitro-phenyl)-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (180 g, 462 mmol) and 17.61 g Pd—C 10% were suspended in 1760 mL THF. The mixture was shaken in a Parr apparatus in an atmosphere of hydrogen at rt. After 6 h the reaction mixture was filtered over celite and evaporated. The residue was crystallized from DCM/heptanes to provide 157.6 g of the title compound as beige crystals.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][CH2:14][O:15][CH2:16][C:17]([CH:19]([CH3:21])[CH3:20])=[CH2:18]>C(Cl)Cl>[CH:19]([C:17]1([CH2:16][O:15][CH2:14][O:13][CH3:12])[CH2:18][O:9]1)([CH3:21])[CH3:20]
Reactant: C=C(COCOC)C(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COCOCC1(C(C)C)CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.5 %

Procedure:
m-Chloroperbenzoic acid (213 g, 861 mmol) was gradually added to a solution of 2-methoxymethoxymethyl-3-methyl-l-butene (89 g, 615 mmol) in methylene chloride (800 ml) while cooling in an ice-bath, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was washed with 10% potassium sulfide aqueous solution and sodium hydrogencarbonate aqueous solution, dried over sodium sulfate, and then concentrated under reduced pressure to afford 2-isopropyl-2-methoxymethoxymethyloxirane (98 g, quantitative) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:6][CH:5]=1)([O-])=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:31].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:31].[ClH:31].[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][NH:10][C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(NCCc2ccccn2)cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(NCCc2ccccn2)cc1

Procedure:
The N-(4-nitrophenyl)-N-(2-pyrid-2-ylethyl)amine (5) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].C([C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=1)#N>>[CH3:21][S:20][C:17]1[CH:18]=[CH:19][C:14]([C:1]2[NH:2][C:3](=[O:11])[C:4]3[C:5]([CH:10]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:15][CH:16]=1
Reactant: CNC(=O)c1ccccc1C
Reactant: CSc1ccc(C#N)cc1
Product: CSc1ccc(-c2cc3ccccc3c(=O)[nH]2)cc1
Yield: 46.7 %

Procedure:
According to the method of Example 10-1, N-methyl-2-methylbenzamide (5.97 g) and 4-cyanothioanisole (5.97 g) were reacted, to give 3-(4-methylthiophenyl)isoquinolin-1-one (5.00 g).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][O:12][C:13]1[N:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[N:18]=[CH:17][C:16]([C:2]2[S:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:15][CH:14]=1
Reactant: Brc1nc2ccccc2s1
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2nc3ccccc3s2)cn1
Yield: 81.3 %

Procedure:
According to Scheme 4 Method A: The title compound was prepared from 2-bromobenzo[d]thiazole (1 eq, 0.91 mmol, 0.20 g) and 6-methoxypyridin-3-ylboronic acid (1.5 eq, 1.36 mmol, 0.21 g) according to the procedure described for Example 2 Step 2. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 25 g SiO2) using cyclohexane/AcOEt 95/5 as eluent to afford 2-(6-methoxypyridin-3-yl)benzo[d]thiazole (0.74 mmol, 0.18 g, 82%) as a white solid.
Reaction SMILES: [C:1]([CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5])#[N:2].P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[Cl:20][C:21]1[C:26](O)=[C:25]([Cl:28])[C:24]([Cl:29])=[C:23]([Cl:30])[C:22]=1[Cl:31].N1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.ClCCl>[Cl:20][C:21]1[C:26]([O:5][C:4](=[O:6])[CH:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:1]#[N:2])=[C:25]([Cl:28])[C:24]([Cl:29])=[C:23]([Cl:30])[C:22]=1[Cl:31]
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: N#CC(C(=O)O)c1ccccc1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CC(C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)c1ccccc1

Procedure:
8 g. (0.05 moles) of α-cyano-phenylacetic acid are dissolved in 80 ml. of dichloromethane, 10.2 g. (0.05 moles) of phosphorous pentachloride are added and the mixture is stirred for 2 hours at the boiling point of the dichloromethane. The reaction is completed when the hydrochloric acid evolution ceases. The solvent is distilled off and the residue containing the obtained acid chloride and phosphoroxychloride is taken up in carbontetrachloride and the solution is added dropwise to 13 g. (0.05 moles) of pentachlorophenol and 4 ml. (0.05 moles) of pyridine dissolved in 200 ml. of carbontetrachloride. The reaction mixture is cooled and the precipitated pyridine chlorohydrate is removed by washing twice with 50 ml. of water, dried, distilled off and the residue is distilled off with diisopropyl ether. The precipitated crystalline product is cooled and filtered. The α-cyanophenylacetic acid pentachlorophenyl ester is air-dried.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:20]3[CH:19]=[CH:18][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[C:12]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:13]=3)[CH:5]=[CH:6][CH:7]=1.[CH3:33][O:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(Cl)Cl.C(O)C>[C:27]1([C:12]2[CH:11]=[CH:10][C:9]3[N:8]([C:4]4[CH:5]=[C:6]([C:37]5[CH:38]=[CH:39][CH:40]=[C:35]([O:34][CH3:33])[CH:36]=5)[CH:7]=[CH:2][CH:3]=4)[C:20]4[C:15]([C:14]=3[CH:13]=2)=[CH:16][C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][CH:19]=4)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Brc1cccc(-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)ccc32)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: COc1cccc(-c2cccc(-n3c4ccc(-c5ccccc5)cc4c4cc(-c5ccccc5)ccc43)c2)c1
Temperature: 25 °C

Procedure:
Mix 2.80 g (8.77 mmol) of 3,6-diphenylcarbazole, 22.18 g (87.7 mmol) of 1-bromo-3-iodine benzene, 0.279 g of copper powder, and 4.85 g of potassium carbonate; heat the mixture at 190° C. for nine hours in nitrogen atmosphere followed by cooling down to room temperature; next, dilute the mixture with methylene chloride followed by water-washing and drying to obtain pale brown liquid; furthermore, refine the resultant with silica gel column chromatography using a liquid mixture of methylene chloride and hexane as an eluting solution to obtain 3.59 g of 9-(3-bromophenyl)-3,6-diphenyl carbazole; add 3.20 g (6.75 mmol) of the thus obtained 9-(3-bromophenyl)-3,6-diphenyl carbazole, 1.54 g (10.1 mmol) of 3-methoxyphenyl boronic acid, and 0.124 g of tetrakis(triphenyl phosphine)palladium to a liquid mixture of 30 ml of toluene and 10 ml of ethanol; add an aqueous solution in which 37.3 g of sodium carbonate is dissolved in 90 ml of distilled water to the mixture; reflux the mixture for nine hours while heating in nitrogen atmosphere followed by cooling down to room temperature; next, dilute the mixture with methylene chloride; remove insoluble matters by filtration; wash the organic layer with water for separation; distill away the solvent under a reduced pressure; and furthermore, refine the resultant with silica gel column chromatography using a liquid mixture of methylene chloride and hexane as an eluting solution to obtain 2.89 g of [3′-(3,6-diphenylcarbazole-9-yl)biphenyl-3-yloxy]methane; and prepare 8-[3′-(3,6-diphenylcarbazole-9-yl)biphenyl-3-yloxy]octane-1-thiol (C-4) (hereinafter referred to as carbazole derivative 7) represented by the chemical structure 13 in the same manner as in preparation of Carbazole Derivative 1 except that the thus obtained [3′-(3,6-diphenylcarbazole-9-yl)biphenyl-3-yloxy]methane is used instead of 3,6-bis(5-methylthiophene-2-yl)-9-(4-methoxyphenyl)carbazole (B-2).
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:19]3[C:27](O)=[CH:26][C:22]4[O:23][CH2:24][O:25][C:21]=4[CH:20]=3)([CH2:17][OH:18])[C:9]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[C:1]1([CH:7]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:19]4=[CH:20][C:21]5[O:25][CH2:24][O:23][C:22]=5[CH:26]=[C:27]4[O:18][CH2:17]3)[C:9]2=[O:29])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3c(cc12)OCO3
Yield: 26 %

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using 1-(diphenylmethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained as a white powder in 26% yield: MS (ES+) m/z 462.3 (M+1).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][OH:10]>>[CH3:9][O:10][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: CO
Product: COCc1ccccc1
Reaction time: 1.5 h

Procedure:
A solution of 10.5 gm(0.03 mol) of diamine 15, 4.0 gm(0.03 mol) of benzyl chloride, and 15 gm of MeOH were charged to the flask and heated to reflux. After 1.5 hours, GC showed 5-10% benzyl present along with amine. The reaction was allowed to reflux overnight(ca. 15 hr). GC showed the benzyl chloride consumed and some amine still present. Benzyl methyl ether was formed as a by-product of the reaction. Excess amine and other residue was removed by vigorous washing of the crude product in ether. After rotary evaporation, 10 gm(70% crude yield) of Quat 5 was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC1C=CC(S(O[C@@H:20]2[CH2:24][CH2:23][O:22][CH2:21]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@H:20]2[CH2:24][CH2:23][O:22][CH2:21]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCOC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1ccc(O[C@H]2CCOC2)cc1
Temperature: 85 °C
Yield: 29.9 %

Procedure:
A mixture of 4-bromophenol (1.8 g, 10.5 mmole), (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (2.3 g, 9.5 mmole) and K2CO3 (4.0 g, 29 mmole) in DMF (15 mL) was heated at 85° C. for 15 h. The reaction mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by ISCO (silica gel, eluting with 5% ethyl acetate in hexane) to give the title compound (690 mg). MS (ESI) m/z: Found: 244.3 (M++1). Calc. 243.1 (M+).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH:10]([C:12]1[CH:13]=[N:14][NH:15][CH:16]=1)=[O:11].[H-].[Na+].O>CN(C=O)C>[CH:10]([C:12]1[CH:13]=[N:14][N:15]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH:16]=1)=[O:11]
Reactant: N#Cc1ccc(F)cc1
Reactant: O=Cc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2cc(C=O)cn2)cc1
Temperature: 60 °C

Procedure:
To a mixture of 4-fluorobenzonitrile (2.49 g, 20.6 mmol) and 4-formylpyrazole (1.98 g, 20.6 mmo) in 50 mL of DMF at 0° C. was added 95% sodium hydride (0.54 g, 22.7 mmol) under nitrogen. The mixture was heated to 60° C. for 6 hours and cooled to room temperature. Water was added carefully and the mixture was then extracted with ethyl acetate. The combined extracts were washed with water and brine, and then dried over sodium sulfate, filtered, and concentrated in vacuo to provide crude 4-(4-formyl-1H-pyrazol-1-yl)benzonitrile.
Reaction SMILES: [C:1]([C:3]([C:10]#[N:11])=[C:4]([CH3:9])[CH:5]=[CH:6]OC)#[N:2].S(=O)(=O)(O)[OH:13]>O>[C:1]([C:3]1[C:10](=[O:13])[NH:11][CH:6]=[CH:5][C:4]=1[CH3:9])#[N:2]
Reactant: COC=CC(C)=C(C#N)C#N
Reactant: O=S(=O)(O)O
Solvent: O
Product: Cc1cc[nH]c(=O)c1C#N
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 81.4 %

Procedure:
The mixture of 4,4-dicyano-3-methyl-3-butenal dimethyl acetatal (1) and 1,1-dicyano-4-methoxy-2-methyl-1,3-butadiene (2) produced by the preceding step was added to a stirred solution of concentrated sulfuric acid (109.8 g, 1.12 moles) at a rate so that the reaction contents did not exceed 30° C. The reaction mixture was then heated to 50° C. and held at that temperature for 1.5 hours. The reaction mixture was cooled to ambient temperature followed by the addition of water (150 mL). The product was filtered from the reaction mixture, washed with water (20 mL) and dried in a vacuum oven at 70° C. and full vacuum for 12 hours to give 40.7 g of 3-cyano-4-methyl-2-pyridone (3).
Reaction SMILES: [F:1][C:2]1([F:21])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](S(C)(=O)=O)[N:12]=3)[C:4]=2[O:3]1.[O:22]1CCOCC1>>[F:1][C:2]1([F:21])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][NH:14][C:13](=[O:22])[N:12]=3)[C:4]=2[O:3]1
Reactant: C1COCCO1
Reactant: CS(=O)(=O)c1nccc(-c2cccc3c2OC(F)(F)O3)n1
Product: O=c1nc(-c2cccc3c2OC(F)(F)O3)cc[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2-methanesulfonyl-pyrimidine (364 mg, 1.15 mmol) was dissolved in dioxane (8.5 ml) and then 2N NaOHaq (5.7 ml, 11 mmol) was added. After stirring at room temperature for 1 hour, the solution was acidified with 37% HClaq. The mixture was evaporated and the residue was purified by flash chromatography with DCM-MeOH (9-1) to give 232 mg of the title compound. (quantitative yield).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C@@H:17]([NH2:19])[CH3:18])=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:9]=2)[CH:4]=[CH:3]1.[Cl:20][C:21]1[C:22]([NH2:29])=[N:23][C:24]([NH2:28])=[N:25][C:26]=1Cl.CCN(CC)CC>CN(C=O)C>[Cl:20][C:21]1[C:26]([NH:19][C@H:17]([C:7]2[N:6]=[C:5]3[CH:4]=[CH:3][N:2]([CH3:1])[C:10]3=[CH:9][C:8]=2[N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH3:18])=[N:25][C:24]([NH2:28])=[N:23][C:22]=1[NH2:29]
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CCOCC1
Reactant: Nc1nc(N)c(Cl)c(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](Nc1nc(N)nc(N)c1Cl)c1nc2ccn(C)c2cc1N1CCOCC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 14.2 %

Procedure:
To a 10 mL vial were added (S)-1-(1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (100 mg, 0.384 mmol), 5,6-dichloropyrimidine-2,4-diamine (68.8 mg, 0.384 mmol) and Et3N (0.11 mL, 0.77 mmol) in DMF (3 mL). The resulting yellow solution was heated to 90° C. and stirred overnight. The reaction mixture was purified by preparative HPLC eluting with 20-40% ACN in water (with 0.05% ammonium formate). The fractions containing the desired product were combined and lyophilized to give the title compound as a white solid (22 mg, 14%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31-1.41 (m, 3 H), 2.70-2.82 (m, 2 H), 3.00-3.15 (m, 3 H), 3.69-3.93 (m, 10 H), 5.55-5.67 (m, 2H), 5.79-5.89 (m, 1 H), 5.89-5.96 (m, 2 H), 6.11-6.22 (m, 1 H), 6.47-6.57 (m, 1 H), 7.49-7.59 (m, 1 H), 7.75-7.84 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C18H23ClN8O, 403. found 403.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1.Br[CH2:30][C:31]([CH3:33])=[CH2:32]>C1COCC1>[CH3:30][CH:31]([CH3:33])[CH:32]=[C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:18][CH:17]=1)[C:20]([OH:22])=[O:21]
Reactant: C=C(C)CBr
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)C=C(C(=O)O)c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71.4 %

Procedure:
To a stirring solution of diisopropylamine (0.537 g, 5.31 mmol) in THF (5.2 mL) at 0° C. was added n-butyllithium (2.1 mL, 5.22 mmol, 2.5M in hexane) dropwise. After stirring for 15 min at 0° C., the mixture was cooled to −78° C. and a solution of 4-biphenylacetic acid (0.500 g, 2.36 mmol) in THF (2 mL) was added dropwise. After again warming to 0° C. and cooling to −78° C., 3-bromo-2-methylpropene (0.485 g, 3.54 mmol) was added to the mixture in one portion. After stirring at −78° C. for 1 h, the reaction was quenched with 2 mL of water then concentrated. The residue was redissolved in water and extracted with ether (100 mL). The aqueous layer was acidified (3N HCl) and extracted with ether (3×100 mL). The organic layers were combined, dried (MgSO4), filtered and concentrated to yield a white solid (0.449 g, 72%). MS(ESI): 265.3 (M+H)−.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH3:7][CH:8]([C:14]([CH3:16])=O)[C:9](OCC)=[O:10]>>[CH3:7][C:8]1[C:9](=[O:10])[N:6]2[CH:5]=[CH:4][S:3][C:2]2=[N:1][C:14]=1[CH3:16]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: Nc1nccs1
Product: Cc1nc2sccn2c(=O)c1C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-amino-thiazole (3.06 g) was reacted with ethyl 2-methylacetoacetate (6.4 g) in polyphosphoric acid (15.3 g: 7.1 g of P2O5 and 8.2 g of 99% H3PO4) under stirring at 100° C. for two hours. After cooling, dilution with ice water and neutralization, the precipitate was filtered, washed with water and crystallized from isopropyl ether to give 6,7-dimethyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 112°-113° C. (5.04 g), which was reacted with 3-pyridine-carboxaldehyde (5.99 g) in methanol (130 ml) in the presence of sodium methoxide (4.55 g) under stirring at reflux temperature for 12 hours. After cooling the precipitate was filtered and washed with water until neutral: crystallization from methanol gave 3.2 g of 6-methyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 192°-194° C., NMR (CDCl3) δ ppm: 2.36 (s) (3H, CH3), 6.97 (d) (H, C-2 proton), 7.38 (dd) (1H, C-5 pyridyl proton), 7.38 (d) (1H, β-ethenyl proton), 7.91 (d) (1H, α-ethenyl proton), 7.97 (d) (1H, C-3 proton), 8.00 (m) (1H, C-4 pyridyl proton), 8.62 (dd) (1H, C-6 pyridyl proton), 8.88 (d) (1H, C-2 pyridyl proton); JHα Hβ =16 Hz.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:48]([N+:52]1[N:56]=[C:55]([CH3:57])[S:54][C:53]=1[CH3:58])[CH2:49][CH2:50][CH3:51]>>[CH2:48]([N:52]1[N:56]=[C:55]([CH3:57])[S:54]/[C:53]/1=[CH:58]\[C:9]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:13][CH:12]=1)=[O:11])[CH2:49][CH2:50][CH3:51]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 4-tert-butylbenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.92 (t, 3 H) 1.30 (s, 9 H) 1.32-1.38 (m, 2 H) 1.71-1.78 (m, 2 H) 2.48 (s, 3 H) 4.21 (t, 2 H) 6.67 (s, 1 H) 7.47 (d, 2 H) 7.91 (d, 2 H); MS (ESI) m/z 331 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[C:4]([CH:23]2[CH2:28][CH2:27][CH:26]([CH2:29][C:30]([NH:32][NH2:33])=[O:31])[CH2:25][CH2:24]2)[CH:3]=1.[C:34](N1C=CN=C1)(N1C=CN=C1)=[O:35]>C1COCC1>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[C:4]([CH:23]2[CH2:24][CH2:25][CH:26]([CH2:29][C:30]3[O:31][C:34](=[O:35])[NH:33][N:32]=3)[CH2:27][CH2:28]2)[CH:3]=1
Reactant: NNC(=O)CC1CCC(c2cc(N)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Nc1cc(C2CCC(Cc3n[nH]c(=O)o3)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 20 mL scintillation vial was charged 2-(4-(7-amino-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetohydrazide (0.12 mmol), THF (5 mL), and 1,1′-carbonyldiimidazole (0.12 mmol, 25 mg). The resulting solution was stirred at room temperature for 2 hours. After 2 hours, the solvent was removed in vacuo and the residue taken up in 3:1 DMSO:MeCN. The solids are removed via centrifugation, and the title compound was purified via reverse-phase HPLC.