Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])=[CH:4][CH:3]=1.[C:16]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:19]([O:18][C:16]([N:23]1[CH2:28][CH2:27][CH:26]([NH:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:25][CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: Nc1ccccc1Oc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2Oc2ccc(Cl)cc2)CC1
Temperature: 85 °C
Yield: 67.9 %

Procedure:
To a solution of 2-(4-chlorophenoxy)phenylamine (900 mg, 4.10 mmol), 1-BOC-4-piperidone (1.76 g, 8.82 mmol) and acetic acid (1.32 g, 22.05 mmol) in DCE (15 ml) was added sodium triacetoxyborohydride (2.34 g, 11.04 mmol). This solution was then split into 4 microwave tubes, which were individually heated at 85° C. for 15 minutes in a CEM discover microwave (fixed hold time set to on). The contents of each tube were added to a saturated aqueous sodium bicarbonate solution (25 ml) with extraction with ethyl acetate (3×25 ml) following. The combined organics were dried (MgSO4), filtered and concentrated in vacuo and purification by flash chromatography proceeded (eluant: 3:1 to 1:1 hexane:DCM) to provide a white solid. Recrystallisation was then carried out, which afforded the title compound as a white crystalline solid (1.122 g, 68%). M.Pt. 112-113.4° C. 1H NMR (300 MHz, CDCl3): δ 1.165-1.308 (2H, m, 2×CH), 1.380 (9H, s, t-Bu), 1.909-1.974 (2H, m, 2×CH), 2.822-2.897 (2H, ‘t’, J=11.3 Hz, CH2), 3.385-3.45 (1H, m, CH), 3.85-4.02 (3H, m, 2×CH, NH), 6.542-6.597 (1H, td, ArH), 6.674-6.842 (4H, m, ArH), 6.946-7.002 (1H, td, ArH), 7.157-7.209 ppm (2H, m, ArH). 13C NMR (67.93 MHz, CDCl3): δ 28.5, 32.3, 43.0, 49.8, 79.7, 112.2, 117.0, 118.7, 119.6, 125.3, 127.8, 129.7, 139.0, 143.0, 154.8, 156.2 ppm. LCMS: M+H, 403.46 HPLC: 99.53% (4.9411 min, isocratic, 90% acetonitrile: 10% water, 1 ml/min). CHN: Expected, N=6.95%, C=65.58%, H=6.75% Observed, N=6.82%, C=65.5%, H=6.71%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:11])[C:9]=1[NH2:10])[C:5]#[N:6].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:22](Cl)(=[O:24])[CH3:23].Cl>C1COCC1.O.C(Cl)Cl>[C:22]([NH:10][C:9]1[C:2]([Cl:1])=[CH:3][C:4]([C:5]#[N:6])=[CH:7][C:8]=1[Cl:11])(=[O:24])[CH3:23]
Reactant: N#Cc1cc(Cl)c(N)c(Cl)c1
Reactant: CC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)Nc1c(Cl)cc(C#N)cc1Cl
Reaction time: 8 h

Procedure:
Step B (1): To a solution of 3,5-dichloro-4-amino-benzonitrile (187 mg, 1 mmol) in 4 mL of THF at room temperature was added 2.2 mL of 1.0 M NaHMDS in THF. The resulting reaction mixture was stirred at room temperature for 30 min, at which time acetyl chloride (3.1 mmol) was added. DCM (100 mL) and water (100 mL) were added to the reaction mixture after being stirred overnight, followed by the addition of 5 mL of a 1.4 N HCl aqueous solution. The layers were separated and the aqueous layer was extracted with DCM (2×100 mL). The extracts were combined and solvents were evaporated in vacuo. The residue was purified by HPLC to give 4-acetamido-3,5-dichloro-benzonitrile. MS (ESI) (M−H)+=227.05. 1H NMR (300 MHz, CDCl3) δ 7.63 (s, 2 H), 2.21 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:17])[C:3]=1[C:18]1[N:19]=[C:20]([NH2:23])[S:21][CH:22]=1.Cl.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:17])[C:3]=1[C:18]1[N:19]=[C:20]([NH:23][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[S:21][CH:22]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: COc1ccc(Oc2cc(C)c(-c3csc(N)n3)c(F)c2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(Oc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
To a solution of 4-(2-fluoro-4-(4-methoxyphenoxy)-6-methylphenyl)thiazol-2-ylamine (30-7, 0.10 g, 0.30 mmol) in CH2Cl2 (10 mL) was added DMAP (73 mg, 0.60 mmol) followed by isonicotinoyl chloride hydrochloride (69 mg, 0.39 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with water. The resultant precipitate was collected and recrystallized in toluene to give N-{4-(2-dluoro-4-(4-methoxyphenoxy)-6-methylphenyl)thiazol-2-yl}isonicotinamide (30, 42 mg, 0.10 mmol) as white solids in 32% yield: 1H NMR (500 MHz, CDCl3) δ 8.86 (d, J=5.8 Hz, 2 H), 8.04 (d, J=5.6 Hz, 2H), 6.99 (d, J=7.2 Hz, 3 H), 6.92 (d, J=9.0 Hz, 2 H), 6.61 (s, 1 H), 6.50 (m, 1 H), 3.82 (s, 3 H), 2.26 (s, 3 H). ESI-MS: m/z 436.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:39](Cl)([O:41][C:42](=[O:48])OC(Cl)(Cl)Cl)Cl.[F:50][C:51]([F:61])([F:60])[C:52]1[CH:59]=[CH:58][C:55](CO)=[CH:54][CH:53]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:42](=[O:48])[O:41][CH2:39][C:55]1[CH:58]=[CH:59][C:52]([C:51]([F:61])([F:60])[F:50])=[CH:53][CH:54]=1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCc4ccc(C(F)(F)F)cc4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Yield: 43.7 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (74 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (99 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 4-trifluoromethylbenzyl alcohol (60 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (52 mg, yield 41%).
Reaction SMILES: [C:1]([C:4]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:5]=1[CH:6]=[C:7]1[S:11]C(=S)N[C:8]1=[O:13])([OH:3])=O.CC[OH:24]>>[CH3:21][O:20][C:15]1[CH:14]=[C:5]2[C:4](=[CH:17][C:16]=1[O:18][CH3:19])[C:1](=[O:3])[S:11][C:7]([C:8]([OH:24])=[O:13])=[CH:6]2
Reactant: COc1cc(C=C2SC(=S)NC2=O)c(C(=O)O)cc1OC
Reactant: CCO
Product: COc1cc2cc(C(=O)O)sc(=O)c2cc1OC

Procedure:
6,7-Dimethoxy-2-thiaisocoumarin-3-carboxylic acid, mp. (EtOH) 300°-2°, (lit. mp. 306°-7°), (Found: C, 54.03; H, 3.80; S, 11.83, C12H10SO5 requires C, 54.13; H, 3.79; S, 12.04) was prepared from 5-(2'-carboxy-4',5'-dimethoxybenzylidene) rhodanine by an analogous procedure to that described in Example 12.
Reaction SMILES: [K+].[C:2]([O:8][CH3:9])(=[O:7])[CH2:3][C:4]([O-:6])=O.C[Si](Cl)(C)C.N1(C2CCCCCCCCCC2)CCCCCCCC[CH2:17]N1.[I:37][C:38]1[CH:39]=[C:40]([CH:44]=[C:45]([O:49][CH3:50])[C:46]=1[O:47][CH3:48])C(Cl)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(#N)C>[I:37][C:38]1[CH:39]=[C:40]([C:4](=[O:6])[CH2:3][C:2]([O:8][CH2:9][CH3:17])=[O:7])[CH:44]=[C:45]([O:49][CH3:50])[C:46]=1[O:47][CH3:48]
Reactant: COC(=O)CC(=O)[O-]
Reactant: COc1cc(C(=O)Cl)cc(I)c1OC
Reactant: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Agent: C[Si](C)(C)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1cc(I)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
272 mg of monomethyl malonate potassium salt and 0.41 ml of trimethylsilyl chloride are stirred at room temperature in 5 ml of acetonitrile for 4 hrs. Subsequently, the mixture is cooled to 0° and 0.75 ml of diaza-bicycloundecane is added. The mixture is stirred at room temperature for 30 min. Thereafter, 0.5 g of 3-iodo-4,5-dimethoxy-benzoyl chloride is added portionwise thereto and the mixture is stirred at room temperature for 19 hrs. The mixture is brought to about pH4 with 10 percent citric acid and extracted three times with ethyl acetate. Chromatography on silica gel with ethyl acetate/hexane 1:1 gives 126 mg of ethyl 3-(3-iodo-4,5-dimethoxy-phenyl)-3-oxo-propionate as a yellowish oil (Keto/Enol mixture). Yield: 26%. Mass spectrum: peaks inter alia at m/e: 378 (M+, 40%); 291 (100%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH2:12])[CH:3]=1.B(O)(O)[C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1>>[CH3:11][C:9]1[CH:10]=[C:6]2[N:5]=[C:4]([NH2:12])[CH:3]=[C:2]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[N:7]2[N:8]=1
Reactant: Cc1cc2nc(N)cc(Cl)n2n1
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2cc(N)nc3cc(C)nn23)cc1

Procedure:
The titled compound was prepared using a procedure analogous to that described in connection with Example 15 except that 7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-amine (1J) and p-tolylboronic acid were used as starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[N:5][CH:4]=1.[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(O)(=O)C.C(Cl)(Cl)Cl>[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][N:39]([CH2:14][CH2:13][N:10]4[C:11]5[C:6](=[N:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=5)[CH:7]=[CH:8][C:9]4=[O:16])[CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cnc2ccc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To 0.11 g of (7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde, 0.15 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamate in 4 mL of dichloromethane, 24 μL of acetic acid and 0.13 g of sodium triacetoxyborohydride were added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, chloroform and a saturated aqueous sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash basic silica gel column chromatography using gradient elution with hexane:ethyl acetate=100:0 to 20:80, and then gradient eluent of chloroform:methanol=100:0 to 90:10 to obtain 0.18 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a light yellow foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1/[CH:10]=[CH:11]/[C:12]([O:14]C)=O>C(#N)C>[CH3:9][O:8][C:6]1[CH:7]=[C:2]2[C:3]([CH:10]=[CH:11][C:12](=[O:14])[NH:1]2)=[CH:4][CH:5]=1
Reactant: COC(=O)/C=C/c1ccc(OC)cc1N
Solvent: CC#N
Product: COc1ccc2ccc(=O)[nH]c2c1
Yield: 84.9 %

Procedure:
A solution of methyl (2E)-3-(2-amino-4-methoxyphenyl)acrylate (Intermediate 4, 500 mg, 2.4 mmol) in acetonitrile (600 mL) was deoxygenated under vacuum, purged with nitrogen and irradiated at 365 nm with a long wave UV lamp (B-100AP, Blak Ray) for 28 hours. The solvent was removed under reduced pressure and the product was precipitated from dichloromethane (20 mL) by the addition of hexanes (100 mL) to give 357 mg (76% yield) of the crude product as a colorless solid, 90% pure by 1H-1-NMR (together with 10% dimer), mp 190° C.
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].C(OC)(=O)C.[NH2:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([CH2:20][C:21]#[N:22])=[O:19])=[CH:16][CH:15]=1.Cl>CO.N1C=CC=CC=1>[CH2:1]([S:4]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([CH2:20][C:21]#[N:22])=[O:19])=[CH:23][CH:24]=1)(=[O:6])=[O:5])[CH2:2][CH3:3]
Reactant: N#CCC(=O)c1ccc(N)cc1
Reactant: CCCS(=O)(=O)Cl
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: COC(C)=O
Product: CCCS(=O)(=O)Nc1ccc(C(=O)CC#N)cc1
Temperature: 0 °C

Procedure:
Dry pyridine (13 ml) was added dropwise to a stirred mixture of 14.3 g (0.1 mole) 1-propanesulfonyl chloride, 15 ml dry methyl acetate and 16.0 g (0.1 mole) 4-aminobenzoylacetonitrile at room temperature. An ice bath was then used to control the exothermic reaction and the mixture was stirred in the ice bath for two hours. Methanol (50 ml) was added and the resulting solution poured into 2 N hydrochloric acid (240 ml) with stirring. The solid was collected, washed with water and dried. Yield 20.7 g (78%). Recrystallization yielded product melting at 150°-151° C.
Reaction SMILES: CC1(C=CCC)C(C)=CC=C(S([O-])(=O)=O)C1.[CH3:17][C:18](=[CH2:22])[CH2:19][CH2:20][OH:21].[Na].[Cl:24][C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1O>CN(C)C=O>[Cl:24][C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[O:21][CH2:20][CH2:19][C:18]([CH3:17])=[CH2:22]
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: C=C(C)CCO
Agent: CCC=CC1(C)CC(S(=O)(=O)[O-])=CC=C1C
Agent: [Na]
Solvent: CN(C)C=O
Product: C=C(C)CCOc1ccc([N+](=O)[O-])cc1Cl
Temperature: 0 °C

Procedure:
3-Methyl-3-butenyltosylate derived from 12.9 g of 3-methyl-3-buten-1-ol by a conventional procedure was reacted with 31 g of sodium salt of 2-chloro-4-nitrophenol in 250 ml of dimethylformamide. The resultant mixture was stirred at 90°-100° C. for 2.5 hours and then poured into ice-water, followed by extraction with benzene. The solvent was removed under reduced pressure, and the precipitated crystals were subjected to filtration by a glass filter and washed with ether to give 29.3 g of 3-chloro-4-(3-methyl-3-butenyloxy)nitrobenzene. M.P. 38°-39° C.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH:15]([CH2:18][CH3:19])[CH2:16][CH3:17].CCN(CC)CC.[CH2:27]([O:29][C:30]1[C:31]([C:58]([OH:60])=O)=[N:32][C:33]([C:42]2[CH:47]=[CH:46][C:45]([NH:48][C:49]([NH:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[O:50])=[CH:44][CH:43]=2)=[N:34][C:35]=1[N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[CH3:28]>CN(C=O)C>[CH2:16]([N:15]([CH2:18][CH3:19])[C:58]([C:31]1[C:30]([O:29][CH2:27][CH3:28])=[C:35]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[N:34]=[C:33]([C:42]2[CH:47]=[CH:46][C:45]([NH:48][C:49]([NH:51][C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)=[O:50])=[CH:44][CH:43]=2)[N:32]=1)=[O:60])[CH3:17]
Reactant: CCOc1c(C(=O)O)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)nc1N1CCOCC1
Reactant: CCNCC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1c(C(=O)N(CC)CC)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)nc1N1CCOCC1
Yield: 48 %

Procedure:
EDC (50 mg, 1.5 eq.), HOBT (40 mg, 1.5 eq.), Et2NH (0.0275 ml, 1.5 eq.) and Et3N (0.05 ml, 2.0 eq.) were added to a stirred solution of 5-ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylic acid (80 mg, 1 eq.) in dry DMF (2 ml) and the mixture reacted overnight at r.t. The mixture was quenched with H2O, extracted with EA, and washed with brine. The crude was purified by chromatography to give a product (43 mg, 48%).
Reaction SMILES: [CH2:1]([Si:3]([C:8]#[C:9][C@:10]1([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:18][CH:13](OC(=O)C)[C@H:12]([O:19][C:20](=[O:22])[CH3:21])[C@@H:11]1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].N[C:41]1[NH:49][C:48]2[C:43](=[N:44][C:45]([NH2:50])=[N:46][CH:47]=2)[N:42]=1.C/C(/O[Si](C)(C)C)=[N:53]\[Si](C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(=O)([O-])O.[Na+]>ClCCCl>[C:20]([O:19][C@@H:12]1[C@H:11]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:10]([C:9]#[C:8][Si:3]([CH2:4][CH3:5])([CH2:6][CH3:7])[CH2:1][CH3:2])([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:18][C@H:13]1[N:42]1[CH:41]=[N:49][C:48]2[C:43]1=[N:44][C:45]([NH2:50])=[N:46][C:47]=2[NH2:53])(=[O:22])[CH3:21]
Reactant: Nc1ncc2[nH]c(N)nc2n1
Reactant: CC[Si](C#C[C@]1(COCc2ccccc2)OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1)(CC)CC
Reactant: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC[Si](C#C[C@]1(COCc2ccccc2)O[C@@H](n2cnc3c(N)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1)(CC)CC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of Compound 6 (1.1 g, 2 mmol) in 1,2-dichloroethane (16.5 ml), diaminopurine (0.45 g, 3 mmol) and N,O-bis(trimethylsilyl)acetamide (4.4 ml, 18 mmol) were added, followed by refluxing for three hours. After the mixture was cooled to room temperature, trimethylsilyl trifluoromethanesulfonate (0.77 ml, 4 mmol) was added dropwise to the mixture at 0° C. in an argon atmosphere. The mixture was stirred for 15 minutes at room temperature, refluxed for 24 hours, and cooled to room temperature. A saturated aqueous solution of sodium hydrogencarbonate was added thereto at 0° C., followed by stirring for 15 minutes at room temperature. Insoluble materials were separated through filtration by use of Celite, and then the organic layer was separated from the filtrate. After an aqueous layer was extracted with chloroform once, the organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was applied to a silica gel column (20 g, eluent; ethyl acetate:n-hexane:ethanol=20:10:1), to thereby yield Compound 25 in an amount of 0.85 g (66%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].O[N:21]=[C:22]([NH2:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][OH:30])[CH:24]=1>>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:12][N:31]=[C:22]([C:23]3[CH:24]=[C:25]([CH2:29][OH:30])[CH:26]=[CH:27][CH:28]=3)[N:21]=2)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: NC(=NO)c1cccc(CO)c1
Product: COCc1cc(-c2nc(-c3cccc(CO)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following the general procedure 3 starting from Intermediate 3 and Intermediate 70 and was isolated as a yellow oil. HPLC (Method A) Rt 5.16 min (Purity: 97.0%).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH2:10][CH3:11])[CH:3]=1.IC1C=[CH:17][C:16]([N:19]=[C:20]=[S:21])=[C:15]([CH2:22][CH2:23][CH3:24])C=1.[OH:25]CCN.O=S(Cl)Cl>>[OH:25][CH2:7][C:5]1([NH2:6])[CH2:4][CH2:9][CH2:10][CH2:11]1.[I:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:20]2[S:21][CH2:17][C:16]3([CH2:15][CH2:22][CH2:23][CH2:24]3)[NH:19]2)=[C:4]([CH2:9][CH2:10][CH3:11])[CH:3]=1
Reactant: NCCO
Reactant: CCCc1cc(I)ccc1N
Reactant: CCCc1cc(I)ccc1N=C=S
Solvent: O=S(Cl)Cl
Product: CCCc1cc(I)ccc1N=C1NC2(CCCC2)CS1
Product: NC1(CO)CCCC1

Procedure:
4-Iodo-2-n-propylaniline was converted to 4-iodo-2-n-propylphenyl isothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was sequentially reacted with SOCl2 and 4-iodo-2-n-propylphenyl isothiocyanate according to Method C2a to give 2-(4-iodo-2-n-propylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-iodo-2-n-propylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The phenyl iodide was reacted with CuCN according to Method D7a to afford 2-(4-cyano-2-n-propylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[N-:23]=[C:24]=[O:25].[K+].O>C(O)(=O)C>[CH3:20][NH:19][C:15]1[N:14]=[C:13]([C:12]2[C:7]([O:6][C:5]3[CH:21]=[CH:22][C:2]([NH:1][C:24]([NH2:23])=[O:25])=[CH:3][CH:4]=3)=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:18]=[CH:17][N:16]=1
Reactant: [N-]=C=O
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(N)cc2)n1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CNc1nccc(-c2cccnc2Oc2ccc(NC(N)=O)cc2)n1

Procedure:
Dissolved 4-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (75 mg, 0.26 mmol) in acetic acid (1.0 mL), then added potassium isocyanate (0.01 ml, 0.33 mmol), water (0.1 ml), and stirred at RT for 18 hours. Concentrated and purified by reverse phase HPLC (Gilson, acidic mobile phase), extracted into CH2Cl2 washed with NaHCO3 and H2O. Product began to crash out of CH2Cl2 layer, transferred to round bottom flask, concentrated to yield 1-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)urea as off-white solid. MS m/z=337 [M+1]+. Calc'd for C17H36N6O2: 336.35.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:2]1[O:4][CH2:3]1.[CH3:10][C:11]([NH2:22])([CH3:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>>[OH:4][CH:2]([CH2:1][O:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][NH:22][C:11]([CH3:21])([CH3:10])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: CCCCOCC1CO1
Reactant: COc1ccc(CC(C)(C)N)cc1
Product: CCCCOCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Yield: 26.2 %

Procedure:
Using the method of Example 15 supra, n-butyl glycidyl ether (143 μL, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 81 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 310 (M+1, 0.01), 174 (100), 163 (19), 132(18), 121(31), 70(20); 1H-NMR(CDCl3) δ 7.03 (2H, d, J=8.6), 6.87 (2H, d, J=8.6), 3.74 (1H, m), 3.72 (3H, s), 3.40 (4H, m), 2.73 (3H, m), 2.59 (3H, m), 1.50 (2H, m), 1.30 (2H, m), 1.01 (3H, s), 0.99 (3H, s), 0.87 (3H, t, J=7.4); 13C-NMR (CDCl3) δ 157.9, 131.2, 129.9, 113.2, 73.5, 71.2, 69.0, 54.9, 53.1, 46.2, 44.5, 31.5, 26.6, 26.4, 19.1, 13.8.