Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:18])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([OH:15])[C:7]=1[CH:16]=[O:17])[CH:2]=[CH2:3].[CH3:19][Si:20]([CH3:28])([C:22]([CH3:27])([CH3:26])[CH:23]([CH3:25])[CH3:24])Cl.C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:4][C:5](=[O:18])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([O:15][Si:20]([CH3:28])([CH3:19])[C:22]([CH3:27])([CH3:26])[CH:23]([CH3:25])[CH3:24])[C:7]=1[CH:16]=[O:17])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1c(C)c(OC)cc(O)c1C=O
Reactant: CC(C)C(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1C=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.4 %

Procedure:
To a solution of 75.1 g of 2-formyl-3-hydroxy-5-methoxy-6-methylbenzoic acid allyl ester in 0.6 l of N,N-dimethylformamide were added 81.0 g of dimethyl-(1,1,2-trimethyl-propyl)-chlorosilane and 45.5 g of triethylamine. The mixture was stirred for 4 h at room temperature and then evaporated in vacuo. The residue was taken up in 2 l of ethyl acetate, and the mixture was successively washed with 1N hydrochloric acid and with brine, and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was crystallized from hexane to give 108.8 g of 2-formyl-5-methoxy-6-methyl-3-[dimethyl-(1,1,2-trimethyl-propyl)silanyloxy]-benzoic acid allyl ester as white crystals of m.p. 81°-82° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH2:32][N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[CH2:43][C:44](Cl)=[O:45]>>[N:33]1([CH2:32][CH2:31][O:30][C:26]2[CH:25]=[C:24]([NH:23][C:19]3[N:18]=[C:17]([C:16]4[C:8]([C:4]5[CH:3]=[C:2]([NH:1][C:44](=[O:45])[CH2:43][C:39]6[S:38][CH:42]=[CH:41][CH:40]=6)[CH:7]=[CH:6][CH:5]=5)=[N:9][N:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=45)[CH:22]=[CH:21][N:20]=3)[CH:29]=[CH:28][CH:27]=2)[CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: O=C(Cl)Cc1cccs1
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCN4CCCC4)c3)n2)c1
Product: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCN4CCCC4)c3)n2)c1
Yield: 44 %

Procedure:
The title compound was prepared from 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-{[2-(1-pyrrolidinyl)ethyl]oxy}phenyl)-2-pyrimidinamine and 2-thiopheneacetyl chloride using acylation conditions described in Example 1, Step F, and purification via column chromatography using a 0-20% gradient of EtOAc/MeOH w/NH4OH to generate the product in 44% yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.6 (s, 4H) 2.7 (s, 3H) 3.8 (s, 2H) 4.0 (t, J=6.0 Hz, 2H) 6.5 (m, 2H) 6.9 (m, 2H) 7.1 (m, 3H) 7.2 (m, 2H) 7.4 (m, 2H) 7.4 (m, 1H) 7.5 (t, J=2.3 Hz, 1H) 7.7 (m, 1H) 7.9 (d, J=1.8 Hz, 1H) 8.2 (d, J=5.3 Hz, 1H) 8.5 (s, 1H) 8.8 (d, J=7.0 Hz, 1H) 9.5 (s, 1H) 10.3 (s, 1H). ES-LC/MS m/z 616 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.O.[NH2:12][NH2:13]>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([NH:12][NH2:13])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: CSc1nc(F)cc(F)n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CSc1nc(F)cc(NN)n1
Yield: 94.7 %

Procedure:
A solution of 15.8 g (0.097 mol) of 4,6-di-fluoro-2-methylthiopyrimidine in 50 ml of ethanol was added slowly with stirring to a solution of 11.6 ml (12.0 g, 0.214 mol) of hydrazine monohydrate in 100 ml of ethanol, keeping the temperature below 0° C. by external cooling. The mixture was allowed to react for an additional 30 min and the volatiles were then removed by evaporation under reduced pressure. The residue was diluted with ethyl acetate and the resulting solution extracted with water, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 16.0 g of the title compound as a white powder melting at 153°-154° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C@H:12]3[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14][CH2:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl.N1C=CC=CC=1.ClCCl>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C@H:12]3[CH2:13][CH2:14][C@H:15]([NH:18][C:19](=[O:21])[CH3:20])[CH2:16][CH2:17]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: N[C@H]1CC[C@H](Oc2ccc3cnccc3c2)CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N[C@H]1CC[C@H](Oc2ccc3cnccc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8.4 g (34.7 mmol) of 4-(isoquinolin-6-yloxy)-cyclohexylamine (15) were dissolved in 100 ml of dichloromethane/pyridine (4:1). At 0° C. a solution of 3.27 g (41.6 mmol) of acetyl chloride in 10 ml of dichloromethane was added and the reaction mixture was stirred at room temperature. After 2 h, the solution was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. After washing twice with 2 N HCl, the product was transferred to the aqueous phase. The HCl-layers were adjusted to alkaline pH by addition of solid NaOH and extracted three times with dichloromethane. Drying the organic layers with magnesium sulfate and evaporation of the solvent gave 7.69 g of the crude product. After silica gel chromatography 4.48 g of the title compound were isolated. Rt=0.87 min (Method A). Detected mass: 285.2 (M+H+).
Reaction SMILES: N(C1C=CC2OCCOC=2C=1)=C=S.[C:14]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][NH2:24])[CH2:19][CH2:18]1)(=[O:16])[CH3:15].CS[C:27]1[S:28][C:29]2[C:34]([N:35]=1)=[CH:33][CH:32]=[CH:31][N:30]=2>>[C:14]([N:17]1[CH2:18][CH2:19][CH:20]([CH2:23][NH:24][C:27]2[S:28][C:29]3[C:34]([N:35]=2)=[CH:33][CH:32]=[CH:31][N:30]=3)[CH2:21][CH2:22]1)(=[O:16])[CH3:15]
Reactant: CSc1nc2cccnc2s1
Reactant: CC(=O)N1CCC(CN)CC1
Agent: S=C=Nc1ccc2c(c1)OCCO2
Product: CC(=O)N1CCC(CNc2nc3cccnc3s2)CC1
Temperature: 140 °C
Yield: 93 %

Procedure:
A mixture of 11 parts of 1-acetyl-4-piperidinemethanamine and 9 parts of 2-(methylthio)thiazolo[5,4-b]pyridine was stirred and heated for 20 hours at 140° C. The whole was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 13.5 parts (93%) of 1-acetyl-N-(thiazolo[5,4-b]-pyridin-2-yl)-4-piperidinemethanamine as a residue (intermediate 51).
Reaction SMILES: [C:1]([O:4][CH:5]1[O:17][C@@H:16]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].O=C[C@H]([C@H]([C@H](CO)O)O)O>>[C:1]([O:4][C@H:5]1[O:17][C@@H:16]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H]1OC(OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C[C@@H](O)[C@@H](O)[C@@H](O)CO
Product: CC(=O)OC[C@@H]1O[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
A 100-ml four-necked flask was subjected to nitrogen substitution. 11.32 g (corresponding to 40 mmol of L-ribose) of the 2,3,5-tri-O-acetyl-1-O-methyl-L-ribofuranose obtained in Example B1(1) and 20 ml of diisopropyl ether were added to the flask. The flask was maintained at a temperature of 0±5° C. in an ice bath, and 8.17 g (2.0 equivalents) of acetic anhydride was added thereto. While stirring in an ice bath, 3.2 g (0.8 equivalents) of concentrated sulfuric acid was added dropwise thereto at an internal temperature of 0±5° C. The mixture was stirred in an ice bath for 3.5 hours, and the reaction product was then maintained at 5° C. or lower in a refrigerator overnight. While stirring in an ice bath, 7.87 g of sodium acetate was added to the reaction product, and the obtained mixture was then stirred in an ice bath for 30 minutes. 120 ml of ethyl acetate and a saturated sodium bicarbonate aqueous solution were added to the reaction solution at room temperature until the aqueous layer was neutralized, followed by liquid separation. The aqueous layer was extracted with 120 ml of ethyl acetate, and organic layers were gathered. The gathered layers were washed with 120 ml of a saturated sodium bicarbonate aqueous solution and then with 120 ml of a saturated sodium chloride aqueous solution 2 times. The organic layer was dried over anhydrous sodium sulfate, and the drying agent was then removed by filtration, concentrated under reduced pressure. Thus, 16.10 g of crude 1,2,3,5-tetra-O-acetyl-L-ribofuranose was obtained in the form of yellow oil. The obtained compound was analyzed by HPLC. As a result, it was found that the crude product contained 9.76 g of 1,2,3,5-tetra-O-acetyl-L-ribofuranose, that the ratio of α-/β-anomers was 7/93, and that the total reaction yield of the β-anomer from L-ribose was 72%.
Reaction SMILES: O[CH2:2][C:3]1[CH2:4][CH2:5][O:6][C:7]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[CH:10][C:8]=2[CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:41].C(=O)(O)[O-].[Na+]>ClCCl>[Br:41][CH2:2][C:3]1[CH2:4][CH2:5][O:6][C:7]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[CH:10][C:8]=2[CH:9]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(CO)CCO3)cc1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(CBr)CCO3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
Into a solution of 4-hydroxymethyl-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine (320 mg) in dichloromethane (10 ml) were added triphenylphosphine (378 mg) and carbon tetrabromide (597 mg), and the resulting mixture was stirred at room temperature for 2 hours. Thereto were additionally added triphenylphosphine (157 mg) and carbon tetrabromide (249 mg), and the resulting mixture was stirred further for 30 minutes, was then mixed with an aqueous solution of sodium bicarbonate under ice cooling and was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, was dried (anhydrous magnesium sulfate) and was concentrated under reduced pressure. The residue was subjected to purification using silica gel column chromatography (ethyl acetate/hexane=1/9) and further to washing with diethyl ether/hexane to obtain 4-bromomethyl-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine (286 mg) as a white powder.
Reaction SMILES: [OH:1][C:2]([CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)([CH3:4])[CH3:3].[H-].[Na+].C1COCC1.[F:18][C:19]([F:37])([F:36])[CH2:20][NH:21][C:22](=[O:35])[C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[C:26]([NH:32][CH3:33])=[CH:25][C:24]=1F>CCOC(C)=O>[F:18][C:19]([F:36])([F:37])[CH2:20][NH:21][C:22](=[O:35])[C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[C:26]([NH:32][CH3:33])=[CH:25][C:24]=1[N:8]1[CH2:9][CH2:10][CH:5]([C:2]([OH:1])([CH3:4])[CH3:3])[CH2:6][CH2:7]1
Reactant: CC(C)(O)C1CCNCC1
Reactant: CNc1cc(F)c(C(=O)NCC(F)(F)F)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNc1cc(N2CCC(C(C)(C)O)CC2)c(C(=O)NCC(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
A mixture of 4-(1-hydroxy-1-methyl-ethyl)-piperidine (24 mg, 0.17 mmol), NaH-suspension (50% in mineral oil, 8 mg, ˜0.17 mmol) and THF (1 mL) is stirred for 10 min. Then, N-(2,2,2-trifluoro-ethyl)-2-fluoro-4-methylamino-5-nitro-benzoic acid amide is added and it is stirred for 1.5 h. The mixture is diluted with EtOAc, washed with water, concentrated, dried and directly used in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.Br[CH2:57][CH2:58][OH:59]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:27][CH2:28][N:29]([CH2:57][CH2:58][OH:59])[CH2:30][CH2:31]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[CH:12]=2)[CH:8]=[N:7]1
Reactant: OCCBr
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(CCO)CC5)cc4)cnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a stirred solution of 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (product of step 1 of example 124) (75 mg, 0.123 mmol), potassium carbonate (24 mg, 0.185 mmol) and DMF (5 ml) was added 2-bromoethanol (24 mg, 0.185 mmol) and the mixture stirred at RT for overnight. Then water was added, this was then extracted into 10% methanol in DCM, organic portion was dried over sodium sulfate and concentrated to give 60 mg (75% yield) of the titled compound. MS: m/z=651.2 (M+1).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[F:10][C:11]([F:19])([F:18])[S:12][C:13]([CH3:17])([CH3:16])[CH:14]=O>CO.O>[F:10][C:11]([F:19])([F:18])[S:12][C:13]([CH3:17])([CH3:16])[CH:14]=[N:2][OH:3]
Reactant: NO
Reactant: CC(C)(C=O)SC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C=NO)SC(F)(F)F

Procedure:
A mixture of hydroxylamine hydrochloride (0.09 mole) in methanol (230 ml), sodium carbonate (4.8 g, 0.045 mole) in 50 ml of water and 2-trifluoromethylthio-2-methylpropionaldehyde (14.85 g, 0.086 mole) from Step 1 was stirred at room temperature overnight. The reaction mixture was poured into water, the oxime was extracted into diethyl ether, the combined ether extracts were washed with water and then dried. The drying agent was removed by filtration and the filtrate was distilled to provide 2-trifluoromethylthio-2-methylpropionaldehyde oxime, b.p. 80°C/18 mm. The structure of this product was confirmed by elemental and spectroscopic analyses.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[C:7]1(=[O:13])[O:12][C:10](=[O:11])[CH2:9][CH2:8]1>N1C=CC=CC=1>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][C:7](=[O:13])[CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CN(C)CCO
Reactant: O=C1CCC(=O)O1
Solvent: c1ccncc1
Product: CN(C)CCOC(=O)CCC(=O)O

Procedure:
The 2-dimethylamino ethanol (10 g, 0.11 mol) was dissolved in pyridine (100 mL) followed by the addition of succinic anhydride (16 g, 0.16 mol). The mixture was stirred at room temperature for 18 h before the pyridine was removed under vacuum at 40 C. The remaining solid was recrystallized from MeOH/Ether. The characterization data were consistent with the chemical structure and formula.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[F:13][CH:14]1[C:19](=O)[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1.N>C(O)(=O)C.OP(O)(O)=O>[F:13][CH:14]1[C:19]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][CH:8]=2)=[CH:18][CH2:17][NH:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Agent: N
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2[nH]cc(C3=CCNCC3F)c2c1
Reaction time: 16 h
Yield: 46.6 %

Procedure:
A solution of 5-nitroindole (38) (1.0 g, 6.167 mmol) in glacial acetic acid (10 mL) at 90° C. was treated with compound 130 (1.33 g, 6.167 mmol) in glacial AcOH (5 mL), 1 M H3PO4 in glacial AcOH (5 mL) and the resulting solution was stirred at same temperature for 16 h. The reaction was brought to room temperature, poured into 15% cold aqueous ammonia solution (100 mL) and product was extracted into ethyl acetate (2 50 mL). The combined ethyl acetate layer was washed with brine (25 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 1:99 to 5:95) to obtain compound 131 (0.75 g, 47%) as a yellow solid. mp 205-207° C.; 1H NMR (DMSO-d6) δ 2.35 (brs, 1H), 2.86-3.06 (m, 1H), 3.19-3.26 (m, 1H), 3.35-3.58 (m, 2H), 5.28 (d, 1H, J=49.5 Hz), 6.53-6.56 (m, 1H), 7.58 (d, 1H, J=8.7 Hz), 7.74 (s, 1H), 8.02 (dd, 1H, J=2.4, 9.0 Hz), 8.68 (d, 1H, J=2.4 Hz), 11.94 (s, 1H); ESI-MS m/z (%): 262 (MH+, 100), 233 (50).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]#[C:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2OC(=O)[S:22][N:21]=2)=[CH:16][CH:15]=1)[CH3:13].ClC1C=CC=C(Cl)C=1>>[CH2:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:3]([C:2]([F:10])([F:11])[F:1])[S:22][N:21]=2)=[CH:16][CH:15]=1)[CH3:13]
Reactant: CCOC(=O)C#CC(F)(F)F
Reactant: CCc1ccc(-c2nsc(=O)o2)cc1
Solvent: Clc1cccc(Cl)c1
Product: CCOC(=O)c1c(-c2ccc(CC)cc2)nsc1C(F)(F)F
Temperature: 150 °C
Reaction time: 16 h

Procedure:
Into a 50-mL sealed tube, was placed ethyl 4,4,4-trifluorobut-2-ynoate (1.25 g, 7.53 mmol, 1.56 equiv), 5-(4-ethylphenyl)-2H-1,3,4-oxathiazol-2-one (1.0 g, 4.83 mmol, 1.00 equiv), 1,3-dichlorobenzene (8 mL). The resulting solution was stirred for 16 h at 150° C. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with petroleum ether (100). This resulted in 1.068 g (67%) of ethyl 3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazole-4-carboxylate as yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][N:3]=1.[C-:10]#[N:11].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:10]#[N:11])=[CH:4][N:3]=1
Reactant: BrCc1ccc(Br)nc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 29.2 %

Procedure:
The 476 g of crude 2-bromo-5-bromomethylpyridine from step 4 was dissolved in 4000 mL of dimethylformamide (DMF)/water (7:1) and treated with 168 g (2.58 mol) of potassium cyanide. The reaction was allowed to stir at ambient temperature for 72 h, concentrated in vacuo, and partitioned between ethyl acetate and water; the organic layer was washed with water, washed with brine, dried (MgSO4), and reconcentrated in vacuo to provide the crude nitrile. Purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (25:75) gave 109 g (32% from 2-bromo-5-picoline) of 2-bromo-5-cyanomethylpyridine as a yellowish orange solid: mp 55.5°-57.5° C.; NMR (CDCl3) δ 3.74 (s, 2H), 7.54 (d, J=8 Hz, 1H), 7.59 (dd, J=8 and 2 HZ, 1H), 8.35 (d, J=2 Hz, 1H); MS (FAB) m/e (rel intensity) 199 (85), 197 (100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.Cl[CH2:13][C:14](=O)[CH2:15][O:16][C:17](=[O:19])[CH3:18].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:13]=[C:14]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[N:11]=2)=[N:6][CH:7]=1
Reactant: NC(=S)Nc1ccc(Br)cn1
Reactant: CC(=O)OCC(=O)CCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1csc(Nc2ccc(Br)cn2)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
(5-Bromo-pyridine-2-yl)-thiourea (1 mmol) is dissolved in DMF (2 ml) and acetic acid 3-chloro-2-oxo-propyl ester (1 eq.) is added and stirred 2 h at 70° C. After cooling to RT the reaction solution is poured into water and the resulting precipitate is filtered, washed with water and dried 16 h in vacuo at 40° C. “A5” is obtained as colourless powder in a yield of 82%; mp. 200.9-201.6° C.; HPLC (method C): 1.80 min; LC-MS (method A): 1.800 min, 327.95 (M+H+); 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] 11.516 (s, 1H), 8.391 (d, 1H, J=2.4 Hz), 7.892 (dd, 1H, J=8.9 Hz, J=2.4 Hz), 7.020 (d, 1H, J=8.9 Hz), 6.998 (s, 1H), 5.015 (s, 2H), 2.062 (s, 3H).
Reaction SMILES: [OH:1][CH:2]1[O:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.N1C(C)=CC=CC=1C.[Si:17](OS(C(F)(F)F)(=O)=O)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C(Cl)Cl>[Si:17]([O:1][CH:2]1[O:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: O=C1C=CC(O)OC1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OC1C=CC(=O)CO1
Temperature: -78 °C
Yield: 54.9 %

Procedure:
6-Hydroxy-2H-pyran-3(6H)-one (9 g, 79 mmol) was dissolved in DCM (250 mL), placed under a nitrogen atmosphere, and cooled to −78° C. 2,6-Lutidine (13.78 mL, 118 mmol) was then added in one portion, followed by slow addition of t-butyldimethylsilyltrifluoromethanesulfonate (21.74 mL, 95 mmol). The reaction was allowed to slowly warm to 0° C. over 4 h. The reaction was quenched by addition of ˜20 mL of water. The solution turned pale yellow upon quenching. After transferring to a separatory funnel, the organic phase was washed successively with 10% citric acid and brine. The organic layer was then dried over sodium sulfate, filtered and condensed to give a yellow oil. The crude material was purified on a 340G SNAP Biotage column (0-20% ethyl acetate in hexane) to give 6-(tert-butyldimethylsilyloxy)-2H-pyran-3(6H)-one (9.90 g, 43.4 mmol, 55.0% yield) as a yellow oil; 1H NMR (400 MHz, CDCl3) δ ppm 6.87 (dd, J=10.54, 3.12 Hz, 1H), 6.08 (d. J=10.15 Hz, 1H), 5.53 (d, J=3.12 Hz, 1H), 4.51 (d, J=16.79 Hz, 1H), 4.08 (d, J=16.79 Hz, 1H), 0.92 (s, 9H), 0.17 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[CH3:21])=[CH:18]/[CH2:19][OH:20])=[CH:13][CH:12]=1.[CH2:22]([O:24][C@@H:25]([CH2:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:23]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[CH:12]=[CH:13][C:14](/[C:17](/[CH3:21])=[CH:18]/[CH2:19][O:20][C:35]2[CH:34]=[CH:33][C:32]([CH2:31][C@H:25]([O:24][CH2:22][CH3:23])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:37][CH:36]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(OC)c(-c2ccc(/C(C)=C/CO)cc2)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(OC)ccc3OC)cc2)cc1)OCC
Yield: 60.6 %

Procedure:
The title compound (0.765 g, 61%) was prepared as a colourless gum from (E)-3-(2′,5′-dimethoxy-biphenyl-4-yl)-but-2-en-1-ol (0.711 g, 2.50 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.655 g, 2.75 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH:11]1([C:14]#[CH:15])[CH2:13][CH2:12]1>C(N(CC)CC)C.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:11]1([C:14]#[C:15][C:2]2[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=2)[C:7]#[N:8])[CH2:13][CH2:12]1
Reactant: C#CC1CC1
Reactant: N#Cc1cc(Br)ccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cc(C#CC2CC2)ccc1F
Temperature: 60 °C

Procedure:
5-Bromo-2-fluorobenzonitrile (3.06 g, 15.3 mmol), dichlorobis(triphenylphosphine)palladium(II) (478 mg, 0.681 mmol), and copper(I) iodide (165 mg, 0.866 mmol) were combined in triethylamine (15 mL) under an inert atmosphere of nitrogen. Cyclopropylacetylene (1.8 mL) was added, and the mixture was heated to 60° C. until it turned to a black solid. The mixture was diluted with methylene chloride and washed with 1 N hydrochloric acid. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 5-40% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 319.0 (M+H)+.