Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[S:11][C:10]=2[CH3:24])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:27])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:27][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[S:11][C:10]=1[CH3:24]
Reactant: O=S(Cl)Cl
Reactant: Cc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(O)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(Cl)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of cyclohexyl{2-methyl-5-[4-(trifluoromethyl)phenyl]thiophen-3-yl}methanol (1.20 g) synthesized above in toluene (20 mL) was added thionyl chloride (297 μL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (1.27 g, quantitative) as a pale-yellow solid.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[C:10]([CH3:12])[O:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[O:13]=P(Cl)(Cl)Cl.C(Cl)(Cl)Cl.CCCCCC>C(OC(=O)C)(=O)C>[CH3:8][C:6]1[NH:7][C:2](=[O:13])[C:3]2[CH:11]=[C:10]([CH3:12])[O:9][C:4]=2[N:5]=1
Reactant: Cc1nc(Cl)c2cc(C)oc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Solvent: CCCCCC
Product: Cc1nc2oc(C)cc2c(=O)[nH]1

Procedure:
4-Chloro-2,6-dimethylfuro[2,3-d]pyrimidine (M).To a 50 mL flask was added 1.64 g (1 mmol) L and 10 mL POCl3. The resulting mixture was refluxed for 2 h, and the solvent was removed under reduced pressure to afford a dark residue. To this was added 30 mL of CHCl3 and 3 g of silica gel. The solvent was evaporated to afford a plug. Column chromatography of the plug with hexane:acetyl acetate=20:1 as eluent afford 1.55 g (85%) M as a yellow solid; Rf 0.26 (Hexane/EtOAC 15:1); 1H NMR (DMSO-d6) δ 2.48 (s, 3 H), 2.63 (s, 3 H), 6.77 (s, 1 H).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[C:13](OC(=O)C)(=[O:15])[CH3:14].[C:20]([O-])(O)=O.[Na+]>S(=O)(=O)(O)O>[C:13]([O:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:20])=[O:5])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(I)cc(C(=O)[O-])c1O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)c1cc(I)cc(C)c1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 2-hydroxy-5-iodo-3-methylbenzoate (1.24 g, 4.25 mmol) in neat acetic anhydride (1.803 mL, 19.10 mmol) was added a 3 drops of concentrated sulfuric acid (0.226 mL, 4.25 mmol). The resultant orange solution was stirred at room temperature overnight. The solution was diluted with 3% aqueous NaHCO3 (13 mL) and extracted with CHCl3 (3×30 mL). The combined organic phases were washed with water (4×20 mL), dried (MgSO4), and concentrated in vacuo to afford methyl 2-(acetyloxy)-5-iodo-3-methylbenzoate, as a colorless solid. 1H NMR (500 MHz, CHCl3): δ 8.17 (s, 1 H); 7.78 (s, 1 H); 3.89 (s, 3 H); 2.25 (s, 3 H); 2.21 (s, 3 H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N[NH:22][C:23]([NH2:25])=[S:24].[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>C1(C)C=CC=CC=1>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[CH:1]1([N:7]2[CH2:8][CH2:9][CH:10]([C:13]3[CH:14]=[CH:15][C:16]([C:17]4[S:24][C:23]([NH2:25])=[N:22][N:18]=4)=[CH:19][CH:20]=3)[CH2:11][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NNC(N)=S
Reactant: N#Cc1ccc(C2CCN(C3CCCCC3)CC2)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(-c2ccc(C3CCN(C4CCCCC4)CC3)cc2)s1
Temperature: 70 °C
Reaction time: 7 h

Procedure:
A mixture of 4-(1-cyclohexyl-4-piperidyl)benzonitrile (0.68 g), thiosemicarbazide (0.58 g) and trifluoroacetic acid (3.5 ml) in toluene (7 ml) was stirred for 7 hours at 70° C. After being cooled to room temperature, the solvent was evaporated in vacuo. Then the residue was dissolved in tetrahydrofuran and poured into water. The solution was adjusted to pH 8 with 1N aqueous sodium hydroxide. The resulting precipitate was collected by filtration and washed with water and isopropyl ether to give 5-[4-(1-cyclohexyl-4-piperidyl)phenyl]-1,3,4-thiadiazol-2-amine trifluroacetate (0.80 g).
Reaction SMILES: CC1N=C(N2C(=O)NN=C2)SC=1C(OCC)=O.[C:18]([C:21]1[S:25][C:24]([N:26]2[CH2:30][CH2:29][NH:28][C:27]2=[O:31])=[N:23][C:22]=1[CH3:32])(=[O:20])[CH3:19].[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1>>[C:18]([C:21]1[S:25][C:24]([N:26]2[CH2:30][CH2:29][N:28]([CH2:38][C:37]3[CH:40]=[CH:41][C:34]([F:33])=[CH:35][CH:36]=3)[C:27]2=[O:31])=[N:23][C:22]=1[CH3:32])(=[O:20])[CH3:19]
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(=O)c1sc(N2CCNC2=O)nc1C
Agent: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Product: CC(=O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)nc1C
Yield: 98 %

Procedure:
Following the procedure as described in Preparation 16, making variations as required to replace ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate with 1-(5-acetyl-4-methylthiazol-2-yl)imidazolidin-2-one to react with 4-fluorobenzyl bromide, the title compound was obtained as a yellow solid in 98% yield: 1H NMR (300 MHz, CDCl3) δ 7.32-7.22 (m, 2H), 7.07-6.97 (m, 2H), 4.45 (s, 2H), 4.10-4.04 (m, 2H), 3.48-3.37 (m, 2H), 2.67 (s, 3H), 2.38 (s, 3H); MS (ES+) m/z 334.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27]([OH:29])=O)[S:26][C:19]=23)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:65]([NH:72][CH2:73][CH2:74][CH2:75][NH2:76])([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66].Cl>C(#N)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27]([NH:76][CH2:75][CH2:74][CH2:73][NH:72][C:65](=[O:66])[O:67][C:68]([CH3:70])([CH3:69])[CH3:71])=[O:29])[S:26][C:19]=23)=[CH:15][CH:14]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)O)sc34)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCCNC(=O)OC(C)(C)C)sc34)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (300 mg, 0.69 mmol), HATU (288 mg, 0.76 mmol) and N,N-diisopropylethylamine (196 mg, 1.52 mmol) in anhydrous acetonitrile (10 ml) was stirred at room temperature for 30 minutes, followed by addition of N-Boc-1,3-propanediamine (180 mg, 1.03 mmol). The mixture was stirred for another 30 minutes and poured into 100 ml of water with vigorous stirring. 2M HCl was added dropwise until pH=6. The precipitates were filtered, washed with water and dried in vacuo to give tert-butyl {3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}carbamate as brown solid. Yield: 380 mg, 93%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]([OH:12])=O)[NH:7][C:6]=2[CH:13]=1.C(N(CC)CC)C.[CH2:21]([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH2:21]([CH:28]1[CH2:33][CH2:32][N:31]([C:10]([C:8]2[NH:7][C:6]3[CH:13]=[C:2]([OH:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)=[O:12])[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)c1nc2ccc(O)cc2[nH]1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1nc2ccc(O)cc2[nH]1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.7 %

Procedure:
A mixture of 3.0 g (16.75 mmol) of 6-hydroxi-1H-benzoimidazol-2-carboxilic acid, 2.4 ml (17.2 mmol) of triethylamin, 3.0 g (17.1 mmol) of 4-benzyl-piperidine, 7.0 g (18.5 mmol) of HBTU and 100 ml of dimethylformamide is stirred at room temperature for 16 h. The reaction mixture is concentrated and the residue is purified by column chromatography using Kieselgel 60 as adsorbent (Merck) and toluene:methanol=4:1 as eluent, then the product is recrystallized from toluene to yield 3.58 g (63.5%) of the title compound. Mp.: 186° C. (toluene).
Reaction SMILES: [ClH:1].Cl.C1(CCC2C=CC([CH:17]([C:25]3([OH:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:18][N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=CC=2)C=CC=CC=1.OC1(C([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[CH2:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)CN2CCN(C(OC(C)(C)C)=O)CC2)CCCCC1>>[ClH:1].[ClH:1].[C:55]1([CH2:60][CH2:61][C:62]2[CH:63]=[CH:64][C:65]([CH:18]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:17][C:25]3([OH:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)=[CH:66][CH:67]=2)[CH:56]=[CH:57][CH:58]=[CH:59][CH:54]=1
Reactant: OC1(C(CN2CCNCC2)c2ccc(CCc3ccccc3)cc2)CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(c2ccccc2CCc2ccccc2)C2(O)CCCCC2)CC1
Agent: Cl
Product: OC1(CC(c2ccc(CCc3ccccc3)cc2)N2CCNCC2)CCCCC1

Procedure:
In an analogous manner to Example 135, step 4 1-{1-[4-(2-phenylethyl)phenyl]-2-piperazin-1-ylethyl]cyclohexanol dihydrochloride was prepared from tert-butyl 4-[(1-hydroxycyclohexyl)(2-phenylethyl phenyl)ethyl]piperazine-1-carboxylate. MS (ESI) m/z 393; HRMS: calcd for C26H36N2O+H+, 393.29004; found (ESI, [M+H]+), 393.2904.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]O[Si](CC(C)C)(C)C.Cl[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].[Mg].ClC1CCC=C1>O1CCCC1.O>[CH3:26][C:25]([Si:22]([CH3:24])([CH3:23])[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:5]1[CH2:4][CH2:3][CH:2]=[CH:6]1)([CH3:28])[CH3:27]
Reactant: CC(C)C[Si](C)(C)OCCCCCCl
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCl
Agent: ClC1C=CCC1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCCCC1C=CCC1
Temperature: 25 °C

Procedure:
All reactions are carried out under an inert atmosphere. The starting material, (5-chloro-1-pentyloxy)(2,2-dimethylethyl) dimethylsilane {[(5-chloropentyl)oxy](1,1-dimethylethyl)dimethylsilane} (534 g, 2.26 moles), diluted in tetrahydrofuran (500 ml), is added portionwise to a refluxing solution of tetrahydrofuran and granular magnesium (75 g). After the addition is complete the reaction is refluxed an additional 2 hours and the resultant Grignard salt is cooled to room temperature, cannulated into a three liter flask, and cooled to -20° C. A solution of Li2CuCl4 (6.4 mmoles) is added, followed by the dropwise addition of 3-chlorocyclopentene (219 g, 2.1 moles) cooled in a -20° C. dry ice/ethanol bath. After the addition is complete the mixture is warmed to room temperature. Water (500 ml) is added. The reaction mixture is extracted with hexane (3×400 ml). The organic layers are combined, washed with brine (2×500 ml) and dried over anhydrous sodium sulfate. The remaining solvent is removed under vacuum leaving a clear yellow oil. The crude product is fractionally distilled under reduced pressure leaving a clear, colorless oil (478 g, 1.78 moles), BP 96° C./0.3 mm.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][N:4]=1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[F:27]>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:4]2[CH:5]=[C:6]([CH2:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=[CH:8][C:3]2=[O:2])=[C:21]([F:27])[CH:22]=1
Reactant: COc1ccc(CCCc2ccccc2)cn1
Reactant: Fc1cc(Cl)ccc1CBr
Product: O=c1ccc(CCCc2ccccc2)cn1Cc1ccc(Cl)cc1F
Yield: 47.7 %

Procedure:
According to Scheme 22 Step 2: The title compound was prepared according to Example 6 Step 2, from 2-methoxy-5-(3-phenylpropyl)pyridine (1 eq, 0.44 mmol, 0.10 g) and 1-(bromomethyl)-4-chloro-2-fluorobenzene (2 eq, 0.88 mmol, 0.20 g). Reaction conditions: overnight at 90° C. The residue was purified by flash chromatography over silicagel (AIT Flashsmart prepacked column SiO2, cyclohexane/AcOEt 70/30) yielding the title compound (75 mg, 0.21 mmol, 48%) as a yellow oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C@@H:16]([O:22][C:23]([C:25]1([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24])[CH2:15]2>CC#N>[Br-:1].[C:10]([C:9]1[CH:12]=[CH:13][C:6]([O:5][CH2:4][CH2:3][CH2:2][N+:14]23[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]2)[C@@H:16]([O:22][C:23]([C:25]2([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])[CH2:15]3)=[CH:7][CH:8]=1)#[N:11]
Reactant: N#Cc1ccc(OCCCBr)cc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Solvent: CC#N
Product: N#Cc1ccc(OCCC[N+]23CCC(CC2)[C@@H](OC(=O)C2(c4ccccc4)CCCCCC2)C3)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.7 %

Procedure:
A mixture of 4-(3-bromo-propoxy)-benzonitrile (41 mg) and 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 14e) (52 mg) in MeCN (1 mL) was stirred at room temperature for 16 h then heated to 80° C. under nitrogen for a further 16 h. The volatiles were evaporated and the residue was triturated with ether to give an off-white solid that was triturated with EtOAc and dried under vacuum to give the title compound (61 mg) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH:12]([CH3:16])[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH:22]=[CH:21][O:20][C:19]=1[C:23]([Cl:25])=[O:24]>C1C=CC=CC=1>[ClH:25].[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:23]([C:19]3[O:20][CH:21]=[CH:22][C:18]=3[CH3:17])=[O:24])[CH:12]([CH3:16])[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccoc1C(=O)Cl
Reactant: CC1CN(CCCc2ccccc2)CCN1
Solvent: c1ccccc1
Product: Cc1ccoc1C(=O)N1CCN(CCCc2ccccc2)CC1C
Product: Cl

Procedure:
The compound was obtained by following the same process as in Example 2 from a mixture of 1-(3-phenylpropyl)-3-methylpiperazine, 3-methyl-2-furoyl chloride and benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:17][OH:18])[C:13]([O:15][CH3:16])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:19]([O-])([O-])=O.[K+].[K+].[CH2:25](I)[CH3:26]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:25][CH3:26])[C@@H:12]([CH2:17][OH:18])[C:13]([O:15][CH2:16][CH3:19])=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCI
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@H](CO)NS(=O)(=O)c1ccc(Cl)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](CO)N(CC)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
Compound 2C (1.65 g, 5.6 mmol) dissolved in DMF (15 ml) was added with K2CO3 (1.1 equiv., 854 mg) and ethyl iodide (1.1 equiv., 0.63 ml) and the reaction was stirred at rt overnight. The reaction was diluted with ethyl acetate and washed several times with water and finally with Brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by crystallization from ethyl ether and petroleum ether afforded 1.6 g of a semisolid. Yield=88%. 1HNMR (DMSO, 200 MHz) δ 1.00 (3H, d, J=6.2 Hz), 3.32 (3H, s), 3.34 (2H, m), 3.75 (2H, m), 4.42 (1H, t), 5.08 (1H, bs), 7.62 (2H, m), 7.76 (2H, m)
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:14]([Li])([CH2:16]C)[CH3:15].COS(OC)(=O)=O>C(OCC)C.O>[C:1]([N:8]1[CH2:9][C@H:10]([OH:13])[CH2:11][C@@H:12]1[CH2:16][CH:14]=[CH2:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: [Li]C(C)CC
Solvent: COS(=O)(=O)OC
Solvent: CCOCC
Solvent: O
Product: C=CC[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Yield: 69.2 %

Procedure:
(3R)-1-BOC-3-hydroxypyrrolidine (1 g, 5.34 mmol) was dissolved in diethylether (50 ml), and filled with nitrogen. The reaction mixture was cooled to −78° C., N,N,N,N′-tetramethylethylenediamine (620 mg, 5.34 mmol) was added, and sec-butyllithium (1.4M cyclohexane solution 4.45 ml, 6.23 mmol) was slowly added. After being stirred for 30 min at the same temperature, dimethylsulfate (1.44 g, 10.68 mmol) was dissolved in diethylether (10 ml). The reaction solution was slowly heated to rt, diluted with water (12 ml), and extracted with diethylether. The organic extracts were dried over MgSO4, and the residue was purified by column chromatography (eluent, EtOAc/Hex=1/4) to give the title compound (840 mg, 70%).
Reaction SMILES: [O:1]=[C:2]1[C:6]2[C:7]([NH:26][C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)=[N:8][C:9]([NH:11][C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][C:5]=2[CH2:4][NH:3]1.[Cl:34]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:34][C:10]1[C:5]2[CH2:4][NH:3][C:2](=[O:1])[C:6]=2[C:7]([NH:26][C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)=[N:8][C:9]=1[NH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)c1
Solvent: ClCCl
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(Cl)c3c2C(=O)NC3)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A vial was charged with tert-butyl (1S,2R)-2-(3-oxo-4-(m-tolylamino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (63 mg, 0.140 mmol) and N-chlorosuccinimide (18.63 mg, 0.140 mmol) in DCM (1.4 mL) to give a yellow solution. The solution was stirred for 1 h at RT. The crude reaction mixture was diluted with DCM (20 mL) and washed with saturated aq NaHCO3 (2×10 mL) followed by water (10 mL) and brine (10 mL). The organic layers were combined, dried over sodium sulfate, and concentrated to a residue which was purified by flash column chromatography. The collected fractions were concentrated to a brown residue to give the title compound as a cream colored solid upon drying (38.1 mg, 56%). [M+H] calc'd for C25H32ClN5O3, 486. found, 486.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH3:26][O:27][CH2:28][CH2:29]Br>COCCBr.O>[CH3:26][O:27][CH2:28][CH2:29][O:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:14])[CH3:13]
Reactant: COCCBr
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc([N+](=O)[O-])ccc1NC(C)=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
The mixture of N-(2-hydroxy-4-nitrophenyl)acetamide (93 g, 0.47 mol, 1.00 equiv), potassium carbonate (184 g, 1.33 mol, 2.81 equiv) and dimethylformamide (465 ml) was stirred at 60° C. as 2-bromoethyl methyl ether (90 g, 0.647 mol, 1.36 equiv) was added over 15 minutes. After 1 hour, additional 2-bromoethyl methyl ether (4 g, 0.028 mol, 0.059 equiv) was added and the mixture was stirred at 60° C. for another hour. The mixture was cooled to room temperature and poured into 1 L of water. After 30 minutes, the product was formed and collected by filtration and washed with water and heptane. The product was dried in a vacuum oven at 60° C. to give the title compound 97 g. MS (ESI) m/z: 255 (M+1).
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].I[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[CH3:17][C:3]1([C:1]#[C:2][C:27]2[C:28]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:24]=[CH:25][CH:26]=2)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: Ic1cccc2ccccc12
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1cccc3ccccc13)O2

Procedure:
rac-3,4-dihydro-2,5,7,8-tetramethyl-2-[(1-naphthyl)ethynyl]-2H-1-benzopyran-6-ol was prepared by coupling rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 1-iodonaphthalene under the conditions described in Example 1. It was isolated by chromatography over 40 fold amount of silica gel using methylene chloride. The combined clean fractions were crystallized from hexane and recrystallized from petroleum ether to give colorless crystals with m.p. 127°-128°.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[CH2:14][CH2:15][OH:16])(O)[CH3:4].C(N(CC)CC)C.CS(Cl)(=O)=O.COC1C=CC(C(O)(C)C(F)(F)F)=C(CCOS(C)(=O)=O)C=1.Cl>ClCCl.CC#N>[CH3:13][O:12][C:9]1[CH:8]=[C:7]2[C:6](=[CH:11][CH:10]=1)[C:3]([CH3:4])([C:2]([F:18])([F:17])[F:1])[O:16][CH2:15][CH2:14]2
Reactant: COc1ccc(C(C)(O)C(F)(F)F)c(CCO)c1
Agent: COc1ccc(C(C)(O)C(F)(F)F)c(CCOS(C)(=O)=O)c1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc2c(c1)CCOC2(C)C(F)(F)F
Temperature: 0 °C
Reaction time: 12 h
Yield: 73.1 %

Procedure:
To a solution of 1,1,1-trifluoro-2-[2-(2-hydroxy-ethyl)-4-methoxy-phenyl]-propan-2-ol (5.00 g, 18.9 mmol) in dichloromethane (30 mL) was added triethylamine (9.20 mL, 66.3 mmol). The solution was cooled to 0° C. and methanesulfonyl chloride (1.61 mL, 20.8 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and was stirred 12 hours. The formation of methanesulfonic acid 2-[5-methoxy-2-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-phenyl]-ethyl ester is rapid and its disappearance was monitored by HPLC (retention time=4.5 minutes, Zorbax Rx-C6 column 4.6×150 mm, 40° C., 50% CH3CN/50% (0.2% Et3N, 0.1% H3PO4 aqueous pH=3.2 buffer), 1 mL/min). At the end of the reaction, the mixture was poured into 1N aqueous hydrochloric acid (30 mL) and was extracted with dichloromethane (20 mL). The organic extracts were dried over magnesium sulfate, filtered, and concentrated to afford 6-methoxy-1-methyl-1-trifluoromethyl-isochroman as an oil (3.40 g, 73%). 1H NMR (300 MHz, CDCl3) δ1.69 (s, 3), 2.85-2.90 (m, 2), 3.85 (s, 3), 3.90-3.98 (m, 1), 4.14-4.21 (m, 1), 6.72 (d, 1, J=2.6), 6.85 (dd, 1, J=8.7, 2.6), 7.31 (d, 1, J=8.7). 13C NMR (100 MHz, CDCl3) δ23.25, 29.42, 55.19, 61.37, 76.10 (q, J=27.4), 112.84, 113.43, 124.85, 125.96 (q, J=289), 127.86, 136.49, 158.98. IR 2946, 2839, 1738, 1611, 1505, 1162, 1137, 1101 cm−1. Analysis calculated for C12H13F3O2: C, 58.54; H, 5.32. Found: C, 58.27; H, 5.35.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C:3]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:2]1.[CH:16]1([CH:19]=O)[CH2:18][CH2:17]1.C>>[CH:16]1([CH2:19][N:1]2[CH2:6][CH2:5][CH2:4][C:3]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]3=[O:15])[CH2:2]2)[CH2:18][CH2:17]1
Reactant: O=C1Nc2ccccc2C12CCCNC2
Reactant: O=CC1CC1
Agent: C
Product: O=C1Nc2ccccc2C12CCCN(CC1CC1)C2
Yield: 90 %

Procedure:
The compound was prepared according to PROCEDURE 1, Method A by reaction of spiro[indoline-3,3′-piperidin]-2-one with 3 equiv. of cyclopropanecarboxaldehyde. Yield: 90%. 13C NMR (CDCl3): δ 3.8, 4.0, 8.3, 21.4, 31.8, 48.6, 53.3, 58.4, 63.6, 109.7, 121.7, 126.1, 127.4, 134.7, 140.0, 182.2; MS (CI, CH4): m/z (rel. int.) 257 (M+1, 100).