Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]3[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:7]=3[N:6]2[CH:23]=1.C(=O)([O-])[OH:25].[Na+]>O1CCOCC1.O>[Cl:22][C:19]1[CH:20]=[CH:21][C:7]2[N:6]3[CH:23]=[C:3]([CH2:2][OH:25])[N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1
Reactant: O=C([O-])O
Reactant: ClCc1cn2c(n1)CN=C(c1ccccn1)c1cc(Cl)ccc1-2
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: OCc1cn2c(n1)CN=C(c1ccccn1)c1cc(Cl)ccc1-2
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 87.2 %

Procedure:
A solution of 2.0 g of 2-chloromethyl-8-chloro-6-(2-pyridyl)-4H-imidazo [1,2-a][1,4]benzodiazepine in 50 ml of dioxan was treated with a solution of 0.62 g of sodium hydrogen carbonate in 18 ml of water and the mixture was stirred at 80° C. for 1.5 h. The mixture was evaporated in a vacuum. The residue was partitioned between dichloromethane and aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted twice with dichloromethane. The dichloromethane extracts were dried over magnesium sulphate and chromatographed over 100 g of silica gel. 1.7 g of the desired product were eluted with dichloromethane/ethanol mixtures containing 8 to 12% ethanol. After recrystallization from ethyl acetate/diethyl (sic) ether there were obtained 1.65 g of 8-chloro-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol of m.p. 206-207° C., which was converted into the hydrochloride (dec. above 300° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1.[N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][CH:12]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1ccc2ccccc2n1
Product: C(#Cc1ccccn1)CCc1ccc2ccccc2n1
Product: c1ccc2ncccc2c1
Reaction time: 0.25 h

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (87 mg, 0.55 mmol) and 2-but-3-ynyl-quinoline (100 mg, 0.55 mmol). Reaction time: 120° C. for 15 minutes. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 1:1) to yield 74 mg (0.29 mmol, 52%) of 2-(pyridin-2-yl)but-3-ynyl)quinoline as a yellow oil.
Reaction SMILES: C(C[C@@H:5]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[S:7][C@H:6]1[C:17]1[CH:22]=[CH:21][C:20]2[O:23][CH2:24][O:25][C:19]=2[CH:18]=1)(O)=O.[OH-:26].[Na+].C[CH2:29][OH:30]>>[C:29]([C@@H:5]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[S:7][C@H:6]1[C:17]1[CH:22]=[CH:21][C:20]2[O:23][CH2:24][O:25][C:19]=2[CH:18]=1)([OH:30])=[O:26]
Reactant: O=C(O)C[C@@H]1C(=O)Nc2ccccc2S[C@H]1c1ccc2c(c1)OCO2
Reactant: CCO
Reactant: [OH-]
Agent: [Na+]
Product: O=C(O)[C@@H]1C(=O)Nc2ccccc2S[C@H]1c1ccc2c(c1)OCO2
Reaction time: 18 h
Yield: 67 %

Procedure:
A solution of (+/-)-trans 3-carboxymethyl-2-(3,4-methylenedioxyphenyl)-2,3dihydro[1,5]benzothiazepine-4(5H)-one (0.050 g, 0.14 mmole) in EtOH (3 ml) was treated with 25% NaOH (0.5 ml) under argon. The mixture was stirred 18 hours, and then the solvent was evaporated. H2O (3 ml) was added to the residue and the mixture acidified to pH 1 with 10% HCl. The mixture was stirred for 0.5 hours and the crystallized product was collected, washed with H2O (3 ml) and dried to give the tide compound (0.032 g, 67%) as a light yellow solid, mp 110° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8].[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].N1C=CN=C1>CN(C)C=O>[Si:17]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1ccc(CO)cc1C(=O)OC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
19 g (84.8 mmol) of dimethyl 4-hydroxymethylphthalate are placed in 250 ml of dimethylformamide in a round-bottomed flask and under a stream of nitrogen. 14 g (93 mmol) of tert-butyldimethylsilyl chloride and 8 g (118 mmol) of imidazole are added. The reaction medium is stirred for 3 hours at room temperature, it is then concentrated and the residue is dissolved in ether and then filtered. The filtrate is evaporated and the product is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (50/50) to give 23.7 g (83%) of the expected product in the form of a yellow oil.
Reaction SMILES: [CH:1]([N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][C:8](Cl)=[N:9][C:10]=2[C:14]1[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=1)([CH2:3][CH3:4])[CH3:2].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CC(N(C)C)=O>[CH:1]([N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][C:8]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[N:9][C:10]=2[C:14]1[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)n1cnc2c(-c3cnc(N)nc3)nc(Cl)nc21
Reactant: C1COCCN1
Solvent: CC(=O)N(C)C
Product: CCC(C)n1cnc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21
Temperature: 94 °C
Yield: 70 %

Procedure:
To a solution of 5-(9-sec-butyl-2-chloro-9H-purin-6-yl)-pyrimidin-2-ylamine (1.12 mmol) in dimethyl acetamide (18 ml) was added morpholine (3.5 mmol). The reaction mix was heated on an oil bath maintained at 94° C. for 12 h. The reaction was monitored for the absence of the give 5-(9-sec-butyl-2-chloro-9H-purin-6-yl)-pyrimidin-2-ylamine, by LC-MS. The crude material was directly loaded onto a preparative HPLC column and purified by chromatography to get the title compound in a yield of 70%. 1H NMR, DMSO-d6: 9.52 (s, 2H); 8.27 (s, 1H); 7.28 (s, 2H); 4.5 (m, 2H); 3.8 (m, 4H); 3.70 (m, 4H); 2.0 (m, 1H); 1.9 (m, 1H); 1.6 (d, 3H); 0.79 (t, 3H). m/z: 355.45 [MH]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@@H:13]2[CH3:25])=[N:4][N:3]=1.[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:27].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[C:26]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@@H:13]3[CH3:25])=[N:4][N:3]=2)=[CH:30][CH:29]=1)#[N:27]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1nnc(Cl)c2ccccc12
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1nnc(-c2ccc(C#N)cc2)c2ccccc12
Yield: 94.4 %

Procedure:
Heat a mixture of (S)-tert-butyl 4-(4-chlorophthalazin-1-yl)-3-methylpiperazine-1-carboxylate (4.0 g, 11.0 mmol), 4-cyanophenylboronic acid (2.43 g, 16.5 mmol), cesium carbonate (14.4 g, 44.1 mmol), and (SP-4-1)-bis[bis(1,1-dimethylethyl)(4-methoxyphenyl)phosphine-κP]dichloro-palladium (J. Org. Chem. 2007, 72, 5104-5112) (75.4 mg, 0.11 mmol) in 1,4-dioxane (80 mL) and water (20 mL) at 90° C. overnight. Partition the reaction mixture between water and CH2Cl2. Extract the aqueous layer with CH2Cl2. Dry the combined organic layer over Na2SO4 and concentrate under reduced pressure. Purify the resulting residue by flash silica gel chromatography (gradient of 0 to 20% EtOAc in CH2Cl2) to provide the title compound as a light orange foam (4.46 g, 94%). ES/MS m/z 430.2 (M+1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:13][CH:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][N:24](C(OCC4C=CC=CC=4)=O)[CH2:23][CH:22]3[O:37][CH2:38][C:39]3[CH:40]=[CH:41][C:42]4[O:47][CH2:46][CH2:45][N:44]([CH2:48][CH2:49][CH2:50][O:51][CH3:52])[C:43]=4[CH:53]=3)=[CH:17][CH:16]=2)[CH2:11]1.CO.[OH-].[K+]>O1CCOCC1.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:11][CH:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH:22]3[O:37][CH2:38][C:39]3[CH:40]=[CH:41][C:42]4[O:47][CH2:46][CH2:45][N:44]([CH2:48][CH2:49][CH2:50][O:51][CH3:52])[C:43]=4[CH:53]=3)=[CH:17][CH:16]=2)[CH2:13]1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC4CN(c5nc6ccccc6s5)C4)cc3)cc21
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: COCCCN1CCOc2ccc(COC3CNCCC3c3ccc(OC4CN(c5nc6ccccc6s5)C4)cc3)cc21
Temperature: 100 °C
Reaction time: 5 h

Procedure:
0.207 g of benzyl 4-[4-(1-benzothiazol-2-ylazetidin-3-yloxy)phenyl]-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidinecarboxylate is dissolved in 8 ml of dioxane. 8 ml each of methanol and 40% KOH are added and the reaction mixture is stirred in a sealed flask at 100° C. over 5 hours. The reaction mixture is subsequently cooled to room temperature, diluted with 40 ml of water and extracted with ethyl acetate (3×40 ml). The combined organic phases are washed with 40 ml of water, dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:13][CH2:12][CH2:11][CH2:10][C:5]=2[C:6]=1[C:7]([NH2:9])=[O:8].C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(Cl)Cl>[Cl:21][CH2:22][C:23]([NH:1][C:2]1[S:3][C:4]2[CH2:13][CH2:12][CH2:11][CH2:10][C:5]=2[C:6]=1[C:7]([NH2:9])=[O:8])=[O:24]
Reactant: NC(=O)c1c(N)sc2c1CCCC2
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1c(NC(=O)CCl)sc2c1CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a mixture of 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide (30 g, 0.153 mol) and triethylamine (18.5 g, 0.183 mol) in DCM (200 ml) was added chloro-acetyl chloride (20.57 g, 0.183 mol) slowly at 0° C., and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to half of the volume to afford the solid product which was filtered, washed with 10 ml of DCM and dried to provide 2-(2-chloro-acetylamino)-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid amide (35 g, 84%) as off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.65-1.75 (m, 4H), 2.58-2.72 (m, 4H), 4.49 (s, 2H), 7.29 (s, 1H), 7.42 (s, 1H), 12.23 (s, 1H); LC-MS: [M+H]=272.8, 275.1, 257.9 & 255.9 m/z.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][CH:6]=1.[C:7]1(=[O:13])[O:12][C:10](=[O:11])[CH:9]=[CH:8]1>>[CH3:1][C:2]12[O:3][CH:4]([CH:5]=[CH:6]1)[CH:8]1[C:7]([O:12][C:10](=[O:11])[CH:9]21)=[O:13]
Reactant: Cc1ccco1
Reactant: O=C1C=CC(=O)O1
Product: CC12C=CC(O1)C1C(=O)OC(=O)C12

Procedure:
2-Methyl furan was reacted with maleic anhydride in a manner similar to the procedure described in Example 1 to yield 1-methyl-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride. An amount of 28 mmol of this compound was dissolved in methanol (50 ml). To this solution, solid sodium methoxide (56 mmol) was added at 0° C. The resulting deep orange solution was stirred for 18 h at room temperature, after which the solvent was evaporated in vacuo. After drying for 1 h at 77° C. under reduced pressure, the solid was dissolved in water and heated under reflux for 5 h followed by treatment with charcoal (stirring for 30 min at reflux). Filtration and evaporation under reduced pressure yielded 3-methylphthalic acid disodium salt (4.4 g, 71%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21].O>CN(C)C=O.C(OCC)(=O)C>[CH2:21]([O:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11])[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: COc1ccc(C(C)=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cc(OC)ccc1C(C)=O

Procedure:
5.00 g of 2′-hydroxy-4′-methoxyacetophenone was dissolved in 40 ml of N,N-dimethylformamide at room temperature. Thereafter, 4.16 g of potassium carbonate and 2.80 ml of allyl bromide were successively added to the reaction solution. After the disappearance of materials had been confirmed, water and ethyl acetate were added to the reaction solution, so as to separate an organic layer. The obtained organic layer was washed with water and a saturated sodium chloride aqueous solution, and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure, and the residue was then purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 5.60 g of the subject compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:23][C:24]([NH2:26])=[S:25])=[N:11][CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:28][C:29](=O)[CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33].C(N(CC)CC)C.C(O)C>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([NH:23][C:24]2[S:25][CH:28]=[C:29]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[N:26]=2)=[N:11][CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCC(=O)CBr
Reactant: NC(=S)Nc1ncc(Oc2ccccc2Cl)cc1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)CCc1csc(Nc2ncc(Oc3ccccc3Cl)cc2OCc2ccccc2)n1
Yield: 71.2 %

Procedure:
A mixture of 1-(3-(benzyloxy)-5-(2-chlorophenoxy)pyridin-2-yl)thiourea (0.471 g, 1.11 mmol), methyl 5-bromo-4-oxopentanoate (0.279 g, 1.33 mmol), triethylamine (0.271 ml, 1.94 mmol), and ethanol (10 mL) was heated at reflux for 2 hours, cooled, partitioned between ethyl acetate and 2N NaOH, washed with water and brine, dried, and concentrated. The residue was purified by MPLC (Biotage) eluting with 3:1 hexane:ethyl acetate to afford methyl 3-(2-(3-(benzyloxy)-5-(2-chlorophenoxy)pyridin-2-ylamino)thiazol-4-yl)propanoate (0.392 g, 71.2% yield) as a white viscous oil/wax. The compound (70 mg) was dissolved in ether (2 mL) and 1N HCl in ether (0.5 mL) was added. The mixture was stirred 5 minutes, and hexanes (5 mL) were added. The mixture was decanted, and a mixture of hexanes:ether (2:1, 3 mL) was added three times with three decantations. The solid material was dried to afford methyl 3-(2-(3-(benzyloxy)-5-(2-chlorophenoxy)pyridin-2-ylamino)thiazol-4-yl)propanoate hydrochloride (0.058 g, 9.81% yield) as a white solid. 1H NMR (DMSO-d6) δ 2.73 (t, 2H), 3.61 (s, 3H), 2.91 (t, 2H), 5.32 (s, 2H), 6.82 (s, 1H), 6.99 (d, 1H), 7.21 (t, 1H), 7.31-7.43 (m, 4H), 7.47 (d, 1H), 7.55-7.66 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([O:19]C)=[O:18])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.O[Li].O.Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(ccn2-c2ccc(F)cc2)c1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2c(ccn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 91.1 %

Procedure:
A mixture of methyl 1-(4-fluorophenyl)-indole-5-carboxylate 7c (0.58 g, 2.15 mmol) and LiOH.H2O (0.36 g, 8.6 mmol) in THF (15 mL) and H2O (10 mL) was stirred at room temperature for 5 days. Aqueous 10% HCl solution was added to the reaction mixture to adjust pH=3˜4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated to give 7d (0.5 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][OH:8].I[CH2:11][CH3:12]>CCCCCC.C1COCC1>[CH2:11]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:9])[CH3:12]
Reactant: CCI
Reactant: OCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOCCCCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
NaH (4.2 g, 0.11 mol) was washed with hexane and then suspended in dry THF (400 mL). Pentane-1,5-diol (10.4 g, 0.1 mol) in THF (50 mL) was added and stirred for 1 h at room temperature. Iodoethane (17.2 g, 0.11 mol) in THF (50 mL) was added and the mixture was refluxed for 48 h. After evaporation of the solvent, the residue was dissolved in EtOAc (300 mL). The organic phase was washed with water (2×50 mL), brine (50 mL), and dried (Na2SO4). The residue was purified by column chromatography on alumina with 10% 2-propanol in hexane, and then Kugelrohr distillation to give the title product (2) (9.4 g, 71%); bp 45° C.-46° C./0.005 torr; IR(neat): 3400 (broad) and 1115 cm-1 ; 1H NMR: 1.22 (t, 3H, J=6.8 Hz), 1.42 (m, 2H), 1.56 (m, 4H), 3.43 (t, 4H, J=5.8 Hz), 3.48 (q, 2H, J=6.8 Hz), and 3.58 ppm (b s, IH).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:51])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[C:30](Cl)[C:29]([CH3:33])=[CH:28][C:27]=5[O:34][C@H:35]([CH2:37][CH:38]=[CH2:39])[CH3:36])[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:40])[C:12]=2[C@H:41]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:42]([O:44]C)=[O:43])[CH2:7][CH2:6]1)C=C.C(OC1(C)CC[N:59](C2N3N=C(C4C=C(C5C(O[C@H](CC=C)C)=CC=C(Cl)C=5C)C=CC=4)C=C3N=C(C)C=2[C@H](OC(C)(C)C)C(OC)=O)CC1)C=C.BrC1C=C(Cl)C(C)=CC=1O[C@H](CC=C)C.BrC1C(C)=C(Cl)C=CC=1O[C@H](CC=C)C>>[C:47]([O:46][C@@H:41]([C:12]1[C:13]([CH3:40])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:7][CH2:6][C:5]([CH3:51])([O:4][CH2:1][CH2:39][CH2:38][CH2:37][C@H:35]([CH3:36])[O:34][C:27]2[CH:28]=[C:29]([C:33]#[N:59])[CH:30]=[CH:31][C:26]=2[C:22]2[CH:21]=[C:20]3[CH:25]=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)[C:42]([OH:44])=[O:43])([CH3:48])([CH3:49])[CH3:50]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(-c5cc(Cl)c(C)cc5O[C@@H](C)CC=C)c4)nn23)CC1
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(-c5c(O[C@@H](C)CC=C)ccc(Cl)c5C)c4)nn23)CC1
Agent: C=CC[C@H](C)Oc1cc(C)c(Cl)cc1Br
Agent: C=CC[C@H](C)Oc1ccc(Cl)c(C)c1Br
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(C#N)ccc1-c1cccc-3c1

Procedure:
(S)-Methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(5′-chloro-4′-methyl-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate and (S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3′-chloro-2′-methyl-6′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate: Prepared from a 2:1 mixture of (S)-1-bromo-5-chloro-4-methyl-2-(pent-4-en-2-yloxy)benzene and (S)-2-bromo-4-chloro-3-methyl-1-(pent-4-en-2-yloxy)benzene using the same procedures as intermediate 182 and 168 to provide an inseperable mixture of the products in 98% yield and 2:1 ratio. (S)-Methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(5′-chloro-4′-methyl-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate. LCMS (M+1)=715.4. (S)-Methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3′-chloro-2′-methyl-6′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate. LCMS (M+1)=715.4.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:8][C@@:7]2([C:16]3[C:11](=[CH:12][C:13]([Cl:26])=[C:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=4)[CH:15]=3)[CH2:10][O:9]2)[C@H:6]([OH:27])[C@@H:5]([OH:28])[C@@H:4]1[OH:29].N1C=CC=CC=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>ClCCl.CN(C)C1C=CN=CC=1>[Cl:26][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][C:14]=1[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH3:25])=[CH:22][CH:23]=1)[C@:7]1([C@H:6]([OH:27])[C@@H:5]([OH:28])[C@H:4]([OH:29])[C@@H:3]([CH2:2][NH:1][C:36](=[O:38])[CH3:37])[O:8]1)[O:9][CH2:10]2
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](CNC(C)=O)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
To a stirred solution of (1S,3′R,4′S,5′S,6′R)-6′-(aminomethyl)-5-chloro-6-(4-ethylbenzyl)-3′,4′,5′,6′-tetrahydro-3H-spiro[isobenzofuran-1,2′-pyran]-3′,4′,5′-triol (20 mg, 0.047 mmol) and 0.04 mL of pyridine in 1 mL of dichloromethane, was added acetic anhydride (45 μL, 0.048 mmol) and 3 mg of 4-dimethylaminopyridine. After being stirred for 2 h at ambient temperature, the reaction mixture was diluted with 20 mL of dichloromethane, washed with 1 M hydrochloric acid and concentrated. The residue was dissolved in 1 mL of methanol and cooled in an ice bath. After addition of 0.3 mL of 4 M potassium hydroxide solution, the mixture was stirred for 2 h at ambient temperature. The reaction mixture was then neutralized with 1 M hydrochloric acid and concentrated. The residue was partitioned between aqueous sodium hydrogen carbonate solution and ethyl acetate, and the organic layer was separated and dried over sodium sulfate. Concentration under reduced pressure provided the crude product, which was purified by preparative TLC to give 5 mg of title compound. 1H NMR (CD3OD, 400 MHz) δ 7.25 (s, 1H), 7.11 (s, 1H), 6.99 (s, 4H), 5.00 (d, J=12.6 Hz, 1H), 4.95 (d, J=12.6 Hz, 1H), 4.00 (d, J=15.4 Hz, 1H), 3.95 (d, J=15.4 Hz, 1H), 3.71-3.57 (m, 3H), 3.45 (dd, J=14.4, 2.8 Hz, 1H), 3.17-3.11 (m, 2H), 2.48 (q, J=7.6 Hz, 2H), 1.09 (t, J=7.6 Hz, 3H); MS ESI (m/z) 484 (M+Na)+, calc. 461.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[CH2:10][OH:11].C(N(CC)CC)C>ClCCl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:1][S:2]([O:11][CH2:10][C:9]1[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=[C:7]([Br:6])[CH:8]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cc(Br)cc(C(F)(F)F)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc(Br)cc(C(F)(F)F)c1
Temperature: -78 °C
Yield: 65.6 %

Procedure:
Methanesulfonyl chloride (342 mg) was added dropwise to a stirred solution of 3-bromo-5-(trifluoromethyl)benzyl alcohol (560 mg) and triethylamine (417 μl) in dry dichloromethane (20 ml) at -78° C. under a dry nitrogen atmosphere. The reaction was maintained at -78° C. for 30 minutes and then allowed to warm to room temperature over 2 hours. After this period the reaction mixture was diluted with 5% aqueous citric acid and the organic layers were separated, dried over MgSO4, filtered and the solvent removed under reduced pressure to give 1-(methanesulfonyloxymethyl)-3-bromo-5-(trifluoromethyl)benzene as a yellow oil (480 mg) 1H NMR (360 MHz,CDCl3) δ 3.06 (3H,s),5.24 (2H, s), 7.59 (1H, s), 7.75 (1H, s), 7.94 (1H, s).