Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([CH3:27])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([S:22][CH2:23][C:24]([OH:26])=O)=[CH:18][CH:17]=3)[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3].ON1C(=O)CCC1=O.Cl.CN(C)CCCN=C=NCC.[CH2:52]([NH2:55])[CH2:53][NH2:54]>CN(C)C=O.CO.C(Cl)(Cl)Cl>[NH2:54][CH2:53][CH2:52][NH:55][C:24](=[O:26])[CH2:23][S:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH:14]([C:9]2[NH:8][C:7]3[N:6]([CH2:28][CH2:29][CH3:30])[C:5](=[O:31])[N:4]([CH2:1][CH2:2][CH3:3])[C:12](=[O:13])[C:11]=3[N:10]=2)[CH3:27])=[CH:17][CH:18]=1
Reactant: CCCn1c(=O)c2nc(C(C)Cc3ccc(SCC(=O)O)cc3)[nH]c2n(CCC)c1=O
Reactant: NCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2nc(C(C)Cc3ccc(SCC(=O)NCCN)cc3)[nH]c2n(CCC)c1=O
Reaction time: 1 h

Procedure:
Dissolve 2-[4-[2-(2,3,6,9-tetrahydro-1,3-dipropyl-2,6-dioxo-1H-purin-8-yl)propyl]phenylthio]acetic acid (785 mg, 1.87 mmol) in dimethylformamide (20 mL) and treat with N-hydroxysuccinimide (215 mg, 1.87 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (751 mg, 3.92 mmol). Stir for 1 hour and add to a stirring solution of ethylenediamine (20 mL of a 10% solution in methanol). Stir for 1 hour and dilute with chloroform (600 mL). Separate the organic phase, wash with 5% sodium carbonate (200 mL), then brine (300 mL). Dry (MgSO4) and evaporate the solvent in vacuo. Purify by radial chromatography to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:25]=[C:24]3[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]4[S:23][CH2:22][C:16]5([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]5)[O:15][C:14]=43)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:28][C:29]1[CH:39]=[CH:38][C:32]([O:33][CH2:34][C@@H:35]2[CH2:37][O:36]2)=[CH:31][CH:30]=1>>[F:28][C:29]1[CH:39]=[CH:38][C:32]([O:33][CH2:34][C@@H:35]([OH:36])[CH2:37][N:19]2[CH2:20][CH2:21][C:16]3([O:15][C:14]4[C:24]5[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]=4[S:23][CH2:22]3)=[CH:9][CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:25]=5)[CH2:17][CH2:18]2)=[CH:31][CH:30]=1
Reactant: O=C1C(=O)c2ccc(-c3ccccc3)cc2C2=C1SCC1(CCNCC1)O2
Reactant: Fc1ccc(OC[C@@H]2CO2)cc1
Product: O=C1C(=O)c2ccc(-c3ccccc3)cc2C2=C1SCC1(CCN(C[C@H](O)COc3ccc(F)cc3)CC1)O2

Procedure:
Compound 225 was synthesized using 9-phenylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-fluorophenoxy)methyl]oxirane and conditions outlined in procedure Z. M.p.=173-175° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.01 (d, J=1.2 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.87 (dd, J=1.6, 7.6 Hz, 1H), 7.76 (d, J=7.6 Hz, 2H), 7.57 (dd, J=7.6, 7.6 Hz, 2H), 7.52-7.47 (m, 1H), 7.10 (dd, J=8.8, 8.8 Hz, 2H), 6.94 (dd, J=4.4, 8.8 Hz, 2H), 4.88 (d, J=4.8 Hz, 1H), 3.97-3.95 (m, 2H), 3.87-3.82 (m, 1H), 3.11 (s, 2H), 2.87-2.78 (m, 2H), 2.54-2.39 (m, 4H), 2.03 (d, J=14.4 Hz, 2H), 1.87-1.81 (m, 2H); LCMS: 546 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22][CH:21]=1>>[N:14]1([CH2:13][CH2:12][N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:26]([C:23]4[CH:24]=[CH:25][C:20]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:21][CH:22]=4)=[O:27])[CH:11]=3)[CH2:6][CH2:7][CH2:8]2)[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: Nc1ccc2c(c1)N(CCN1CCOCC1)CCC2
Product: O=C(Nc1ccc2c(c1)N(CCN1CCOCC1)CCC2)c1ccc(-c2ccccc2)cc1

Procedure:
Using the procedure outlined in Example 35, the title compound was prepared from 7-amino-1-(2-morpholin-4-ylethyl)-1,2,3,4-tetrahydroquinoline (D17) (0.1 mmol) and 4-biphenylcarboxylic acid (24 mg, 0.12 mmol) as a red gum. 1H NMR (250 MHz, CDCl3) δ (ppm): 7.94 (d, 2H), 7.86 (br, 1H), 7.69 (d, 2H), 7.62 (d, 2H), 7.50 (t, 2H), 7.39 (t, 1H), 7.13 (d, 1H), 6.91 (d, 1H), 6.78 (dd, 1H), 3.75 (m, 4H), 3.46 (m, 2H), 3.33 (m, 2H), 2.80-2.40 (m, 8H), 1.92 (qn, 2H).
Reaction SMILES: CC([O-])(C)C.[K+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1.[Br:22][C:23]1[CH:24]=[CH:25][C:26](F)=[C:27]([CH:30]=1)[C:28]#[N:29]>CS(C)=O>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[O:15])=[CH:12][CH:13]=2)=[C:27]([CH:30]=1)[C:28]#[N:29]
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: N#Cc1cc(Br)ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cc(Br)ccc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 92.1 %

Procedure:
KOtBu (2.78 g, 24.75 mmol) was dissolved into 20 ml DMSO in a round bottom flask. (4-aminophenyl)(morpholino)methanone (5.10 g, 24.75 mmol) in 10 ml DMSO was added and the resulting mixture was stirred for 35 mins at r.t. The mixture was cooled in an iced bath for 5 mins 5-bromo-2-fluorobenzonitrile (4.5 g, 22.50 mmol) in 10 ml DMSO was added dropwise. Iced bath was removed and the mixture was stirred for 1 hr at r.t. The mixture was diluted with ethyl acetate, 100 ml saturated NH4Cl water solution was added. The organic layer was separated. The water layer was extracted with ethyl acetate. The organic layers were combined and washed with H2O (4×), brine, dried over MgSO4 and concentrated. 8 g crude product (84% purity) was obtained. MS (ESI) m/z 386 (M+H)−. 1H NMR (CDCl3) δ ppm 7.61 (d, 1H, J=2.3), 7.47 (dd, 1H, J=9, 2.5), 7.41 (m, 2H), 7.15 (m, 3H), 6.35 (bs, 1H), 3.65 (bm, 8H).
Reaction SMILES: COC[O:4][CH2:5][C:6]1[N:7]=[C:8]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:9][C:10]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:15][CH:14]=1.Cl.O1CCCC1>O>[CH3:26][C:25]1[O:24][C:23]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:22][C:21]=1[CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:10]2[O:9][C:8]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[N:7][C:6]=2[CH2:5][OH:4])=[CH:14][CH:15]=1
Reactant: COCOCc1nc(-c2ccccc2)oc1COc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(OCc2oc(-c3ccccc3)nc2CO)cc1
Yield: 30.1 %

Procedure:
A mixture of 4-[(methoxymethoxy)methyl]-5-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenoxy}methyl)-2-phenyl-1,3-oxazole (0.80 g), 1N hydrochloric acid (20 mL) and tetrahydrofuran (20 mL) was heated under reflux for 20 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give [5-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenoxy}methyl)-2-phenyl-1,3-oxazol-4-yl]methanol as colorless crystals (0.22 g, yield 29%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 143-144° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][C@@H:24]2[CH2:26][C@H:21]1[CH2:22][NH:23]2)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([N:20]1[CH2:25][C@@H:24]2[CH2:26][C@H:21]1[CH2:22][N:23]2[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([Cl:1])[N:11]=1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1nc(Cl)nc2ccccc12
Temperature: 60 °C

Procedure:
To a solution of 2,4-dichloro-quinazoline (0.25 g, 1.26 mmol) in isoprapanol (6 mL) were added t-butyl-(1S,4S)-(−)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.25 g, 1.26 mmol) and the solution was heated at 60° C. for 4 h. The reaction was concentrated in vacuo and the residue was chromatographed over silica with 25:10:65, 35:10:55, and 50:10:40 EtOAc-CH2Cl2-Hexane; 1%, 3%, and 5% MeOH/CH2Cl2 to give the title compound. MS (ES+): 361.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH:23]([C:26]1[CH:30]=[C:29]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[N:28]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[N:27]=1)([CH3:25])[CH3:24]>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:32]([NH:31][C:29]2[N:28]([C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[N:27]=[C:26]([CH:23]([CH3:25])[CH3:24])[CH:30]=2)=[O:33])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: COc1ccc(-n2nc(C(C)C)cc2NC(=O)Oc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C(C)C)cc2NC(=O)Nc2cccc(Oc3ncnc4cc(OC)c(OC)cc34)c2)cc1
Yield: 39.1 %

Procedure:
Using the procedure described in Example 306A, to a solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.3 mmol), prepared as described in Example 113A, in THF (3.3 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-ylcarbamate (105 mg, 0.3 mmol), described in the previous step, to afford 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)urea (65 mg, 39%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.20 (d, J=7 Hz, 6H), 2.85 (m, 1H), 3.81 (s, 3H), 3.97 (s, 6H), 6.27 (s, 1H), 6.91 (d, J=7.5 Hz, 1H), 7.07 (d, J=9 Hz, 2H), 7.16 (d, J=9 Hz, 1H), 7.33-7.41 (m, 4H), 7.55 (s, 2H), 8.35 (s, 1H), 8.55 (s, 1H), 9.18 (s, 1H); LC-MS (ESI) m/z 555 (M+H)+.
Reaction SMILES: [OH:1][C:2]([CH3:8])([CH2:6][CH3:7])[C:3](O)=[O:4].S(Cl)(Cl)=O.[C:13]1([S:19]([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C>CC(N(C)C)=O>[C:13]1([S:19]([C:22]2[CH:23]=[CH:24][C:25]([NH:26][C:3](=[O:4])[C:2]([OH:1])([CH3:8])[CH2:6][CH3:7])=[CH:27][CH:28]=2)(=[O:20])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCC(C)(O)C(=O)O
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: C
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CCC(C)(O)C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 2-hydroxy-2-methyl butyric acid (0.76 g, 6.4 mmol) in dry dimethylacetamide (15 ml) was stirred under a nitrogen atmosphere at -10° C. Thionyl chloride (0.76 g, 6.4 mmol) was added and the resulting mixture was allowed to stir at -10° C. for 1 hour. 4-Phenylsulfonylaniline (1.0 g, 4.29 mmol) was then added and the reaction mixture was stirred at -10° C. for a further 15 mins. The solution was then allowed to warm to room temperature where it was stirred overnight. The reaction mixture was poured onto water, extracted with ethyl acetate, and the combined ethyl acetate portions were washed with water, and brine. After drying (Na2SO4) the ethyl acetate was removed by evaporation. Crystallization from ethyl acetate/hexane yielded the title tertiary carbinol (0.89 g, 62.5%) as a colorless crystalline solid; mp=163.0°-165.0° C. 1H-NMR (250 MHz, d6 -DMSO): 0.82 (t, J=7 Hz, 3H, CH3), 1.32 (s, 3H, CH3), 1.56 (m, J=7 Hz, 1H, CH2), 1.76 (m, J=7 Hz, 1H, CH2), 5.65 (s, 1H, OH), 7.64 (m, 3H, ArH), 7.91 (m, 4H, ArH, 8.01 (d, J=11.1 Hz, 2H, ArH), 9.98 (s, 1H, NH). MS (CI, CH4): 334(M+1, 100).
Reaction SMILES: [CH3:1][C:2]([OH:8])([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[CH:9]12[CH2:15][CH:12]([CH:13]=[CH:14]1)[CH2:11][CH:10]2[C:16](OC)=[O:17]>C[O-].[Na+].C1(C)C=CC=CC=1>[CH:9]12[CH2:15][CH:12]([CH:13]=[CH:14]1)[CH2:11][CH:10]2[C:16]([O:6][CH2:5][CH2:4][CH2:3][C:2]([OH:8])([CH3:7])[CH3:1])=[O:17]
Reactant: CC(C)(O)CCCO
Reactant: COC(=O)C1CC2C=CC1C2
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(O)CCCOC(=O)C1CC2C=CC1C2
Yield: 92.9 %

Procedure:
A mixture of 118 g of 4-methyl-1,4-pentanediol, 173 g of methyl 5-norbornene-2-carboxylate, 1.4 g of sodium methoxide and 400 ml of toluene was heated under reflux for 5 hours while distilling off the methanol which formed during the reaction. The reaction solution was cooled, washed with saturated sodium bicarbonate water, dried over anhydrous sodium sulfate, and concentrated in vacuum. It was purified by vacuum distillation, collecting 221 g of 4-hydroxy-4-methylpentyl 5-norbornene-2-carboxylate (yield: 93%). The physical data of this product were in good coincidence with those of Synthesis Example 1.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)[CH:5]=[CH:4][C:3]1=2.O[Li].O>C1COCC1.O>[CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccccn2)=CCC3(C)C)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CC=C(c2ccccn2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
A solution of 80.0 mg (0.196 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(2-pyridyl)-2-naphthalenyl)ethynyl]benzoate (Compound 10) and 20.6 mg (0.491 mmol) of LiOH-H2O in 3 ml of THF/water (3:1, v/v), was stirred overnight at room temperature. The reaction was quenched by the addition of saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid. 1H NMR (d6-DMSO): δ 8.64 (1H, m), 7.94 (2H, d, J=8.3 Hz), 7.87 (1H, dt, J=1.7, 7.8 Hz), 7.58 (2H, d, J=8.3 Hz), 7.50 (1H, d, J=8.2 Hz), 7.47 (2H, s), 7.37 (1H, m), 7.25 (1H, s), 6.30 (1H, t, J=4.6 Hz), 2.39 (2H, d, J=4.6 Hz), 1.31 (6H, s).
Reaction SMILES: [CH3:1][Si:2]([CH2:5][C:6](=[CH2:11])[CH2:7][C:8]([OH:10])=[O:9])([CH3:4])[CH3:3].[N+](=[CH2:14])=[N-].C(O)(=O)C>C(OCC)C>[CH3:1][Si:2]([CH2:5][C:6](=[CH2:11])[CH2:7][C:8]([O:10][CH3:14])=[O:9])([CH3:4])[CH3:3]
Reactant: C=[N+]=[N-]
Reactant: C=C(CC(=O)O)C[Si](C)(C)C
Solvent: CCOCC
Solvent: CC(=O)O
Product: C=C(CC(=O)OC)C[Si](C)(C)C

Procedure:
To a solution of 3-(trimethylsilylmethyl)but-3-enoic acid (36.5 g) in diethyl ether (200 ml) at 10°-15° C. was added a solution of diazomethane in diethyl ether (ca 0.6 M solution, 400 ml). The excess of diazomethane was decomposed by addition of acetic acid. The resultant solution was concentrated in vacuo to 200 ml and the concentrate was washed with an aqueous sodium bicarbonate and brine. Drying over magnesium sulfate and evaporation of the solvent left a yellow oil, which was distilled in vacuo to give methyl 3-(trimethylsilylmethyl)but-3-enoate (34.74 g) as a colorless oil, bp 74°-75° C. (10 Torr).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>COCCOC.[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.O>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:9]1[CH:2]=[C:3]([CH:6]=[CH:7][C:8]=1[F:10])[CH:4]=[O:5]
Reactant: O=Cc1ccc(F)cc1Br
Reactant: OB(O)c1ccccc1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: O=Cc1ccc(F)c(-c2ccccc2Cl)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 54.1 %

Procedure:
To a solution of 2-bromo-4-fluorobenzaldehyde (2.0 g, 9.85 mmol) and 2-chlorophenylboronic acid (2.0 g, 12.1 mmol) in ethylene glycol dimethyl ether (20 mL) is added 2N sodium carbonate (19.7 mL) followed by tetrakis(triphenylphosphine) palladium (0) (573 mg, 0.50 mmol). The reaction is subsequently stirred at 80° C. for 4 hours under an argon atmosphere. Once complete, the reaction mixture is poured into CH2Cl2 and water is added. The organic layer is separated, dried over sodium sulfate and concentrated to provide a crude oil. The crude product is purified by column chromatography (10% ethyl acetate in hexanes) to afford 1.25 g of 3-(2-chlorophenyl)-4-fluorobenzaldehyde.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.[H-].[Na+].[CH2:14]([O:21][C:22]1[C:23]([CH3:32])=[C:24]2[N:29]([CH:30]=1)[N:28]=[CH:27][N:26]=[C:25]2Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>CN(C=O)C>[CH2:14]([O:21][C:22]1[C:23]([CH3:32])=[C:24]2[N:29]([CH:30]=1)[N:28]=[CH:27][N:26]=[C:25]2[O:8][C:7]1[C:2]([F:1])=[C:3]2[CH:11]=[CH:10][NH:9][C:4]2=[N:5][CH:6]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1c(OCc2ccccc2)cn2ncnc(Cl)c12
Reactant: Oc1cnc2[nH]ccc2c1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1c(OCc2ccccc2)cn2ncnc(Oc3cnc4[nH]ccc4c3F)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
To a solution of 4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-ol (53.5 mg, 0.35 mmol) in DMF (2 mL) at −78° C., sodium hydride (60% in oil, 14 mg, 0.35 mmol) was added and the mixture was warmed to 0° C. After 30 minutes, the flask was cooled to −78° C., 6-benzyloxy-4-chloro-5-methyl-pyrrolo[2,1-f][1,2,4]triazine (80 mg, 0.29 mmol) was added and the mixture was allowed to reach RT over 30 min. A solution of saturated ammonium chloride was added, the solution was extracted with ethyl acetate (3×15 mL), combined organic layers were washed with water (30 mL), brine (30 mL), dried, and concentrated in vacuo. The crude material was purified by trituration with acetonitrile to give the title compound (90 mg, 80%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.17 (1H, s), 8.30 (1H, d, J=9.6 Hz), 8.00 (1H, s), 7.94 (1H, s), 7.61 (1H, t, J=3.0 Hz), 7.49 (2H, d, J=7.1 Hz), 7.41 (2H, t, J=7.1 Hz), 7.34 (1H, t, J=7.3 Hz), 6.59 (1H, dd, J=2.0, 3.5 Hz), 5.16 (2H, s), 2.43 (3H, s). LC/MS; (M+H)+=m/z 390.
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[O:22][C:23]([F:26])([F:25])[F:24])[C:12]2[C:11](=[O:27])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:28])(=[O:3])[CH3:2].FC(F)(F)S(O[CH2:35][CH3:36])(=O)=O.C(=O)(O)[O-].[Na+]>C1COCC1>[C:1]([C:4]1[CH:13]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[O:22][C:23]([F:26])([F:25])[F:24])[C:12]2[C:7](=[CH:8][CH:9]=[N:10][C:11]=2[O:27][CH2:35][CH3:36])[NH:6][C:5]=1[CH3:28])(=[O:3])[CH3:2]
Reactant: CCOS(=O)(=O)C(F)(F)F
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1ccc(C#N)cc1OC(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1OC(F)(F)F)C(C(C)=O)=C(C)N2
Reaction time: 0.08 h

Procedure:
2.40 g (6.16 mmol) of 4-(3-acetyl-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridin-4-yl)-3-(trifluoromethoxy)benzonitrile (example 10A) are suspended in 5 ml of abs. THF and, after addition of 6.78 ml (6.78 mmol) of N″′-(tert-butyl)-N,N′,N″-tris[tris(dimethylamino)-phosphoranylidene]phosphorimide triamide (phosphazene base P4-t-Bu; 1 M in hexane), stirred for 5 min. Then 1.32 g (7.40 mmol) of ethyl trifluoromethanesulfonate are added. After stirring for a further 5 min, the mixture is hydrolyzed with saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried with sodium sulfate and then concentrated in a rotary evaporator. The residue is purified by column chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate 3:7). Recrystallization from acetonitrile finally affords 745 mg (29% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[NH:13][C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[N:13]=[C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]2[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1
Reactant: COc1ccc(OC)c(Sc2nc3c(N)ncnc3[nH]2)c1
Reactant: Fc1ccc(CBr)cc1
Product: COc1ccc(OC)c(Sc2nc3c(N)ncn(Cc4ccc(F)cc4)c-3n2)c1
Yield: 34 %

Procedure:
The title compound was prepared from 8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine and 1-bromomethyl-4-fluoro-benzene by a procedure similar to examples 1 and 2. The compound was purified by preparative HPLC. 8-(2,5-Dimethoxy-phenylsulfanyl)-3-(4-fluoro-benzyl)-3H-purin-6-ylamine: Yield 34%, 1H NMR (DMSO-d6) δ 8.55 (s, 1H), 8.1 (bs, 2H), 7.51 (m, 2H), 7.15 (m, 2H), 6.97 (m, 2H), 6.76 (dd, J=8.8, 2.8 Hz, 1H), 5.44 (s, 2H), 3.74 (s, 3H), 3.50 (s, 3H); LC-MS [M+H]+ 412.1.
Reaction SMILES: [C:1]1([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][CH:15]([C:16]([O:18]C(C)C)=[O:17])[C:11]3=[CH:10][C:9]=2[CH3:22])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.CO.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]1([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][CH:15]([C:16]([OH:18])=[O:17])[C:11]3=[CH:10][C:9]=2[CH3:22])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cc2n(c1C(=O)c1cccs1)CCC2C(=O)OC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1cc2n(c1C(=O)c1cccs1)CCC2C(=O)O

Procedure:
A solution of 500 mg. of isopropyl 5-(2-thenoyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate in 15 ml. of methanol is treated with a solution of 1.05 g. of potassium carbonate in 8 ml. of water. The reaction mixture is refluxed under nitrogen atmosphere for 3 hours, cooled, and evaporated to dryness. The residue is taken up in 10 ml. of 10% aqueous hydrochloric acid and 50 ml. of water and the resultant mixture extracted with ethyl acetate (3 × 50 ml.). The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure, to give 5-(2-thenoyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid [(A), R = CH3, R1 = H, X = S], having a melting point of 166° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14](OCC)=[O:15])[N:10]=2)=[CH:5][CH:4]=1)#[N:2].O1CCCC1.[BH4-].[Na+].O>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[C:11]([CH2:14][OH:15])[N:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)c1noc(-c2ccc(C#N)cc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: N#Cc1ccc(-c2nc(CO)no2)cc1
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To a solution of 5-(4-cyanophenyl)-3-ethoxycarbonyl-1,2,4-oxadiazole (5.0 g) in methanol (50 ml)--tetrahydrofuran (50 ml) was added sodium borohydride (0.93 g) at 0° C. After stirring at 5°-10° C. for 1 hour, the mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was recrystallized from diethyl ether to give 5-(4-cyanophenyl)-3-hydroxymethyl-1,2,4-oxadiazole (4.0 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].Cl[CH2:12][CH2:13][O:14][CH2:15][CH2:16]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:7]1([C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][CH:8]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: ClCCOCCCl
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(N2CCOCC2)c1
Reaction time: 4 h

Procedure:
3-Nitroaniline (10 g, 72 mmol)in DMF (100 ml) was added bis(2-chloroethyl) ether (11.7 ml, 100 mmol) and potassium carbonate (27.6 g, 200 mmol). The mixture was heated to reflux for 10 hours. Additional bis(2-chloroethyl) ether (3 ml) was added and reflux was maintained for 18 hours. Addition of bis(2-chloroethyl) ether was repeated and reflux was continued for 4 hours. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The organic phase was dried and evaporated. The residue was extracted with diethyl ether. The extract was concentrated and purified by column chromatography on silica gel with ethyl acetate/petroleum ether (3:7) as the eluent. Yield 3.4 g. Mp 87°-90° C.