Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].C1N=CN([C:12](N2C=NC=C2)=[O:13])C=1.[CH2:19]([C@H:21]1[CH2:25][NH:24][CH2:23][C@H:22]1[C:26]1[N:30]2[C:31]3[CH:37]=[CH:36][N:35]([S:38]([C:41]4[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=4)(=[O:40])=[O:39])[C:32]=3[N:33]=[CH:34][C:29]2=[N:28][N:27]=1)[CH3:20]>CN(C=O)C>[CH2:19]([C@H:21]1[C@@H:22]([C:26]2[N:30]3[C:31]4[CH:37]=[CH:36][N:35]([S:38]([C:41]5[CH:42]=[CH:43][C:44]([CH3:45])=[CH:46][CH:47]=5)(=[O:40])=[O:39])[C:32]=4[N:33]=[CH:34][C:29]3=[N:28][N:27]=2)[CH2:23][N:24]([C:12]([NH:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[O:13])[CH2:25]1)[CH3:20]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCC(F)(F)F
Reactant: CC[C@H]1CNC[C@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Solvent: CN(C)C=O
Product: CC[C@@H]1CN(C(=O)NCC(F)(F)F)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To a solution of 2,2,2-trifluoroethanamine (0.080 g, 0.804 mmol) in DMF (3 mL) was added CDI (0.150 g, 0.926 mmol). The resulting solution was stirred at about 65° C. for about 2 h. 1-((cis)-4-ethylpyrrolidin-3-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.250 g, 0.609 mmol) was added and the reaction continued stirring at about 65° C. for about 2 h. The reaction was cooled to about ambient temperature. The solvent was removed under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with a gradient of 0-10% MeOH in afford (cis)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (0.306 g, 94%) as a brown residue: LC/MS (Table 1, Method a) Rt=2.19 min; MS m/z: 536 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:21][C:5]2=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][C:12]=3[CH:13]=[C:4]2[NH:3]1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[O:1]=[C:2]1[NH:21][C:5]2=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][C:18]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[O:20])=[CH:11][C:12]=3[CH:13]=[C:4]2[NH:3]1
Reactant: C1CCNCC1
Reactant: O=C(O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Product: O=C(CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1)N1CCCCC1

Procedure:
This compound, m.p. 284.5°-285.5° C., was prepared analogous to Example 15 from 4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butyric acid and piperidine.
Reaction SMILES: [CH2:1](ONC1C=CC=CC=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]CC.Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[N:22][N:21]=1.Cl.O1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>C(O)C>[CH2:40]([O:41][C:42]1[CH:43]=[C:20]([CH:29]=[CH:28][CH:27]=1)[NH:21][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[N:22][N:21]=1)[CH2:39][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: C1COCCO1
Reactant: CCCCCCCCCCONc1ccccc1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCOc1cccc(Nc2nnc(Cc3ccncc3)c3ccccc23)c1
Reaction time: 0.05 h

Procedure:
To 262 mg (1.05 mmol) decyloxyaniline (Salor) in 5 ml ethanol, 0.26 ml HCl/dioxane 4N is added, the mixture stirred for ≈3 min, and then 256 mg (1.00 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine (Example 67A.1) is added. After 2 h boiling under reflux, the mixture is cooled and concentrated by evaporation. The residue is stirred with 6 ml NH3 solution (10% in water: or 10 ml sat. NaHCO3 solution) and 15 ml dichloromethane/methanol SO: 1 for 30 min. The aqueous phase is then separated off and extracted again with dichloromethane. The organic phase is dried (Na2SO4) and concentrated by evaporation. Crystallization [possibly after chromatography on SiO2 (ethyl acetate/CH3OH 19:1)] from acetonitrile (or methanol) yields the title compound: m.p.: 116-119° C.; Anal. calc. (C30H36N4O) C 76.89%, H 7.74%, N 11.96%; found C 76.7%, H 7.7%, N 11.9%; FAB MS (M+H)+=469.
Reaction SMILES: CC1(C)C[O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14](=[O:26])[CH2:15][CH2:16][N:17]([CH3:25])C(=O)OC(C)(C)C)=N1.[CH3:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][Mg]Cl.C(OCC)(=O)C>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[F:13][C:10]1[CH:9]=[C:8]2[C:7](=[CH:12][CH:11]=1)[C:4](=[O:5])[O:26][C:14]2([CH2:33][CH2:32][CH2:31][CH2:30][O:29][CH3:28])[CH2:15][CH2:16][NH:17][CH3:25]
Reactant: CN(CCC(=O)c1cc(F)ccc1C1=NC(C)(C)CO1)C(=O)OC(C)(C)C
Reactant: COCCCC[Mg]Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CNCCC1(CCCCOC)OC(=O)c2ccc(F)cc21
Temperature: -30 °C
Reaction time: 2 h
Yield: 110 %

Procedure:
To a solution of tert-butyl 3-(2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-5-fluorophenyl)-3-oxopropyl(methyl)carbamate (153 mg, 0.4 mmol) in dry toluene (2 mL) at −30° C. was added 4-methoxybutylmagnesium chloride (2.0 M, 0.6 mL, 1.2 mmol, prepared by refluxing 4-methoxybutylchloride and magnesium in THF for 4 h). The reaction was stirred at −30° C. for 2 h. After warming to room temperature, the reaction mixture was poured into a mixture of ethyl acetate and brine, separated. The aqueous phase was extracted with ethyl acetate once. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (40 g column, EtOAc/Hexanes) to give the Grignard-addition adduct (130 mg, 70%). A portion of the adduct (30 mg, 0.064 mmol) was dissolved in acetonitrile (4 mL), put in a seal tube and added concentrated sulfuric acid (3 drops). The tube was then sealed and heated at 100° C. for 2 h. After cooling to room temperature, the reaction mixture was purified by preparative HPLC (C-18 column, 2 to 60% CH3CN in H2O containing 0.01% CF3CO2H over 20 min, 20 mL min−1) to afford product as TFA salt (17 mg, 65%).
Reaction SMILES: ClC1N=C2C(N=C([C:11]([OH:14])(C)C)N2)=C(N2CCOCC2)N=1.C(OCCBr)(=O)C.C(O[CH2:32][CH2:33][N:34]1[C:42]([C:43]([OH:46])([CH3:45])[CH3:44])=[N:41][C:40]2[C:35]1=[N:36][C:37](Cl)=[N:38][C:39]=2[N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)(=O)C.[NH2:54][C:55]1[N:60]=[CH:59][C:58](B(O)O)=[CH:57][N:56]=1>>[NH2:54][C:55]1[N:60]=[CH:59][C:58]([C:37]2[N:36]=[C:35]3[C:40]([N:41]=[C:42]([C:43]([OH:46])([CH3:45])[CH3:44])[N:34]3[CH2:33][CH2:32][CH2:11][OH:14])=[C:39]([N:47]3[CH2:48][CH2:49][O:50][CH2:51][CH2:52]3)[N:38]=2)=[CH:57][N:56]=1
Reactant: CC(C)(O)c1nc2c(N3CCOCC3)nc(Cl)nc2[nH]1
Reactant: Nc1ncc(B(O)O)cn1
Reactant: CC(=O)OCCn1c(C(C)(C)O)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: CC(=O)OCCBr
Product: CC(C)(O)c1nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc2n1CCCO

Procedure:
100 mg of 2-(2-chloro-6-morpholino-9H-purin-8-yl)propan-2-ol was treated with 2-bromoethyl acetate via General Procedure C. Crude intermediate 2-(2-chloro-8-(2-hydroxypropan-2-yl)-6-morpholino-9H-purin-9-yl)ethyl acetate was treated with 2-aminopyrimidine-5-boronic acid, pinacol ester via General Procedure A and was purified via reverse phase HPLC to give 54 mg of 106 as a white solid. MS (Q1) 401.2 (M)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][C:16]=2[Cl:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)[CH2:28][CH2:29][CH2:30][N:31]=[C:32]=NCC.ClCCl.N1CCCC1>O>[Cl:24][C:16]1[CH:17]=[C:18]([C:19]([N:31]2[CH2:32][CH2:28][CH2:29][CH2:30]2)=[O:21])[CH:22]=[CH:23][C:15]=1[CH2:14][N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(=O)O)cc2Cl)CC1
Agent: Cl
Solvent: O
Solvent: C1CCNC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(=O)N3CCCC3)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
A 100 mL round-bottom flask was charged with 4-([4-[(tert-butoxy)carbonyl]piperazin-1-yl]methyl)-3-chlorobenzoic acid (600 mg, 1.69 mmol, 1.00 equiv), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (487 mg, 2.54 mmol, 1.50 equiv), 1-Hydroxybenzotrizole (342 mg, 2.53 mmol, 1.50 equiv), dichloromethane (15 mL). The resulting solution was stirred for 30 min at room temperature and pyrrolidine (240 mg, 3.37 mmol, 2.00 equiv) was added. The resulting solution was stirred for 3 h at room temperature and diluted with H2O (10 mL). The resulting solution was extracted with dichloromethane (3×15 mL) and the organic layers were combined, washed with brine (1×15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (80/20) to provide 430 mg (62% yield) of tert-butyl 4-([2-chloro-4-[(pyrrolidin-1-yl)carbonyl]phenyl]methyl)piperazine-1-carboxylate as a white solid. LCMS (ESI, m/z): 408 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18](F)[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:15]=2[F:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:31][C:32]([F:43])([F:42])[O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>CN(C=O)C.ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH:39][CH2:38][C:37]3[CH:40]=[CH:41][C:34]([O:33][C:32]([F:31])([F:42])[F:43])=[CH:35][CH:36]=3)[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:15]=2[F:24])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(F)c([N+](=O)[O-])cc2F)CC1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(NCc3ccc(OC(F)(F)F)cc3)c([N+](=O)[O-])cc2F)CC1
Yield: 80.3 %

Procedure:
8 g of 4-(2,5-difluoro-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (23 mmol) and 3.82 g potassium carbonate (27.65 mmol) were suspended in 80 ml DMF under stirring and then treated dropwise within 10 min with a solution of 5.29 g of 4-trifluoromethoxy-benzylamine (27.65 mmol) in 30 ml DMF. The reaction mixture was then stirred for 48 h at rt, diluted with 500 ml dichloromethane and 1 liter of water. After separation, the organic phase was washed with brine (500 ml). The two aqueous phases were then reextracted with 2×250 ml dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The solid residue was stirred with 150 ml heptane/ethylacetate 4:1. After 10 minutes the suspension was diluted with 100 ml heptane, and after additional 10 min stirring, filtered. After drying in vacuo, 9.5 g of 4-[2-fluoro-4-nitro-5-(4-trifluoromethoxy-benzylamino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester was obtained as a yellow solid (80%). MS(ISP): 515.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[Mg].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16].OC(C1(O[C@@H]([C@@H]([C@@H](CO)O)O)[C@H](N)[C@@H](O)C1)O)=O.Cl>O1CCCC1>[CH2:16]([C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1)[CH2:15][CH2:14][CH2:13][CH:12]=[CH2:11]
Reactant: C=CCCCCBr
Reactant: Clc1ccc(Cl)cc1
Agent: Cl
Agent: N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(O)(C(=O)O)C[C@@H]1O
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCCCCc1ccc(Cl)cc1
Reaction time: 4 h
Yield: 40 %

Procedure:
A solution containing 294 g (2 Mol) of 1,4-dichlorobenzene in 500 ml of anhydrous tetrahydrofuran was added dropwise at 80° C. under nitrogen over a period of 110 minutes to a stirred suspension of 48.6 g (2.0 Mol) of magnesium turnings. The mixture was subsequently heated at 80° to 84° C. for an additional 2 hours, then decanted off from the excess magnesium. The resultant solution of Grignard compound was added dropwise at 80° C. over a period of 30 minutes to a stirred solution containing 194 g (1.8 Mol) of 6-bromo-1-hexene (commercially available from Fluka GmbH, D-7910 Neu-Ulm) in 200 ml of tetrahydrofuran. The mixture was then stirred at 80° for an additional four hours and poured onto ice. The mixture was acidified using hydrochloric acid and extracted three times using a 1:1 mixture of diethyl ether/methyl tert-butyl ether, and the ether fractions were stirred with activated charcoal and dried over sodium sulfate. After the filtrate had been evaporated, the residue was fractionated under reduced pressure. About 156 g (corresponding to a yield of 40 percent of theory) of 4-(5-hexenyl)-1-chlorobenzene were obtained at a pressure of 13 hPa and at a temperature of 116° to 118° C. 4-(4-pentenyl)-1-chlorobenzene (b.p. 102° to 105° C. at 13 hPa), 4-(11-dodecenyl)-1-chlorobenzene (b.p. 147° to 150° at 0.2 hPa) and 4-(8-nonenyl)-1-chlorobenzene (b.p. 87° C. at 0.3 hPa) can also be prepared in the same manner.
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][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[CH2:42]([N:46]([CH2:50][CH2:51][CH2:52][CH3:53])[CH2:47][CH2:48][NH2:49])[CH2:43][CH2:44][CH3:45]>C(Cl)(Cl)Cl.O>[CH2:42]([N:46]([CH2:50][CH2:51][CH2:52][CH3:53])[CH2:47][CH2:48][NH:49][C:34]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][CH:18]=1)=[O:40])[CH2:43][CH2:44][CH3:45]
Reactant: CCCCN(CCN)CCCC
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCN(CCCC)CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (151 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1,N1-dibutyl-1,2-ethanediamine (88 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (72 mg, yield 43%).
Reaction SMILES: [CH3:1][N:2]1[C:10]([NH:11][C:12]([NH:14]C(=O)C2C=CC=CC=2)=[S:13])=[C:9]2[C:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)=[N:3]1>[OH-].[Na+]>[CH3:1][N:2]1[C:10]([NH:11][C:12]([NH2:14])=[S:13])=[C:9]2[C:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)=[N:3]1
Reactant: Cn1nc2c(c1NC(=S)NC(=O)c1ccccc1)CCCC2
Agent: [Na+]
Agent: [OH-]
Product: Cn1nc2c(c1NC(N)=S)CCCC2
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A suspension of compound 125 (3.1 g, 9.5 mmol) in 30 mL of 5% NaOH aqueous solution was stirred in an oil bath of 90° C. for 8 hrs and cooled down to room temperature. Ice was added while stirring to the reaction mixture. The resulting suspension was filtered, and the cake was washed with cold water (10 mL×3) and further dried in vacuo to afford the desired product 113 as an off-white powder.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].Cl.[CH3:18]O>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:18])=[O:15]
Reactant: O=C(O)CCCCc1nc2ccccc2s1
Reactant: CO
Agent: Cl
Product: COC(=O)CCCCc1nc2ccccc2s1
Yield: 67 %

Procedure:
A solution of 5-(2-benzothiazolyl)pentanoic acid (1.54 g, 6.5 mmol, prepared according to the procedure of Example 12 in JP, A, 8-208631 (1996)) in hydrochloric acid-methanol (40 ml) was stirred at room temperature overnight, and evaporated. The residue was dissolved in chloroform, and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulfate, evaporated, and purified through flash column chromatography to give methyl 5-(2-benzothiazolyl)pentanoate (1.08 g, 67%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][O:10][CH3:11])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH2:12]/[C:13](/[CH3:21])=[CH:14]\[C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16].[N+:22]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O)([O-:24])=[O:23]>CC(O)C.ClCCl>[CH3:5][C:3]1[NH:12][C:13]([CH3:21])=[C:14]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH:28]([C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([N+:22]([O-:24])=[O:23])[CH:26]=2)[C:2]=1[C:1]([O:7][CH2:8][CH2:9][O:10][CH3:11])=[O:6]
Reactant: C/C(N)=C/C(=O)OC(C)C
Reactant: COCCOC(=O)CC(C)=O
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CC(C)O
Product: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+](=O)[O-])c1
Yield: 57.5 %

Procedure:
A solution of 2-methoxyethyl acetoacetate (51) (32 g, 0.2 mol), 1-methylethyl 3-aminocrotonate (52) (28.8 g, 0.2 mol) and 3-nitrobenzaldehyde (30.6 g, 0.2 mol) in 2-propanol (280 mL) was refluxed for 9 h. The mixture was diluted with dichloromethane (1000 mL) and dried (MgSO4), and the solvent was removed with a rotary evaporator. The crude produce was recrystallized from ethyl acetate-petroleum ether to afford 48 g (0.115 mol, 58%) of 50 as a yellow crystalline solid: mp 122°-123° C. (lit.81 mp 125° C.); IR (CH2Cl2) 3440, 2975, 1692, 1620, 1530, 1460, 1345, 1210, 1095 cm-1 ; 1H NMR (CDCl3) δ 1.08 (d, J=6.2 Hz, 3H), 1.25 (d, J=6.2 Hz, 3H), 2.33 (s, 6H), 3.33 (s, 3H), 3.55 (t, J=4.8 Hz, 2H), 4.12-4.20 (m, 2H), 4.93 (septet, J=6.2 Hz, 1H), 5.09 (s, 1H), 6.31 (s, 1H), 7.34-8.13 (m, 4H); 13C NMR (CDCl3) δ 19.38, 19.53, 21.85, 22.17, 40.14, 58.90, 63.05, 67.43, 70.58, 102.93, 103.75, 121.36, 123.33, 128.70, 134.81, 144.84, 145.62, 148.16, 150.20, 166.75, 167.26.
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([NH2:11])[N:9]=[CH:10][C:5]=2[S:4][CH:3]=1.B([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=[O:19])(O)O>>[NH2:11][C:8]1[N:9]=[CH:10][C:5]2[S:4][CH:3]=[C:2]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([OH:20])=[O:19])[C:6]=2[N:7]=1
Reactant: Nc1ncc2scc(Br)c2n1
Reactant: O=C(O)c1cccc(B(O)O)c1
Product: Nc1ncc2scc(-c3cccc(C(=O)O)c3)c2n1
Yield: 56.3 %

Procedure:
3-(2-Aminothieno[3,2-d]pyrimidin-7-yl)benzoic acid (800 mg, 56% yield) was prepared in the same manner as Step 6 of Example 1 using 7-bromothieno[3,2-d]pyrimidin-2-amine (1.2 g, 5.24 mmol) and 3-boronobenzoic acid (870 mg, 5.24 mmol).
Reaction SMILES: Br[C:2]1[C:3](=[O:35])[N:4]([CH2:19][C@H:20]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5](=[O:18])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:7]=1[CH3:8].[F:36][C:37]1[C:42]([O:43][CH3:44])=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O>CCO.COCCOC>[C:31]([O:30][C:28]([NH:27][C@H:20]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:19][N:4]1[C:3](=[O:35])[C:2]([C:38]2[CH:39]=[CH:40][CH:41]=[C:42]([O:43][CH3:44])[C:37]=2[F:36])=[C:7]([CH3:8])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:5]1=[O:18])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1c(Br)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C2CCCCC2)c(=O)n1Cc1c(F)cccc1F
Reactant: COc1cccc(B(O)O)c1F
Solvent: COCCOC
Solvent: CCO
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3F)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C3CCCCC3)c2=O)c1F
Temperature: 80 °C
Yield: 32.3 %

Procedure:
5-Bromo-3-[2(R)-tert-butoxycarbonylamino-2-cyclohexylethyl]-1-[2,6-difluorobenzyl]-6-methyl-pyrimidine-2,4(1H,3H)-dione 2b (1.0 g, 1.79 mmol) in bezene/EtOH/ethylene glycol dimethyl ether (20/2/22 mL) was added 2-fluoro-3-methoxyphenylboronic acid (382 mg, 2.24 mmol) and saturated Ba(OH)2/water (˜0.5 M, 15 mL). The reaction mixture was deoxygenated with N2 for 10 minutes, tetrakis(triphenylphosine) palladium (0) (208 mg, 0.18 mmol) was added and the reaction mixture was heated at 80° C. overnight under N2. The reaction mixture was partitioned between brine and EtOAc. The organic layer was dried (sodium sulfate), evaporated, and purified by flash chromatography (silica, 30% EtOAc/hexanes) to give compound 2c (348 mg, 32.3%). MS (CI) m/z 502.20 (MH+-Boc).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.Cl.[CH3:13][O:14][C:15]1[C:19]([NH2:20])=[CH:18][N:17]([CH3:21])[N:16]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[F:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][NH:6]2)=[C:2]([NH:20][C:19]2[C:15]([O:14][CH3:13])=[N:16][N:17]([CH3:21])[CH:18]=2)[N:10]=1
Reactant: COc1nn(C)cc1N
Reactant: Fc1nc(Cl)c2nc[nH]c2n1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1nn(C)cc1Nc1nc(F)nc2[nH]cnc12
Temperature: 25 °C
Reaction time: 19 h
Yield: 86.7 %

Procedure:
A suspension of 6-chloro-2-fluoro-9H-purine (5.49 g, 31.8 mmol, 1.00 eq), 3-methoxy-1-methyl-1H-pyrazol-4-amine hydrochloride (6.60 g, 40.34 mmol, 1.26 eq), and N,N-diisopropylethylamine (16.6 mL, 95.5 mmol, 3.00 eq) in DMSO (31.8 mL) was stirred at ambient temperature for 19 hr. The reaction mixture was then concentrated in vacuo at 50° C., poured into water (250 mL), and stirred vigorously at 0° C. for 1 hr. The resulting solids were filtered off, washed with ice cold water (20 mL), and dried for 16 hr at 50° C. to give the title compound (7.26 g, 87% yield, 96% purity) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.03 (br. s., 1 H) 9.21 (br. s., 1 H) 8.18 (br. s., 1 H) 7.74 (br. s., 1 H) 3.81 (br. s., 3 H) 3.71 (s, 3H). m/z (APCI+) for C10H11FN7O 264.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH:23]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[C:14]=2[CH3:23])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(-n2cc(C#Cc3ccnc(Cl)c3)nc2C)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccc(-n2c(C)nc(C#Cc3ccnc(Cl)c3)c2C)cc1
Temperature: -75 °C
Reaction time: 0.25 h

Procedure:
This compound was prepared according to the general procedure 3 as described hereinabove. 2-Chloro-4-(2-methyl-1-p-tolyl-1H-imidazol-4-ylethynyl)-pyridine (220 mg, 0.71 mmol) was dissolved in 5 mL THF and cooled to −75° C. Lithiumdiisopropylamide (0.61 ml, 1.22 mmol) was added, and the mixture stirred for 15 min at −75° C. Iodomethane (0.08 ml, 1.14 mmol) was added and stirring was continued at −75° C. for 2 hrs. The reaction mixture was quenched with sat. NaHCO3− solution and extracted with water and ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethylacetate 90:10→0:100 gradient) and by recrystallization from dichloromethane and diisopropylether. The desired compound was obtained as a light yellow solid (30 mg, 13%), MS: m/e=322.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].[CH2:14](Br)[CH:15]=[CH2:16]>O1CCCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:16][CH:15]=[CH2:14])[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: C=CCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCC(C#N)c1ccc(Cl)c(Cl)c1
Temperature: -20 °C
Yield: 31.5 %

Procedure:
A solution of 3,4-dichlorophenyl acetonitrile (200 g, 1.075 mol) in dry tetrahydrofuran (400 ml) was added dropwise, over one hour to sodium hydride 60% w/w dispersion in oil (32.26 g, 1.075 mole) in dry tetrahydrofuran (400 ml) at 0° C. under nitrogen. After a further thirty minutes the solution was cooled to -20° C. and a solution of allyl bromide (92.9 ml, 1 mol equivalent) in tetrahydrofuran (200 ml) was added, the mixture allowed to warm to room temperature and stirred for fourteen hours. Saturated brine (600 ml) was added and the mixture extracted with dichloromethane (2×600 ml). The organic layers were combined, dried over magnesium sulphate, and the solvent removed under reduced pressure. The residue was chromatographed on silica gel, eluting with a solvent gradient of ethyl acetate/hexane to provide the title compound as an oil (71.3 g). TLC Rf=0.71 (silica, diethylether:hexane, 1:1 by volume). 1H-NMR (CDCl3): δ=2.6-2.75(m,2H), 3.85(t,1H), 5.1-5.25(m,2H), 5.7-5.9(m,1H), 7.2-7.25(m,1H), 7.5-7.55(m,2H) ppm.