Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[N:10][C:9]([C:12]([OH:14])=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[N:17]1[CH:18]=[CH:19][N:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[CH2:30][CH2:29][C@@H:28]([NH2:31])[CH2:27]3)[C:21]=12.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:17]1[CH:18]=[CH:19][N:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[CH2:30][CH2:29][C@@H:28]([NH:31][C:12]([C:9]4[N:10]=[CH:11][N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:8]=4)=[O:14])[CH2:27]3)[C:21]=12
Reactant: N[C@@H]1CCN(c2nccn3ccnc23)C1
Reactant: O=C(O)c1ncn(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CCN(c2nccn3ccnc23)C1)c1ncn(-c2ccccc2)n1
Reaction time: 0.05 h
Yield: 39.7 %

Procedure:
1-Phenyl-1,2,4-triazole-3-carboxylic acid (1.2 g, 6.3 mmol), (3R)-1-imidazo[1,2-a]pyrazin-8-ylpyrrolidin-3-amine dihydrochloride (2.0 g, 7.4 mmol), and diisopropylethylamine (13 mL, 75 mmol) were combined together in 50 mL DMF. To this mixture was added HATU (2.5 g, 6.6 mmol). After stirring 3 minutes, LCMS of an aliquot indicated the reaction was complete. DIPEA and most of the DMF were removed under reduced pressure. The residue was diluted in 400 mL EtOAc and washed with 50 mL saturated NaH2PO4. It was determined that a large amount of the desired product was present in the organic phase, therefore it was extracted with 400 mL 10 vol % i-PrOH/CHCl3. The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (SiO2, 2-5% MeOH/dichloromethane) to provide 936 mg of the desired product (39% yield). 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1 H), 7.74 (td, J=1.1, 7.5 Hz, 2 H), 7.56-7.48 (m, 4 H), 7.47-7.40 (m, 2 H), 7.37 (d, J=8.2 Hz, 1 H), 7.33 (d, J=4.3 Hz, 1 H), 5.00-4.80 (m, 1H), 4.50-4.35 (br, 1 H), 4.30-4.15 (br, 3 H), 3.45-3.30 (m, 1H), 2.90-2.75 (m, 1 H), 2.50-2.38 (m, 1 H), 2.25-2.15 (m, 1 H). MS: (ES) 375.2 (M+H+).
Reaction SMILES: CC1(C)OC2C3C(CCC)=CC(=O)OC=3C=C(O)C=2C=C1.[CH3:22][CH2:23][CH2:24][C:25]1[C:31]2[C:32]3[O:37][C:36]([CH3:39])([CH3:38])[CH:35]=[CH:34][C:33]=3[C:40]3[O:45][CH:44](C)[CH:43](C)[CH:42]([OH:48])[C:41]=3[C:30]=2[O:29][C:27](=[O:28])[CH:26]=1>>[CH3:39][C:36]1([CH3:38])[O:37][C:32]2[C:31]3[C:25]([CH2:24][CH2:23][CH3:22])=[CH:26][C:27](=[O:28])[O:29][C:30]=3[C:41]([C:42](=[O:48])[CH2:43][CH3:44])=[C:40]([OH:45])[C:33]=2[CH:34]=[CH:35]1
Reactant: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)OC(C)C(C)C3O
Agent: CCCc1cc(=O)oc2cc(O)c3c(c12)OC(C)(C)C=C3
Product: CCCc1cc(=O)oc2c(C(=O)CC)c(O)c3c(c12)OC(C)(C)C=C3

Procedure:
The present invention relates to methods for preparing 2,2-dimethyl-5-acyloxy -10-propyl-2H,8H-benzo[1,2-b:3,4-b′]dipyran-8-one (5) and 2,2-dimethyl-5-hydroxy-10 -propyl-2H,8H-benzo[1,2-b:3,4-b′]dipyran-8-one (6) and their use as intermediates for the synthesis of antiviral calanolide compounds. For example, Fries rearrangement on compound 5 or Friedel-Crafts reaction on 6, yields intermediate 2,2-dimethyl-5-hydroxy -6-propionyl-10-propyl-2H,8H-benzo[1,2-b:3,4-b′]dipyran-8-one (4), which, in turn, can be converted to (+)-calanolide A and (−)-calanolide B. The coupling of compound 6 with the appropriate chiral molecule under Mitsunobu or nucleophilic displacement leads to the asymmetric synthesis of antiviral calanolide compounds.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=1)([O-:34])=[O:33].[CH2:44]([O:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]2[CH2:63][CH2:62][N:61]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:60][CH:59]2O)=[CH:54][CH:53]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>O1CCCC1.O>[CH2:44]([O:51][C:52]1[CH:57]=[CH:56][C:55]([C@H:58]2[CH2:63][CH2:62][N:61]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:60][C@H:59]2[O:40][C:39](=[O:41])[C:38]2[CH:37]=[CH:36][C:35]([N+:32]([O-:34])=[O:33])=[CH:43][CH:42]=2)=[CH:54][CH:53]=1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2)C(O)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCc3ccccc3)cc2)[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.17 h
Yield: 53.9 %

Procedure:
A mixture of diethylazodicarboxylate (12.9 mL, 81 mmol of 40% toluene solution), triphenyl phosphine (22 mL, 83 mmol), 4-nitrobenzoic acid (6.97 g, 42 mmol) and 200 mL tetrahydrofuran was stirred for 10 min under an Ar atmosphere. Then was added a solution of tert-butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (Example 56, step D, 8 g, 20.9 mmol) in tetrahydrofuran (100 mL) and the resulting mixture was stirred at rt overnight. It was then diluted with water and extracted twice with 50 mL ethyl acetate. The combined organic fractions were dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified via silica gel chromatography (750 μm column, eluting with 0-50% ethyl acetate/hexane) to yield 6 gms (±)-rel-(3S,4R)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-(4-nitrobenzoyloxyl)piperidine-1-carboxylate. LCMS (Method F) RT 2.68 min (87% AP), m/z 476.8 (MH+−t-butyl).
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>ClCCl>[C:1]1([N:7]([CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[S:22]([CH3:21])(=[O:24])=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(NCc2cccnc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1cccnc1)c1ccccc1

Procedure:
A 3.7 g. portion of 3-(phenylaminomethyl)pyridine was dissolved in 20 ml. of dichloromethane, and to it was added 4.1 g. of potassium carbonate and 2.5 ml. of methanesulfonyl chloride. The mixture was stirred under reflux overnight, and was then diluted with 20 ml. of aqueous sodium bicarbonate and 20 ml. of dichloromethane. The organic phase was separated, washed with 20 ml. of water, dried over magnesium sulfate and evaporated under vacuum. The residue was triturated with diethyl ether and dried to give 4.9 g. of impure product. It was dissolved in 10 ml. of dichloromethane and 20 ml. of ethyl acetate and filtered. The filtrate was evaporated under vacuum, and the residue was triturated with petroleum ether, filtered and dried to obtain 4.4 g. of the desired product, m.p. 104°-105°.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([CH2:15][NH2:16])[OH:14].[BH4-].[Na+]>>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:16][CH2:15][CH2:13][OH:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: NCCO
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)c1ccc(CNCCO)cc1
Yield: 93 %

Procedure:
The title compound was synthesized in analogy to example S3-C using 4-tert-butylbenzaldehyde (1000 mg, 6.17 mmol), ethanolamine (371 μl, 6.17 mmol) and sodium borohydride (350 mg, 9.25 mmol). The desired product (1190 mg, 93%) was isolated without further purification as a colorless oil. MS (ISP) 208.3 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:36]=[CH:35][C:31]4[O:32][CH2:33][O:34][C:30]=4[CH:29]=3)[CH:25]=[C:24]([C:37](=[O:39])[CH3:38])[CH:23]=2)[C:10]=1[CH2:40][CH2:41][C:42]([O:44]CC)=[O:43])C.[OH-].[Na+]>>[C:37]([C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([C:28]2[CH:36]=[CH:35][C:31]3[O:32][CH2:33][O:34][C:30]=3[CH:29]=2)[CH:25]=1)[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]1[C:10]([CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:47])=[O:3])(=[O:39])[CH3:38]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(C)=O)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3c(c2)OCO3)c1
Yield: 90.3 %

Procedure:
A similar procedure as described in Example 43, step 5 was used, starting from 4-[3-[6-(3-acetyl-5-benzo[1,3]-dioxol-5-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (230 mg, 0.36 mmol) and 1.0 N aqueous sodium hydroxide (8 mL) to afford 4-[3-[6-(3-acetyl-5-benzo[1,3]dioxol-5-yl-phenoxy)-hexyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (192 mg, 92%) as a white solid: ES(+)-HRMS m/e calcd for C34H38O9 (M+Na)+ 613.2408. found 613.2407.
Reaction SMILES: [CH3:1][N:2]1[CH2:28][CH2:27][C:5]2[N:6]([CH2:14][CH:15](OS(C)(=O)=O)[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:29]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30]1>O>[CH:29]1([NH:34][CH:15]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:14][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:28][CH2:27][C:5]2=3)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2ccncc2)CCN(C)C1
Reactant: NC1CCCC1
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(NC2CCCC2)c2ccncc2)CCN(C)C1
Temperature: 100 °C

Procedure:
Methanesulfonic acid 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethylester (240 mg, 0.60 mmol) was dissolved in 10 mL of 70% cyclopentylamine solution in water and heated at 100° C. for 18 h. The reaction mixture was cooled to RT and concentrated to obtain the crude product, which was purified by reverse phase chromatography to obtain 11 mg of cyclopentyl-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethyl]-amine. 1H NMR (CDCl3, freebase): δ (ppm): 8.51 (d, 2H), 7.17 (m, 4H), 7.003 (d, 1H), 4.16 (m, 2H), 4.05 (dd, 1H), 3.79 (dd, 2H), 2.9 (m, 1H), 2.83 (m, 2H), 2.55 (s, 3H), 2.44 (s, 3H), 2.39 (m, 1H), 1.99 (s, 2H), 1.7 (m, 2H), 1.5 (m, 2H), 1.4 (m, 1H), 1.9 (m, 2H). Chiral HPLC separates the racemate into enantiomers II-9a-b.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[C:25]([C:27](=[O:38])[NH:28][C:29]5([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=6)[CH2:31][CH2:30]5)[CH:24]=[CH:23][C:22]=4[O:39]C)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.[B-](Br)(Br)(Br)[S+](C)C>ClCCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[C:25]([C:27](=[O:38])[NH:28][C:29]5([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=6)[CH2:30][CH2:31]5)[CH:24]=[CH:23][C:22]=4[OH:39])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccccn5)CC4)ccc3OC)cc12
Agent: C[S+](C)[B-](Br)(Br)Br
Solvent: ClCCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccccn5)CC4)ccc3O)cc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To a 100 mL round-bottomed flask equipped with a reflux condenser was added 2-(4-fluorophenyl)-5-(2-methoxy-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide (400 mg, 0.747 mmol), DCE (42 mL) and boron tribromide-methyl sulfide complex (1868 mg, 5.97 mmol). The solution was placed under nitrogen and stirred overnight at 90° C. The reaction mixture was cooled to room temperature, quenched with methanol and evaporated to near dryness. The mixture was taken up in 10 mL of methanol and purified using a Shimadzu preparative HPLC employing methanol/water/0.1% trifluoroacetic acid where solvent A was 10% methanol/90% water/0.1% trifluoroacetic acid and solvent B was 10% water/90% methanol/0.1% trifluoroacetic acid with a Phenomenex-Luna 10 μm C18 30×100 mm column at a gradient of 40-100% B and a flow rate of 40 mL/min. over 10 minutes with a 5 minute hold. The solvent was evaporated giving 234 mgs (60% yield) of 2-(4-fluorophenyl)-5-(2-hydroxy-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide as a white solid. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Sunfire 5 μm C18, 4.6×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade methanol/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade methanol), in 4 minutes with a 1 minute hold at a rate of 4 mL/minute. 1H NMR (400 MHz, THF-d8) δ ppm 1.25-1.31 (m, 2H), 1.59-1.66 (m, 2H), 2.90 (d, J=4.52 Hz, 3H), 6.91 (d, J=8.53 Hz, 1H), 7.08 (dd, J=6.90, 5.40 Hz, 1H), 7.17-7.24 (m, 2H), 7.45-7.65 (m, 5H), 7.79 (dd, J=8.41, 2.13 Hz, 1H), 7.88 (d, J=1.25 Hz, 1H), 7.93 (d, J=2.01 Hz, 1H), 8.08-8.17 (m, 2H), 8.39-8.45 (m, 1H), 8.49 (br. s., 1H). LCMS Rt=1.495 min., m/z 522.33 (M+H), 94% purity.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C4CCCCO4)=[CH:13][CH:12]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.C1(S)C=CC=CC=1.Cl>ClCCl.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:25])=[O:26])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(OC4CCCCO4)cc3)c3cc(Br)cnc32)cc1
Agent: Cl
Agent: Sc1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(O)cc3)c3cc(Br)cnc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
575 g (1.09 mmol) of 5-bromo-3-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine was dissolved in 250 ml of dichloromethane. To this solution was added 2.50 g (3.53 mmol) of PS-thiophenol (Argonaut Technologies) and 1.5 ml of a 2 M solution of hydrochloric acid in ether. The mixture was stirred at room temperature for 3 hours before the resin was filtered off, washing extensively with dichloromethane. The filtrate was evaporated to afford 389 mg (877 μmol, 81%) of 4-[5-bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-phenol as a pale yellow solid. 1H-NMR (d6-DMSO) δ: 9.67 [1H] s, 8.52 [1H] d, 8.43 [1H] d, 8.11 [1H] s, 8.03 [2H] d, 7.58 [2H] d(m), 7.43 [2H] d, 6.89 [2H] d(m), 2.35 [3H] s. MS, m/z: 443 [MH+].
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH2:7])[CH3:6])[CH3:2].[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[CH:21]=O)[CH:14]=[CH:13][CH:12]=1>>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH:7][CH2:21][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:20]=1[N:11]=[CH:12][CH:13]=[CH:14]2)[CH3:6])[CH3:2]
Reactant: O=Cc1cccc2cccnc12
Reactant: CCOC(OCC)[C@H](C)N
Product: CCOC(OCC)[C@H](C)NCc1cccc2cccnc12
Yield: 90 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-6, (S)-1,1-diethoxypropan-2-amine (Compound XVIII-1) (442 mg, 3.00 mmol) was reacted with 8-quinolinecarboaldehyde (393 mg, 2.50 mmol) to obtain the title compound (649 mg, 90.7%).
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:9])[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.Cl.[N:11]1[CH:16]=[CH:15][C:14]([CH2:17]Cl)=[CH:13][CH:12]=1.C1CCCCC1>CN(C=O)C>[N:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:7]2[C:6](=[O:8])[CH2:5][CH2:4][C:3]2=[O:9])=[CH:13][CH:12]=1
Reactant: ClCc1ccncc1
Reactant: O=C1CCC(=O)N1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCCCC1
Product: O=C1CCC(=O)N1Cc1ccncc1
Reaction time: 48 h

Procedure:
A suspension of sodium hydride (17.6 g, 0.44 mol) in DMF (500 mL) was stirred with ice bath cooling as succinimide (29.73 g, 0.3 mol) was cautiously added. 4-Picolyl chloride hydrochloride (32.81 g, 0.2 mol) was then added cautiously with vigorous stirring. The mixture was stirred at room temperature for 1 day and then at 100° C. for 2 days. The mixture was then cooled and filtered. The filtrate was concentrated in vacuo to give a black oil. This dark crude product was stirred four times with boiling cyclohexane (150 mL), each time decanting the boiling cyclohexane from the dark residue. Upon cooling the cyclohexane extracts, the desired product crystallized as colorless needles (23.05 g, 60.9%) which were filtered and air dried.
Reaction SMILES: [OH:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18].[C:19](Cl)(=[O:21])[CH3:20].S([O-])(O)(=O)=O.[K+]>N1C=CC=CC=1>[C:19]([O:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18])(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: CC1=C2C[C@@]3(C)C(=CC[C@H](O)[C@@H]3C)C=C2OC1=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC=C2C=C3OC(=O)C(C)=C3C[C@]2(C)[C@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
The compound prepared in Example B1 (in the general formula (II), R3=H, R4=CH3, and R5=H) (50 mg, 0.20 mmol) was dissolved in pyridine (5 ml), acetyl chloride (80 mg, 0.70 mmol) was added thereto, and the mixture was stirred at 25° C. for one hr. A 15% aqueous potassium hydrogensulfate solution was added to the reaction solution, followed by extraction with methylene chloride. The organic layer was washed with saturated saline and dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1) to give the title compound (55 mg, 80%).
Reaction SMILES: [CH:1]1([OH:13])[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.[CH2:14]([O:16][CH2:17]OCC)[CH3:15].[Br-].[Li+].O.C1(C)C(S(O)(=O)=O)=CC=CC=1>CC(OC)(C)C>[CH2:14]([O:16][CH2:17][O:13][CH:1]1[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1)[CH3:15]
Reactant: CCOCOCC
Reactant: OC1CCC=CCCC=CCCC1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: COC(C)(C)C
Product: CCOCOC1CCC=CCCC=CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mechanically stirred mixture of 4,8-cyclododecadien-1-ol (5.4 g, 30 mmol; in the form of a 47% E,Z-, 48% Z,E- and 5% E,E isomer mixture), formaldehyde diethyl acetal (31.2 g, 294 mmol) and lithium bromide (0.52 g, 6 mmol) was added toluene sulphonic acid monohydrate (0.57 g, 3 mmol). The mixture was stirred at room temperature for 3 hours, then diluted with MTBE, washed with aqueous NaHCO3, water and brine. The solvent was evaporated and the product purified by liquid chromatography (silica gel 230 g; eluent=heptane/ethyl acetate 95/5).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])[CH3:7])[CH3:2].[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:17])[CH:5]=[C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])[CH2:7][Br:18])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C=C(C)Oc1ccc(F)cc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C=C(CBr)Oc1ccc(F)cc1F
Temperature: 105 °C
Yield: 81.1 %

Procedure:
A solution of 3-(2,4-difluoro-phenoxy)-but-2-enoic acid ethyl ester (1.35 g, 5.57 mmol) in carbon tetrachloride (30.9 mL) was treated with N-bromosuccinimide (1.09 g, 6.13 mmol) and benzoyl peroxide (108 mg, 0.44 mmol). The reaction was then heated to reflux (105° C.) for 5 h. At this time, the reaction was cooled to 25° C. and then was placed in the refrigerator overnight. At this time, the reaction was removed from the refrigerator. The resulting precipitate was removed by filtration and was rinsed with carbon tetrachloride (10 mL). The filtrate was concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 2% ethyl acetate/hexanes) afforded impure 4-bromo-3-(2,4-difluoro-phenoxy)-but-2-enoic acid ethyl ester (1.45 g, 81%) as a clear oil. The material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[CH2:11]O.P(Br)(Br)[Br:14].O>C(OCC)C>[Br:14][CH2:11][C:3]1[S:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[Cl:1]
Reactant: OCc1sc2ccccc2c1Cl
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: O
Product: Clc1c(CBr)sc2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (3-chloro-1-benzothiophen-2-yl)methanol (480 mg, 2.4 mmol) in anhydrous diethyl ether (8 mL) was added dropwise a solution of phosphorus tribromide (230 μL, 2.4 mmol) in anhydrous diethyl ether (2 mL) at 0° C. The mixture was stirred for 3 hours at room temperature. Water was added and extracted 3 times with ethyl acetate. The combined organic phase was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, 2-(bromomethyl)-3-chloro-1-benzothiophene was obtained as a pink pale solid (537 mg, 85% yield) and used for the next step without further purification; 1H NMR (400 MHz, CDCl3): δ 4.81 (s, 2H), 7.40-7.48 (m, 2H), 7.76-7.82 (m, 2H).
Reaction SMILES: [OH-].[Li+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[C:16]([CH3:18])[N:15]=[C:14]([NH:19][C:20]3[S:21][C:22]([C:25]([O:27]C)=[O:26])=[CH:23][N:24]=3)[CH:13]=2)[CH2:8][CH2:7]1.Cl>O>[OH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[C:16]([CH3:18])[N:15]=[C:14]([NH:19][C:20]3[S:21][C:22]([C:25]([OH:27])=[O:26])=[CH:23][N:24]=3)[CH:13]=2)[CH2:8][CH2:7]1
Reactant: COC(=O)c1cnc(Nc2cc(N3CCN(CCO)CC3)nc(C)n2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(Nc2ncc(C(=O)O)s2)cc(N2CCN(CCO)CC2)n1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
Lithium hydroxide (23.4 g, 0.35 mol) and water (265 mL) were mixed in four-necked flask and dissolved by stirring, and then methyl 2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-formate (Compound 6) (37.8 g, 0.1 mol) was added. After reaction at 50° C. for 3 h, cooled down to room temperature and pH value was adjusted to 6-6.5 by hydrochloric acid (6N). In cold storage grew the grain overnight. After suction filtration, the cake was dried to constant weight to give target Compound 7 (35.2 g, yield: 96.7%).
Reaction SMILES: I[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.[Cl:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([O:16][CH3:17])[C:10]=1[C@H:18]([C:20]1[C:28]2[C:23](=[N:24][CH:25]=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:27]=2)[NH:22][CH:21]=1)[CH3:19].C(=O)([O-])[O-].[K+].[K+].ClCCl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[Cl:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([O:16][CH3:17])[C:10]=1[C@H:18]([C:20]1[C:28]2[C:23](=[N:24][CH:25]=[C:26]([C:2]3[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=3)[CH:27]=2)[NH:22][CH:21]=1)[CH3:19]
Reactant: Cn1cncc1I
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cncn3C)cc12
Temperature: 100 °C

Procedure:
A solution of 5-iodo-1-methyl-1H-imidazole (0.0217 g, 0.104 mmol), 3-[(S)-1-(2-chloro-3-fluoro-6-methoxy-phenyl)-ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.030 g, 0.070 mmol), potassium carbonate (0.0289 g, 0.209 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, dichloromethane (2.84 mg, 0.00348 mmol) in previously degassed 4:1 dioxane:water (1.50 mL) was evacuated and charged with N2 (2×) and heated under microwave conditions [Biotage, 100° C., 30 min, high absorption]. The reaction mixture was partitioned between EtOAc and H2O and separated. The aqueous was back extracted with EtOAc (3×) and the combined organic fractions were dried over Na2SO4, filtered and concentrated in vacuo resulting in a crude brown oil. The crude was purified by chromatography on silica gel [ISCO Combiflash, 12 g cartridge, eluting with 100% DCM→8% MeOH in DCM]. This resulted in the title compound as an off-white solid. 1H NMR (400 MHz, CD3OD): δ=1.82 (d, J=7.3 Hz, 3H), 3.51 (s, 3H), 3.66 (br. s., 3H), 5.12 (q, J=7.1 Hz, 1H), 6.90 (dd, J=4.2, 9.0 Hz, 1H), 6.95 (s, 1H), 7.08 (dd, J=8.8, 8.8 Hz, 1H), 7.41 (d, J=1.0 Hz, 1H), 7.51 (s, 1H), 7.69 (s, 1H), 8.17 (d, J=2.0 Hz, 1H). MS (ES+): m/z 385.11, 387.07 (76/24) [MH+]. HPLC: tR=2.87 min (polar—5 min, ZQ3).