Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C@@H:15]2[C@@H:10]([CH2:11][CH2:12][CH2:13][NH:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl.C(N(CC)CC)C.C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:16][C@@H:15]2[C@@H:10]([CH2:11][CH2:12][CH2:13][N:14]2[C:17](=[O:19])[CH3:18])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2C[C@@H]3CCCN[C@@H]3C2)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCC[C@H]2CN(Cc3ccccc3)C[C@H]21
Yield: 85.5 %

Procedure:
The preparation comprises dissolving cis-8-benzyl-2,8-diazabicyclo[4,3,0]nonane (5.0 g, 23.1 mmol) in dichloromethane (50 mL) and triethylamine (5 mL) under stirring in ice bath, dropwise adding a solution of acetyl chloride (1.8 g, 23.1 mmol) in chloroform (10 mL), continuing with the stirring until the reaction finishes, distilling off the solvent, and chromatographing on silica gel with petroleum ether and ethyl acetate to give cis-8-benzyl-2-acetyl-2,8-diazabicyclo[4,3,0]nonane (5.1 g, 85.5%).
Reaction SMILES: [Br:1][C:2]1[C:16]2=[C:17]3[C:5]([NH:6][CH:7]=[C:8]3[CH2:9][C@@H:10]3[C@@H:15]2[CH2:14][C@H:13]([NH:18][C:19](=O)[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:12][N:11]3[CH3:26])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.C(OC([S-])=[S:36])C.[K+]>C(Cl)Cl>[Br:1][C:2]1[C:16]2=[C:17]3[C:5]([NH:6][CH:7]=[C:8]3[CH2:9][C@@H:10]3[C@@H:15]2[CH2:14][C@H:13]([NH:18][C:19](=[S:36])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:12][N:11]3[CH3:26])=[CH:4][CH:3]=1
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(Br)ccc4[nH]cc(c34)C[C@H]2N(C)C1
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)C(=S)N[C@H]1C[C@@H]2c3c(Br)ccc4[nH]cc(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
At -20° C., 6.29 g of 3-(12-bromo-6-methyl-8α-ergolinyl)-1,1-diethylurea (15 mmol) is dissolved in a mixture of 4.13 g of freshly distilled phosphorus oxychloride (45 mmol) and 50 ml of anhydrous methylene chloride, and the temperature is allowed to rise to +10° C. within 4 hours. The mixture is agitated overnight at room temperature, then for another 2 hours at 40° C., and subsequently the solvent is distilled off under vacuum. The residue is dissolved in 50 ml of anhydrous acetonitrile, cooled to -10° C., combined with 7.2 g of potassium ethylxanthate (45 mmol) and stirred for 20 hours at room temperature. The solvent is extensively distilled off, then the mixture is divided between ethyl acetate and saturated sodium carbonate solution, the organic phase is dried with sodium sulfate, and evaporated. The residue is crystallized from ethyl acetate, thus obtaining 5.03 g (77%) of 3-(12-bromo- 6-methyl-8α-ergolinyl)-1,1-diethylthiourea.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:12][NH:13][CH3:14].CO>>[CH3:12][N:13]([CH3:14])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: CNC
Reactant: COC(=O)c1ccc(Cl)nc1
Solvent: CO
Product: COC(=O)c1ccc(N(C)C)nc1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
A solution of methyl 6-chloronicotinate (4.0 g, 23 mmol) in dimethylamine/MeOH (2 M, 80 mL, 160 mmol) in a pressure vessel was stirred at 95° C. for 2 h, cooled to rt and concentrated. The residue was dissolved in EtOAc (250 mL), washed with water (2×150 mL), dried over Na2SO4, and concentrated to afford the title compound as a tan solid (4.1 g, 98%). MS (ESI), (M+H)+181.24; 1H NMR (CDCl3) δ8.79 (s, 1H), 7.99 (d, 1H, J =9.2), 6.45 (d, 1H, J=9.2), 3.85 (s, 3H), 3.15 (s, 6H).
Reaction SMILES: CC1C=CC(C2C=CC=CN=2)=C(C=1)C(OC)=O.Br[C:19]1[C:20]([C:26]([N:28]2[CH2:33][CH2:32][CH2:31][C@@H:30]([CH3:34])[C@H:29]2[CH2:35][N:36]2[C:44](=[O:45])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]2=[O:46])=[O:27])=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=1.C([Sn](CCCC)(CCCC)[C:52]1[N:57]=[CH:56][CH:55]=[CH:54][N:53]=1)CCC>>[CH3:34][C@@H:30]1[CH2:31][CH2:32][CH2:33][N:28]([C:26](=[O:27])[C:20]2[C:19]([C:52]3[N:57]=[CH:56][CH:55]=[CH:54][N:53]=3)=[CH:24][CH:23]=[C:22]([CH3:25])[N:21]=2)[C@@H:29]1[CH2:35][N:36]1[C:44](=[O:45])[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]1=[O:46]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: Cc1ccc(Br)c(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)n1
Agent: COC(=O)c1cc(C)ccc1-c1ccccn1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)n1

Procedure:
The title compound was prepared following the same general protocol as described for methyl 5-methyl-2-(pyridin-2-yl)benzoate in Example A9, using 2-(((2S,3R)-1-(3-bromo-6-methylpicolinoyl)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione and 2-(tributylstannyl)pyrimidine. ESI-MS (m/z): 456, [M+1]+.
Reaction SMILES: BrCCBr.I[CH2:6][CH2:7][C@H:8]([NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:53]1[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][N:54]=1>CN(C)C=O.C(OCC)(=O)C.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C[Si](Cl)(C)C>[N+:59]([C:56]1[CH:57]=[CH:58][C:53]([CH2:6][CH2:7][C@H:8]([NH:19][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[N:54][CH:55]=1)([O-:61])=[O:60]
Reactant: O=C(N[C@@H](CCI)C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: BrCCBr
Product: O=C(N[C@@H](CCc1ccc([N+](=O)[O-])cn1)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 74.5 %

Procedure:
A suspension of 6 g (92 mmol) of zinc powder and 0.4 ml (4.7 mmol) of 1,2-dibromoethane in 7 ml of anhydrous N,N-dimethylformamide is heated at 60° C. with stirring and under argon for 45 min. 0.126 ml (1 mmol) of trimethylsilyl chloride is then added and the mixture is stirred vigorously at room temperature for 30 min. A solution of 7 g (15.4 mmol) of phenylmethyl (S)-4-iodo-2-[[(phenylmethoxy)carbonyl]amino]butanoate in 1 ml of anhydrous N,N-dimethylformamide is then added. After 30 min at room temperature, 0.28 g (0.31 mmol) of tris(dibenzylideneacetone)dipalladium (0), 0.38 g (1.24 mmol) of tri-ortho-tolylphosphine, 3.78 g (18.5 mmol) of 2-bromo-5-nitropyridine and 1 ml of anhydrous N,N-dimethylformamide are added at room temperature and the mixture is stirred for 3 h at room temperature. The reaction medium is taken up in 200 ml of ethyl acetate and 5 g of active charcoal and then filtered through a cake of Celite. The cake is rinsed with 2×100 ml of ethyl acetate and the organic phases are combined, washed with 5×100 ml of water, dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by filtration on a column of silica gel, eluting with a cyclohexane/ethyl acetate gradient of from 0 to 20% ethyl acetate. 5.16 g of phenylmethyl (S)-5-nitro-α-[[(phenylmethoxy)carbonyl]amino]-2-pyridinebutanoate are thus obtained in the form of a yellow foam.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[N:10]=[C:9]([CH3:19])[C:8]=2[CH:20]=O)=[C:5]([CH3:22])[O:4][N:3]=1.Cl.[NH2:24][OH:25].N1C=CC=CC=1.Cl>C(O)C.C(Cl)Cl>[CH3:1][C:2]1[C:6]([C:7]2[N:11]([C:12]3[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=3)[N:10]=[C:9]([CH3:19])[C:8]=2[CH:20]=[N:24][OH:25])=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: NO
Reactant: Cc1nn(-c2ccc(O)cc2)c(-c2c(C)noc2C)c1C=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: ClCCl
Product: Cc1nn(-c2ccc(O)cc2)c(-c2c(C)noc2C)c1C=NO
Temperature: 150 °C
Yield: 50 %

Procedure:
The semi-crude 5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbaldehyde was mixed with hydroxylamine hydrochloride (100 mg, 0.014 mmol) and pyridine (0.15 mL) in dry ethanol (1.5 mL) and heated at 150° C. for 10 min in the microwave. 1 M HCl and CH2Cl2 were added and the phases were separated. The oxime was purified on preparative HPLC to give E3 5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbaldehyde oxime (37 mg, 50%). Identification of the title compound by 1H-NMR showed that the product was an approximately 1:1 mixture of the (E) and (Z) oxime isomers. ES/MS m/z: 313.17 (M+H), 311.19 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.83 s 1H, 7.13 m 2H, 6.87 m 2H; 2.41 s 3H, 1.88 s 3H.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[N:16]3[CH2:17][C@@H:18]([CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([CH:28]5[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]5)=[CH:24][CH:23]=4)[O:19][C:15]3=[N:14][C:13](=[O:34])[CH:12]=2)(=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B1([O-])OO1.O.O.O.O.[Na+].[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>CC(O)=O>[CH:28]1([C:25]2[CH:26]=[CH:27][C:22]([O:21][CH2:20][C@H:18]3[O:19][C:15]4=[N:14][C:13](=[O:34])[CH:12]=[C:11]([CH2:10][S:7][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:16]4[CH2:17]3)=[CH:23][CH:24]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=c1cc(CS(=O)(=O)c2ccccc2)n2c(n1)O[C@H](COc1ccc(C3CCCCC3)cc1)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Solvent: O
Product: O=c1cc(CSc2ccccc2)n2c(n1)O[C@H](COc1ccc(C3CCCCC3)cc1)C2
Temperature: 25 °C
Reaction time: 9 h
Yield: 85.4 %

Procedure:
To a solution of (S)-5-benzenesulfonylmethyl-2-(4-cyclohexyl-phenoxymethyl) -2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one (0.5 g, 1.11 mmol), prepared in accordance with the procedures described in Step 1 and 2 of Example 120, in HOAc (20 mL) was added sodium perborate tetrahydrate (0.446 g, 2.90 mmol). The reaction mixture was stirred at room temperature for 9 hours. The reaction mixture was neutralized with NaOH (2N) to pH˜7 and further to pH˜10 with Na2CO3. The mixture was extracted with EtOAc three times. The organic phase was washed with brine and dried (Na2SO4). Silica gel chromatography (2-8% methanol/CH2Cl2) provided 0.425 g of (S)-2-(4-cyclohexyl-phenoxymethyl)-5-phenylsulfanylmethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one. [α]D25 −3.80 (c 0.5, CHCl3).
Reaction SMILES: O1CCOCC1.[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1.COCCN1CCNCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C>[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(Br)cc1
Agent: COCCN1CCNCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To 10 ml of 1,4-dioxan is added 0.645 g (3.0 mmol) of methyl-4-bromobenzoate 0.519 g (3.6 mmol) of 1-(2-methoxy-ethyl-piperazine, 0.892 g (8.47 mmol) of potassium phosphate, 0.177 g (0.45 mmol) of 2-dicycohexylphosphino-2′-(N,N-dimethylamino)biphenyl and 0.137 g (0.15 mmol) tris-(benzylideneacetone)palladium (0). The resulting reaction mixture is stirred under argon for 5 hours at 100° C., then cooled to room temperature, diluted with ethyl acetate and filtered. The filtrate is washed once with H2O and once with brine, the organic layer separated and dried over Na2SO4. Purification of the crude product by flash chromatography (dichloromethane/methanol) yields 0.52 g of 4-[4-(2-methoxy-ethyl)-piperazin-1-yl)]benzoic acid methyl ester as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>ClCCl>[CH2:19]([O:18][C:16]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
20 g of 4-aminophenol (Mw=109.13; 0.18324 mol) are suspended in 200 cm3 of anhydrous dichloromethane, under an inert atmosphere. The suspension is cooled to a temperature of 0° C. in a bath of ice and 16.4 cm3 of anhydrous pyridine (Mw=79.10; d=0.981; 0.2034 mol) are then added. 17.6 cm3 of ethyl chloroformate (Mw=108.53; d=1.13; 0.18324 mol) are then added dropwise so as to keep the mixture at a temperature below 10° C. The reaction mixture is kept stirring for two hours. The mixture is poured onto one liter of ice-cold water and then extracted with ethyl acetate. The organic phase is washed with water and then dried, filtered and evaporated under vacuum. After recrystallization from a heptane/ethyl acetate mixture, 21 g of a white powder are obtained, which corresponds to a yield of 63%. The melting point of the product obtained is 127.2° C. The H NMR spectrum and the elemental analysis are in accordance with the expected product.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]([NH2:9])=[O:8])=[O:5])#[N:2].[CH3:10][C:11]([CH3:13])=O.C(O)(=O)C.C([O-])(=O)C.[NH4+]>C(O)(C)C.[C].[Pd]>[C:1]([CH:3]([CH:11]([CH3:13])[CH3:10])[C:4]([NH:6][C:7]([NH2:9])=[O:8])=[O:5])#[N:2]
Reactant: N#CCC(=O)NC(N)=O
Reactant: CC(C)=O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(C)C(C#N)C(=O)NC(N)=O
Temperature: 80 °C

Procedure:
Cyanoacetylurea (38.7 g) was suspended in isopropanol (77.4 ml), and acetone (24.6 ml), acetic acid (3.43 ml) and ammonium acetate (2.31 g) were added. This suspension was subjected to catalytic hydrogenation in the presence of 10% palladium carbon (0.78 g, 50% wet product) under normal pressure at 30° C. for 8 hours. The reaction mixture was heated to 80° C. for 1 hour, and the catalyst was filtered off. Water (150 ml) was added to the filtrate to allow precipitation of crystals. The crystals were collected by filtration to give crystals of N-(2-cyano-3-methylbutanoyl)urea (yield 21.7 g).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CC(N(C)C)=O>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:9][CH:10]=3)[C:22]=12
Reactant: Nc1ncnc2[nH]nc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCCC1
Reaction time: 8 h

Procedure:
4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound 15) (0.91 g) in 50 mL dry dimethylacetamide was stirred under nitrogen at 25° C. while adding 60% sodium hydride (0.20 g). After stirring for 30 minutes bromocyclopentane (0.8 mL) was added and the mixture stirred overnight. After evaporation in vacuo the residue was treated with water and extracted into ethyl acetate. Flash chromatography (3:2 cyclohexane:ethyl acetate) eluted 0.36 g of 1-Cyclopentyl-4-(cyclopentylamino)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine as colourless oil. 1H n.m.r. (DMSO) 8.319(s, 1H), 7.65-7.69(m, 2H), 7.40-7.48(m, 2H), 7.09-7.23(m, 5H), 5.926/5.955(d, 1H), 5.17-5.29(quin, 1H), 4.44-4.52(m, 1H), 1.86-2.12(m, 8H), 1.39-1.72(m, 8H).
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[C:12]([C:19]([OH:21])=O)[CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1.[S:23]1[CH:27]=[CH:26][N:25]=[C:24]1[NH2:28].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.C([O-])(O)=O.[Na+]>CN(C=O)C>[F:1][CH:2]([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[C:12]([C:19]([NH:28][C:24]4[S:23][CH:27]=[CH:26][N:25]=4)=[O:21])[CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1cccc2ccc(-c3cccc(C(F)F)c3)nc12
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nccs1)c1cccc2ccc(-c3cccc(C(F)F)c3)nc12
Temperature: 40 °C
Reaction time: 12 h
Yield: 39 %

Procedure:
A mixture of 2-(3-(difluoromethyl)phenyl)quinoline-8-carboxylic acid (250 mg, 0.84 mmol), thiazol-2-amine (84 mg, 1.2 mmol), HATU (0.64 g, 1.68 mmol) and DIPEA (0.22 g, 1.68 mmol) in DMF (25 mL) was stirred at 40° C. for 12 hours. A saturated solution of NaHCO3 (5 mL) was added and the mixture was filtered, the residue was washed with methanol (2×5 mL) and solid was dried in vacuo to give 2-(3-(difluoromethyl)phenyl)-N-(thiazol-2-yl)quinoline-8-carboxamide as a solid. (125 mg, 39% yield) MS (ESI) calcd for C20H13F2N3OS (m/z): 381.07. found: 382 [M+1].
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@H:13]2[C@@H:9]([O:10][C:11]([CH3:15])([CH3:14])[O:12]2)[C@H:8]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3Cl)[O:7]1)(=[O:3])[CH3:2].[Cl-].[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][Zn+])=[CH:30][CH:29]=1.[NH4+].[Cl-].C(N(CC([O-])=O)CC(O)=O)CN(CC([O-])=O)CC(O)=O.[Na+].[Na+]>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:13]2[C@@H:9]([O:10][C:11]([CH3:15])([CH3:14])[O:12]2)[C@H:8]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3[CH2:32][C:31]2[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=2)[O:7]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc(C[Zn+])cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cc4ccc(F)cc4)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
[(3aR,4R,6R,6aR)-6-(6-Chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl acetate (369 mg, 0.00100 mol) and tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.000050 mol) were dissolved in tetrahydrofuran (10 mL) at room temperature under nitrogen. 0.5 M of 4-fluorobenzylzinc chloride in tetrahydrofuran (3 mL) was added dropwise over 10 min. The solution was stirred under nitrogen at room temperature for 15 min then heated at 60° C. for 3 h. The reaction was allowed to cool to r.t then poured on saturated NH4Cl (10 mL). Saturated Na2EDTA (10 mL) was added and the solution extracted three times with EtOAc. The organics were pooled and extracted twice with saturated Na2EDTA then once with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (DCM/EtOAc 10% to 50%) to obtain the product (322 mg, 73%) as an oil.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=1)=[O:2].[Cl:16]N1C(=O)CCC1=O.O>CN(C=O)C>[CH:1]([NH:3][C:4]1[S:5][C:6]([Cl:16])=[C:7]([C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=1)=[O:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C(=O)c1csc(NC=O)n1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1nc(NC=O)sc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 2-(Formylaminothiazol-4-yl)-2-oxoacetate (9.1 g, 39.87 mmol) (obtained from Aldrich, Milwaukee, Wis.) was slurried in 50 mL of anhydrous DMF. N-Chlorosuccinimide (5.6 g, 41.86 mmol) was added as a solid and the suspension was stirred at room temperature. After 18 hours, the reaction mixture was poured into 500 mL of water. The resulting white precipitate was filtered, washed with water and air dried to afford the title intermediate as a white solid.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:19][C:18](=O)[C:17]2[C:12](=[CH:13][C:14]([C:21]([F:24])([F:23])[F:22])=[CH:15][CH:16]=2)[N:11]=1)[CH3:2].P(Cl)(Cl)([Cl:27])=O.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:27][C:18]1[C:17]2[C:12](=[CH:13][C:14]([C:21]([F:24])([F:23])[F:22])=[CH:15][CH:16]=2)[N:11]=[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][CH2:1][CH3:2])[N:19]=1
Reactant: CCSc1ccccc1-c1nc2cc(C(F)(F)F)ccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCSc1ccccc1-c1nc(Cl)c2ccc(C(F)(F)F)cc2n1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 1.29 g of 2-(2-ethylsulfanylphenyl)-7-trifluoromethyl-3H-quinazolin-4-one, 0.38 ml of phosphorus oxychloride, 523 mg of N,N-diisopropylethylamine and 20 ml of toluene was stirred at 90° C. for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure to obtain 1.23 g of 4-chloro-2-(2-ethylsulfanylphenyl)-7-trifluoromethylquinazoline (Compound of Present Invention 4).
Reaction SMILES: O[C:2]([CH:16]([CH3:18])[CH3:17])([CH:6]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:7]([OH:9])=[O:8])[C:3](O)=[O:4].CCCCCC.C(OCC)(=O)C>C(OC(=O)C)(=O)C>[CH:16]([C:2]1=[C:6]([CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:7]([O:9][C:3]1=[O:4])=[O:8])([CH3:18])[CH3:17]
Reactant: CC(C)C(O)(C(=O)O)C(C(=O)O)C1CCOCC1
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)C1=C(C2CCOCC2)C(=O)OC1=O
Reaction time: 10 h
Yield: 62.8 %

Procedure:
2-Hydroxy-2-isopropyl-3-(tetrahydropyran-4-yl)succinic acid (70 mg, 0.27 mmol) was dissolved in acetic anhydride (1 mL), and the solution was left standing at 120° C. for 10 h. The acetic anhydride was evaporated under reduced pressure and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 3:1) to give 38 mg of the title compound as a solid (yield: 67%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH:25]([NH2:27])[CH3:26])=[N:23][CH:24]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:17][C:5]1[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)=[N:7][C:2]([NH:27][CH:25]([C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:24][N:23]=2)[CH3:26])=[N:3][CH:4]=1
Reactant: CC(N)c1ccc(F)cn1
Reactant: Clc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cn1
Temperature: 185 °C
Yield: 36.2 %

Procedure:
A mixture of 2,5-dichloro-4-(5-cyclopropyl-1H-pyrazole-3-ylamino)pyrimidine (Method 7; 0.14 g, 0.518 mmol), 1-(5-fluoropyridin-2-yl)ethanamine (Method 4; 0.091 g, 0.648 mmol), and DIEA (0.11 ml, 0.648 mmol) in n-BuOH (2 ml) was heated in a sealed tube at 185° C. for 18 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane-EtOAc=1:2) to give the title compound as a white solid (0.070 g, 36%). 1H NMR (400 MHz) 12.51 and 12.09 (s, 1H), 9.65 (s, 1H), 8.48 (s, 1H), 8.38 (s, 1H), 8.02 and 7.93 (b, 1H), 7.64 (m, 1H), 7.41 (m, 1H), 5.93 and 5.80 (b, 1H), 5.06 (m, 1H), 1.83 (m, 1H), 1.45 (d, J=6.8 Hz, 3H), 0.95 (m, 1H), 0.84 (m, 1H), 0.74 (m, 1H), 0.63 (m, 1H). MS: Calcd.: 373. Found: [M+H]+374.