Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[NH:5]1[CH2:10][CH2:9][S:8](=[O:12])(=[O:11])[CH2:7][CH2:6]1.C[O:14][C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[C:25]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[N:26][O:27][C:28]=2[C:29]([F:32])([F:31])[F:30])=[N:18][CH:17]=1.O>O1CCOCC1>[O:11]=[S:8]1(=[O:12])[CH2:9][CH2:10][N:5]([C:15]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][C:24]3[C:25]([C:33]4[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=4)=[N:26][O:27][C:28]=3[C:29]([F:30])([F:32])[F:31])=[CH:20][CH:21]=2)=[O:14])[CH2:6][CH2:7]1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Reactant: O=S1(=O)CCNCC1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1)N1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.6 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 504 μL, 1.0 mmol) was added dropwise (exothermic) to a solution of thiomorpholine-S,S-dioxide (136 mg, 1.0 mmol) in dioxane (7 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.25 mmol) in dioxane (4 mL) was added. The resulting mixture was then heated at 85-95° C. for 4 days and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (32 mg, 25%) which was obtained as an off white solid. MS: m/e=500.0 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]3[S:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:12]=13)[CH:9]=[N:8][CH:7]=[CH:6]2)#[N:2].S(=O)(=O)(O)[OH:21].[OH-].[NH4+]>O>[CH:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]([NH2:2])=[O:21])=[C:12]3[C:13]4[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=4[S:15][C:11]3=2)[CH:6]=[CH:7][N:8]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cc2ccncc2c2sc3ccccc3c12
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1cc2ccncc2c2sc3ccccc3c12
Temperature: 0 °C

Procedure:
Two hundred mg of 6-cyanobenzothieno[3,2-h]isoquinoline (4), prepared in the preceding Example, was mixed with a solution of 2 ml water ,and 3 ml concentrated sulfuric acid. The reaction mixture was heated at 110° C.-120° C., and gave rise to a yellowish brown solution. After heating for approximately 5 hr, when TLC indicated the absence of starting material, the reaction mixture was poured onto 40 ml ice and water. The yellow solution thus obtained was made alkaline (to a pH of about 8) with concentrated ammonium hydroxide. The gray flocculent solid that precipitated was collected and washed with water to yield 130 mg dried product. This material was recrystallized from 75 ml CHCl3, to give 85 mg of a white solid, m.p. 295° C.-302° C. characterized as compound 5 by I.R. and mass spectrometry.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[C:15]([CH2:20][C:21]([O:23]CC)=[O:22])(=O)[CH:16]([CH3:18])[CH3:17].[O-]CC.[Na+].O>C(O)C>[CH2:11]([NH:10][C:8]([C:7]1[CH:6]=[CH:5][C:4]([N:1]2[C:15]([CH:16]([CH3:18])[CH3:17])=[C:20]([C:21]([OH:23])=[O:22])[N:3]=[N:2]2)=[CH:14][CH:13]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2C(C)C)cc1
Temperature: 50 °C
Reaction time: 63 h
Yield: 93.4 %

Procedure:
4-Azido-N-ethylbenzamide (0.94 g, 4.70 mmol) and ethyl isobutyrylacetate (1.03 g, 6.10 mmol, 1.3 eq.) were dissolved in ethanol (20 ml), sodium ethoxide (461 mg, 6.10 mmol, 1.3 eq.) was added, and the mixture was stirred at room temperature for 30 min and at 50° C. for 63 hr. Water (20 ml) was added to the reaction mixture, and ethanol was evaporated. The residue was diluted with 2% aqueous sodium carbonate solution (20 ml), and the mixture was washed with ethyl acetate-hexane (2:1, 50 ml). The aqueous layer was acidified (pH<3) with 6N hydrochloric acid and stood still at 0° C. The precipitate was collected by filtration, washed with ice-cold water and dried to give the title compound as a pale-brown powder (1.33 g, 4.39 mmol, 93.4%).
Reaction SMILES: [O:1]([CH:8]([CH3:11])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:10][CH2:9][CH:8]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:11])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC(CO)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(COS(C)(=O)=O)Oc1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 15.2 g of 2-phenoxy-1-propanol, 20.8 ml of triethylamine and 300 ml of dichloromethane chilled to -10° C. in an ice-salt bath, is added dropwise 7.78 ml of methanesulfonyl chloride over 10 minutes. The solution is stirred at -10° C. for 30 minutes, washed with 100 ml of ice water, 100 ml of cold 10% hydrochloric acid, 100 ml of cold saturated sodium bicarbonate solution, 100 ml of cold saturated sodium chloride solution and dried (magnesium sulfate). The solvent is removed under vacuum to give the product as an oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:10][CH2:11]C)(=O)C.C(O)(=O)C.[Si:17]([O:24][C@@H:25]1[C@@H:29]([CH:30](OC)[OH:31])[O:28][C@@:27](C)([N:34]2[CH:42]=[C:40]([CH3:41])[C:38](=[O:39])[NH:37][C:35]2=[O:36])[CH2:26]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CO>[Si:17]([O:24][C@@H:25]1[C@@H:29]([CH:30]([CH2:7][O:10][CH3:11])[OH:31])[O:28][C@@H:27]([N:34]2[CH:42]=[C:40]([CH3:41])[C:38](=[O:39])[NH:37][C:35]2=[O:36])[CH2:26]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CCOC(C)=O
Reactant: COC(O)[C@H]1O[C@@](C)(n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: COCC(O)[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
A solution of 3′-O-t-butyldimethylsilyl-5′-(R)-C,O-methylenethymidine (1.84 g, 5 mmol) and anhydrous potassium carbonate (1.38 g, 10 mmol) in methanol was stirred at room temperature for 90 h. Ethyl acetate (70 ml) was added and the mixture neutralized with acetic acid to pH 7. Solvents were evaporated and the residue was dissolved in methylene chloride (30 ml). Precipitates were filtered and the solution concentrated- The residue was purified by chromatography on silica (EtOAc-hexane, 1:1) to give 310 mg of intact starting material and 578 mg of 3′-O-t-butyldimethylsilyl-5′-C-methoxy-methylthymidine as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][N:6]=[CH:5][CH:4]=1.[NH2:14][CH:15]1[C:20](=[O:21])[N:19]2[CH:22]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[C:23](=[O:29])[N:24]([CH:26]([CH3:28])[CH3:27])[CH2:25][CH:18]2[N:17]([S:38]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=2[Cl:48])(=[O:40])=[O:39])[CH2:16]1>>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH:22]2[N:19]3[C:20](=[O:21])[CH:15]([NH:14][C:9](=[O:11])[C:8]4[C:3]([C:2]([F:1])([F:13])[F:12])=[CH:4][CH:5]=[N:6][CH:7]=4)[CH2:16][N:17]([S:38]([C:41]4[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=4[Cl:48])(=[O:40])=[O:39])[CH:18]3[CH2:25][N:24]([CH:26]([CH3:28])[CH3:27])[C:23]2=[O:29])=[CH:32][CH:33]=1
Reactant: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Reactant: O=C(O)c1cnccc1C(F)(F)F
Product: CC(C)N1CC2N(C(=O)C(NC(=O)c3cnccc3C(F)(F)F)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O

Procedure:
Synthesis took place in analogy to Example 29e using 4-(trifluoromethyl)nicotinic acid and 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW=731.08 (calculated, monoisotopic); measured value (M+H)+: 732.07
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][C@H:12]([CH3:15])[CH2:13]O)[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:42]I>CCCCCCC.CCOC(C)=O>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][C@H:12]([CH3:15])[CH2:13][I:42])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: II
Reactant: C[C@H](CO)CN1C(=O)COc2cc(F)ccc21
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: C[C@H](CI)CN1C(=O)COc2cc(F)ccc21
Yield: 86.2 %

Procedure:
The compound (S)-7-Fluoro-4-(3-hydroxy-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (111MF18) (2.57 g, 11.0 mmol), triphenylphosphine (6.61 g, 23.7 mmol), imidazole (1.76 g, 25.8 mmol) and I2 (7.64 g, 30.1 mmol) were mixed according to GP9. CC (SiO2; Heptane/EtOAc 9:1-4) gave the title compound (111MF20) (3.31 g, 89%). 1H NMR (CDCl3) δ 7.00-6.96 (m, 1H), 6.78-6.74 (m, 2H), 4.65-4.56 (m, 2H), 3.92 (d, J=7.6 Hz, 2H), 3.21-3.13 (m, 2H), 2.13-2.03 (m, 1H), 1.04 (d, J=6.4 Hz, 3H); 13C NMR (CDCl3) δ 164.3, 159.0 (d, J=244.4 Hz), 146.6 (d, J=12.0 Hz), 125.0 (d, J=3.0 Hz), 115.9 (d, J=9.7 Hz), 109.4 (d, J=22.5 Hz), 105.5 (d, J=26.0 Hz), 67.8, 46.3, 33.6, 18.9, 11.8.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:30][Si:31]([C:34]#[C:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=1)([CH3:33])[CH3:32]>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:40]([C:39]2[CH:43]=[CH:44][C:36]([C:35]#[C:34][Si:31]([CH3:30])([CH3:33])[CH3:32])=[CH:37][CH:38]=2)=[O:41])[CH2:4][CH2:3]1
Reactant: C[Si](C)(C)C#Cc1ccc(C(=O)O)cc1
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc(C#C[Si](C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.3 %

Procedure:
1-Methylpiperazine (0.66 mL, 6.0 mmol), HOBt (0.84 g, 6.2 mmol) and EDCl (1.15 g, 6.0 mmol) were added to a solution of 4-[(trimethylsilyl)ethynyl]benzoic acid (1.0 g, 4.6 mmol) in dry DCM (45 mL). The mixture was stirred at room temperature for 4 h, washed with saturated aqueous sodium bicarbonate (30 mL), brine, dried over sodium sulphate, and evaporated. The crude was purified by flash chromatography on silica gel (DCM/MeOH 96/4) to afford the title compound (1.29 g, 93%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][N:6]2[CH:9]=[CH:10][N:11]=[C:5]2[CH:4]=1.C([O-])(=O)C.[Na+].[Br:19]Br>C(O)(=O)C>[Br:19][C:9]1[N:6]2[CH:7]=[N:8][C:3]([C:2]([F:12])([F:1])[F:13])=[CH:4][C:5]2=[N:11][CH:10]=1
Reactant: FC(F)(F)c1cc2nccn2cn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: FC(F)(F)c1cc2ncc(Br)n2cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-trifluoromethylimidazo[1,2-c]pyrimidine (1.9239 g, 10.3 mmol) in acetic acid (40 ml) was added sodium acetate (1.265 g, 15.4 mmol), then a solution of bromine (0.529 ml, 10.3 mmol) in acetic acid (7.5 ml). The solution was stirred at room temperature for 30 min, then partitioned between saturated aqueous NaHCO3 (1 l) and ethyl acetate (500 ml). The aqueous layer (pH 8) was further extracted with ethyl acetate (500 ml), and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 20% EtOAc/isohexane) to afford 0.88 g (34% over 2 steps) of the title compound as a white solid: 1H NMR (360 MHz, CDCl3) δ 7.81 (1H, s), 7.93 (1H, s), 9.09 (1H, s).
Reaction SMILES: [F:1][C:2]1([C:23]([O:25]C)=[O:24])[CH2:7][CH2:6][N:5]([CH:8]2[CH2:11][C:10]3([CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]3)[CH2:9]2)[CH2:4][CH2:3]1.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[CH2:11]1[C:10]2([CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:9][CH:8]1[N:5]1[CH2:6][CH2:7][C:2]([F:1])([C:23]([O:25][CH2:27][CH3:29])=[O:24])[CH2:3][CH2:4]1
Reactant: COC(=O)C1(F)CCN(C2CC3(CCN(C(=O)OC(C)(C)C)C3)C2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(F)CCN(C2CC3(CCNC3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-[4-fluoro-4-(methoxycarbonyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.300 g, 0.81 mmol) was dissolved in DCM (4 mL) and TFA (1 mL) was added. The reaction mixture was stirred at rt overnight under nitrogen, then the solvents were removed in vacuo, to give ethyl 1-(6-azaspiro[3.4]oct-2-yl)-4-fluoropiperidine-4-carboxylate trifluoroacetate, as a dark yellow oil which was used directly without further purification. The residue was dissolved in DCM (8 mL) at rt. NEt3 (0.246 g, 0.34 mL, 2.43 mmol) and ethyl chloroformate (0.176 g, 0.16 mL, 1.62 mmol) were added and the reaction mixture was stirred at rt overnight under nitrogen. The reaction mixture was partitioned between DCM and sat. NaHCO3 sol., organic layer washed with sat. NaCl sol. and dried over MgSO4. The residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63 μm, 60 A, 12 mL per min, gradient 0% to 10% MeOH in DCM]) to give ethyl 2-[4-fluoro-4-(methoxycarbonyl) piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.440 g, 158% impure) as a pale yellow oil.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][Cl:25])=[CH:20][N:19]=3)[CH:15]=2)[N:10]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)[C:9]=1[CH2:37][C:38]([O:40]CC)=[O:39])=[O:7])[CH3:4].Cl>O.CCO>[CH2:3]([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][Cl:25])=[CH:20][N:19]=3)[CH:15]=2)[N:10]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)[C:9]=1[CH2:37][C:38]([OH:40])=[O:39])=[O:7])[CH3:4]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(CCl)cn3)ccc2n1-c1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(CC(=O)O)n(-c2ccc(OC(F)(F)F)cc2)c2ccc(Oc3ccc(CCl)cn3)cc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
NaOH (17 mg, 0.43 mmol) in water (5 mL) was slowly added to 5-(5-chloromethylpyridin-2-yloxy)-2-ethoxycarbonylmethyl-1-(4-trifluoromethoxyphenyl)indole-3-carboxylic acid ethyl ester (50 mg, 0.086 mmol, see step (a) above) in EtOH (15 mL). The mixture was stirred at rt for 48 h, neutralized by addition of HCl (aq), concentrated and purified by preparative TLC. Yield 35 mg (74%), mp 168-170° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8].C(OC(=O)C)(=O)C.[PH2](O)=O.[CH:21](=O)[C:22]([CH3:25])([CH3:24])[CH3:23]>I.O>[CH3:1][C:2]1[NH:3][C:4]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8]
Reactant: CC(=O)c1c(C)c[nH]c1C
Reactant: CC(C)(C)C=O
Agent: I
Agent: O=[PH2]O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)c1c(C)[nH]c(CC(C)(C)C)c1C
Temperature: 35 °C

Procedure:
2,4-Dimethyl-3 -acetyl-pyrrole (548 mg) was warmed to solution in a mixture of 10 ml of aqueous hydriodic acid, 10 ml of acetic anhydride and 2 ml of hypophosphorous acid. The solution was cooled to 35° C. and 0.85 ml of pivalaldehyde were added. The solution was stirred for ten minutes, by which time the initially dark brown color had changed to yellow, then poured into 125 ml of water. The product separated as a colourless powder (769 mg, 93%), m.p. 156°-163 ° C. For analysis, it was recrystallized from ether-pentane, sublimed at 115° C. (10-4 mm), and again recrystallized by extraction into hexane (thimble) as long colourless plates, m.p. 166°-167° C. after changing to prisms below 130° C. Anal. Calc. for C13H21NO: C, 75.31; H, 10.21; N, 6.76. Found: C, 75.13; H, 10.30; N, 6.58.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[CH3:20])[CH3:11].[S-:21][C:22]#[N:23].[K+].BrBr>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([CH3:20])=[CH:15][C:16]2[N:17]=[C:22]([NH2:23])[S:21][C:18]=2[CH:19]=1)[CH3:11]
Reactant: Cc1cc(N)ccc1OC(C)c1c(Cl)ccc(F)c1Cl
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Product: Cc1cc2nc(N)sc2cc1OC(C)c1c(Cl)ccc(F)c1Cl
Yield: 17.5 %

Procedure:
6-[1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-methyl-1,3-benzothiazol-2-amine was prepared according to the method described in Example 20d but from 3.12 g of 4-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-methylaniline, 3.86 g of potassium thiocyanate and 0.509 cm3 of dibromine. We obtain 0.644 g of 6-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-methyl-1,3-benzothiazol-2-amine in the form of a yellow-coloured solid, which has the following characteristics:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([OH:12])([C:8]([F:11])([F:10])[F:9])[C:4]([F:7])([F:6])[F:5].[C:15](Cl)(=[O:19])[C:16]([CH3:18])=[CH2:17].CC1C=CC=CN=1>>[C:15]([O:12][C:3]([C:4]([F:7])([F:6])[F:5])([C:8]([F:9])([F:11])[F:10])[C:2]([F:13])([F:14])[F:1])(=[O:19])[C:16]([CH3:18])=[CH2:17]
Reactant: C=C(C)C(=O)Cl
Reactant: OC(C(F)(F)F)(C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccn1
Product: C=C(C)C(=O)OC(C(F)(F)F)(C(F)(F)F)C(F)(F)F
Yield: 78 %

Procedure:
Perfluoro-tertiary-butyl methacrylate was prepared from perfluoro-tertiary-butyl alcohol and methacrylyl chloride with 2-methyl pyridine as the acid acceptor without added solvent. The yield was 78%. The boiling point was 30°C./0.5 mm. This material is useful as a monomer for making plastics and resins.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:26][O:25][C:24]3[CH:27]=[C:28]4[C:32](=[CH:33][C:23]1=3)[CH2:31][CH2:30][O:29]4)[C:5](=[O:22])[N:6]2[CH2:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])=[O:13].BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2CCCCC.[N:61]1[CH:66]=[C:65](B(O)O)[CH:64]=[N:63][CH:62]=1.CN(C)C1N=CC(B(O)O)=CC=1>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][C:12](=[O:13])[CH2:11][N:6]1[C:7]2[C:3](=[C:2]([C:65]3[CH:66]=[N:61][CH:62]=[N:63][CH:64]=3)[CH:10]=[CH:9][CH:8]=2)[C:4]2([CH2:26][O:25][C:24]3[CH:27]=[C:28]4[C:32](=[CH:33][C:23]2=3)[CH2:31][CH2:30][O:29]4)[C:5]1=[O:22]
Reactant: OB(O)c1cncnc1
Reactant: O=C(CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2c(Br)cccc21)Nc1ccccc1F
Agent: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Agent: CN(C)c1ccc(B(O)O)cn1
Product: O=C(CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2c(-c3cncnc3)cccc21)Nc1ccccc1F

Procedure:
Following the procedure as described in EXAMPLE 4, and making non-critical variations using 2-(4′-bromo-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and pyrimidine-5-boronic acid to replace [6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound was obtained (53%) as a colorless solid: mp 229-230° C.; 1H NMR (300 MHz, CDCl3) δ 9.10 (s, 1H), 8.26-8.15 (m, 3H), 7.98 (s, 1H), 7.41 (t, 1H), 7.15-7.05 (m, 4H), 6.89 (d, 1H), 6.68 (s, 1H), 6.06 (s, 1H), 4.81-4.76 (m, 2H), 4.59-4.42 (m, 4H), 3.00 (t, 2H); 13C NMR (75 MHz, CDCl3) δ 178.2, 164.4, 162.5, 161.0, 157.0, 155.8, 141.8, 132.6, 131.1, 129.4, 125.8, 125.5, 125.4, 125.2, 125.1, 124.7, 121.9, 120.6, 119.9, 118.7, 115.1, 114.8, 109.5, 93.4, 79.0, 72.4, 57.8, 44.9, 28.9; MS (ES+) m/z 509.5 (M+1).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12]Cl)(=[O:3])[CH3:2].[I-:14].[Na+]>CC(C)=O>[C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][I:14])(=[O:3])[CH3:2]
Reactant: [I-]
Reactant: CC(=O)OCCOCCOCCCl
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)OCCOCCOCCI
Yield: 109 %

Procedure:
A mixture of 2-[2-(2-chloroethoxy)ethoxy]ethyl acetate (6.23 g) and sodium iodide (22.2 g) in acetone (60 mL) was refluxed for 4 hours. The mixture was further refluxed for 4 hours after adding sodium iodide (11.0 g). The solvent was evaporated off, and the residue was partitioend between EtOAc (50 mL) and water (50 mL). The aqueous layer was washed with 10% sodium thiosulfate and brine, dried over MgSO4, and evaporated to give 2-[2-(2-iodoethoxy)ethoxy]ethyl acetate as a pale yellow oil (9.74 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:10][C:11]([C@@H:13]1[C@@H:17]([OH:18])[C@@H:16]([OH:19])[C@H:15]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][C:23]([N:44]2[CH2:48][CH2:47][C@@H:46]([NH2:49])[CH2:45]2)=[N:24][C:25]=3[NH:29][CH2:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:14]1)=[O:12])[CH3:9].C1([O:56][C:57](=O)[NH:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[C:62]([OH:66])[CH:61]=2)C=CC=CC=1>CO>[CH2:8]([NH:10][C:11]([C@@H:13]1[C@@H:17]([OH:18])[C@@H:16]([OH:19])[C@H:15]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][C:23]([N:44]2[CH2:48][CH2:47][C@@H:46]([NH:49][C:57]([NH:58][CH2:59][C:60]4[CH:65]=[CH:64][CH:63]=[C:62]([OH:66])[CH:61]=4)=[O:56])[CH2:45]2)=[N:24][C:25]=3[NH:29][CH2:30][CH:31]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:14]1)=[O:12])[CH3:9]
Reactant: O=C(NCc1cccc(O)c1)Oc1ccccc1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)NCc5cccc(O)c5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
(2S,3S,4R,5R)-5-[2-((R)-3-Amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-3,4-dihydroxy-tetrahydro-furan-2-carboxylic acid ethylamide trifluoroacetate (Intermediate E) and (3-Hydroxy-benzyl)-carbamic acid phenyl ester (Intermediate UA) are dissolved in methanol and TEA. The reaction mixture is heated using microwave radiation at 100° C. for 30 minutes in the Personal Chemistry Emrys™ Optimizer microwave reactor. The reaction mixture is concentrated in vacuo and purified by C-18 reverse phase column chromatography eluting with acetonitrile:water (0.1% TFA) (gradient 0-100% acetonitrile) to afford the titled compound.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(N[S:23]([C:26]3[C:31](F)=[CH:30][CH:29]=[CH:28][C:27]=3F)(=[O:25])=[O:24])C=CC=2)C=CN=1.[NH2:34][C:35]1[C:36]([F:57])=[C:37]([C:41]2[N:42]=[C:43]([C:53]([CH3:56])([CH3:55])[CH3:54])[S:44][C:45]=2[C:46]2[CH:51]=[CH:50][N:49]=[C:48]([NH2:52])[N:47]=2)[CH:38]=[CH:39][CH:40]=1.C1(S(Cl)(=O)=O)C=CC=CC=1>>[NH2:52][C:48]1[N:47]=[C:46]([C:45]2[S:44][C:43]([C:53]([CH3:54])([CH3:56])[CH3:55])=[N:42][C:41]=2[C:37]2[C:36]([F:57])=[C:35]([NH:34][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:40]=[CH:39][CH:38]=2)[CH:51]=[CH:50][N:49]=1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Agent: O=S(=O)(Cl)c1ccccc1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccccc3)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (65 mg, 0.189 mmol) and benzenesulfonyl chloride (0.029 mL, 0.227 mmol), the title compound was obtained as an off white solid (60 mg, 65% yield). MS (ESI): 484 [M+H]+.
Reaction SMILES: [C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Cl)[CH:13]=1)=[CH:10]\[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[F:19]CCC(C1C=CC=CC=1)=O.[Si](OS(C(F)(F)F)(=O)=O)(C(C)(C)C)(C)C.CCN(CC)CC>C(Cl)Cl>[C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:19])[CH:13]=1)=[CH:10]\[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(CCF)c1ccccc1
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(F)c1
Yield: 93 %

Procedure:
Compound 9c was synthesized by a procedure similar to that described for 9a using commercially available 3-fluoropropiophenone (8c, 5.0 g, 0.033 mol), TBDMSOTf (8.3 mL, 36.1 mmol), and Et3N (7.3 mL) in CH2Cl2 (50 mL). After purification, 8.1 g (93%) of 9c was isolated as colorless oil: 1H NMR (CDCl3) δ 7.38-7.10 (m, 2H), 7.00-6.87 (m, 1H), 5.26 (q, 1H, J=6.9 Hz), 1.75 (d, 3H, J=6.9 Hz), 1.00 (s, 9H), −0.02 (s, 6H); 13C NMR (CDCl3) δ 164.5, 161.2, 149.2, 142.4, 129.4, 121.4, 114.3, 114.0, 112.8, 112.5, 107.1, 105.9, 26.0, 18.5, 11.9, −3.9. C15H23FOSi.