Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([CH2:12][C:13]1[N:14]=[C:15]([NH:18][C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)=[O:20])[S:16][CH:17]=1)[CH3:11])(C)(C)C.Cl>O1CCOCC1>[ClH:29].[NH2:7][CH2:8][CH2:9][N:10]([CH2:12][C:13]1[N:14]=[C:15]([NH:18][C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)=[O:20])[S:16][CH:17]=1)[CH3:11]
Reactant: CN(CCNC(=O)OC(C)(C)C)Cc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Agent: Cl
Solvent: C1COCCO1
Product: CN(CCN)Cc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1

Procedure:
[2-({2-[3-(3,4-Dichloro-benzyl)-ureido]-thiazol-4-ylmethyl}-methyl-amino)-ethyl]-carbamic acid tert-butyl ester (Example 102) was treated with HCl, 4.0M in dioxane in a similar way as Example 78 to give the title compound. 1H NMR (400 MHz, CD3OD): 7.50-7.44 (m, 2H), 7.28-7.24 (m, 2H), 4.41 (s, 4H), 3.46 (br s, 4H), 2.95 (s, 3H). MS (ES+): M/Z 388, 390 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:12][Mg]Br>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])([CH3:12])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(=O)c1cc(F)cc(F)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(F)cc(F)c1
Reaction time: 4 h

Procedure:
To a solution of 1-(3,5-difluorophenyl)ethanone (1.0 equiv) in THF (0.2 M) at 0° C. was added methylmagnesium bromide (1.0 M in THF, 1.15 equiv). After stirring for 4 hours the reaction was quenched by addition of NH4Cl(sat), diluted with EtOAc, washed with NaCl(sat), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield 2-(3,5-difluorophenyl)propan-2-ol. To a solution of 2-(3,5-difluorophenyl)propan-2-ol in CH2Cl2 (0.1 M) at 0° C. was added 2,6 lutidine (6 equiv.) and than triisopropylsilyl trifluoromethanesulfonate (3.0 equiv.). After stirring for 3 hours at 0° C. and six hours at rt the solution was partitioned between EtOAc and NaHCO3(sat), separated, washed with NaCl(sat), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield (2-(3,5-difluorophenyl)propan-2-yloxy)triisopropylsilane. (400 MHz, <cdcl3>) δ ppm 1.05-1.08 (m, 21 H) 1.57 (s, 6 H) 6.63 (s, 1 H) 7.00 (dd, J=9.39, 2.35 Hz, 2 H).
Reaction SMILES: N12CS[CH2:9][CH:8]1[CH2:7][CH:6]1[CH:2]2[CH2:3]N(C(OCC)=O)C1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:3][CH2:2][CH2:6][CH2:7][CH2:8][CH2:9][CH2:8][CH2:7][CH2:6][CH2:2][CH3:3]
Reactant: CCOC(=O)N1CC2CC3CSCN3C2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCCCCCCCCC

Procedure:
12.5 g (50 mmol) of ethyl 10-thia-1,4-diazatricyclo[6.3.0.02,6 ]undecane-4-carboxylate together with 32 g of Ba(OH)2 ×8H2O are refluxed overnight in 225 ml of water. Potassium carbonate is added, barium carbonate is filtered off with suction, and the filtrate is extracted ten times using 100 ml portions of chloroform. The extracts are dried over potassium carbonate, concentrated and distilled.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C@@H:13]2[CH2:15][C@H:14]2[CH2:16][NH2:17])=[N:5]1.C(N(CC)CC)C.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>O1CCCC1>[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:17][CH2:16][C@@H:14]2[CH2:15][C@H:13]2[C:10]2[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=2)=[N:5][N:4]([CH3:3])[CH:12]=3)=[O:31])=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Cn1cc2c([C@@H]3C[C@H]3CN)cccc2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1cc2c([C@@H]3C[C@H]3CNC(=O)c3ccc(Br)cc3)cccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a solution of 1-[(1R,2R)-2-(2-methyl-2H-indazol-4-yl)cyclopropyl]methanamine dihydrochloride (200 mg, 0.729 mmol) and triethylamine (407 μL, 2.92 mmol) in tetrahydrofuran (7 mL) was added 4-bromobenzoyl chloride (192 mg, 0.875 mmol), and the mixture was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→90/10) to give the title compound (247 mg, yield 88%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[N:4]=[CH:5][N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=1.[Li]CCCC.CN([CH:26]=[O:27])C>>[F:17][C:2]([F:16])([F:1])[C:3]1[N:4]=[C:5]([CH:26]=[O:27])[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:13])([CH3:14])[CH3:15])[CH:7]=1
Reactant: C[Si](C)(C)CCOCn1cnc(C(F)(F)F)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1C=O
Yield: 14.2 %

Procedure:
Reaction of 4-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (590 mg, 2.2 mmol), 2.3 M n-BuLi (1.3 mL, 3.0 mmol), and DMF (0.51 mL, 6.6 mmol) followed by purification of the crude material on silica gel (10% EtOAc/hexanes) gave the title compound as a yellow oil (92 mg, 14% over two steps). 1H NMR (CDCl3) □0.02 (s, 9H), 0.95 (m, 2H), 3.60 (m, 2H), 5.79 (s, 2H), 7.28 (s, 1H), 7.67 (s, 1H), 9.86 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].CCN(CC)CC.[Si:14](Cl)([CH3:17])([CH3:16])[CH3:15]>CN(C1C=CN=CC=1)C>[CH3:15][Si:14]([CH3:17])([CH3:16])[O:6][C:2]([CH3:3])([C:4]#[CH:5])[CH3:1]
Reactant: C[Si](C)(C)Cl
Reactant: C#CC(C)(C)O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: C#CC(C)(C)O[Si](C)(C)C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
To a solution of 2-methylbut-3-yn-2-ol (140 g, 1.67 mol) was added DMAP (20 g 0.17 mol), Et3N (927 ml, 3.33 mol) and TMS-Cl (289 g, 2.66 mol) at 5 degree under a nitrogen atmosphere. After being stirred one hour, the mixture was washed with water, dried (MgSO4), filtered, concentrated, and distilled to obtain trimethyl[(2-methylbut-3-yn-2-yl)oxy]silane (150 g, 0.96 mol).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH3:12])=[N:6][N:5]2[C:13]=1[S:14]([N:17]=CN(CC(C)C)CC(C)C)(=[O:16])=[O:15].ClC1N=C2C=CC(C3CC3)=NN2C=1S(N=CN(CC(C)C)CC(C)C)(=O)=O>>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[CH3:12])=[N:6][N:5]2[C:13]=1[S:14]([NH2:17])(=[O:15])=[O:16]
Reactant: CC=Cc1ccc2nc(Cl)c(S(=O)(=O)N=CN(CC(C)C)CC(C)C)n2n1
Agent: CC(C)CN(C=NS(=O)(=O)c1c(Cl)nc2ccc(C3CC3)nn12)CC(C)C
Product: C/C=C/c1ccc2nc(Cl)c(S(N)(=O)=O)n2n1
Yield: 70.1 %

Procedure:
The reaction was carried out in the same manner as in Reference Example 12 except that N′-(2-chloro-6-(1-propenyl)imidazo[1,2-b]pyridazin-3-ylsulfonyl)-N,N-diisobutylformamidine as a mixture of E and Z was used in place of N′-(2-chloro-6-cyclopropylimidazo[1,2-b]pyridazin-3-ylsulfonyl)-N,N-diisobutylformamidine. The resulting crystals were purified by silica gel column chromatography (chloroform:methanol=20:1), to give the title compound as white crystals. The yield was 70.1%.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:8]2[CH2:9][CH:10]([OH:12])[CH2:11][CH:5]1[CH2:6][CH2:7]2.C(NC1C=C(OC)C=CC=1C1CCC2C(=CC=C(OC)C=2)C1)C.FC1C=C(C=CC=1F)C(Cl)=O.[CH2:47]([N:49]([C:60]1[CH:65]=[C:64]([O:66][CH3:67])[CH:63]=[CH:62][C:61]=1[CH:68]1[CH2:77][CH2:76][C:75]2[C:70](=[CH:71][CH:72]=[C:73]([O:78][CH3:79])[CH:74]=2)[CH2:69]1)[C:50](=[O:59])[C:51]1[CH:56]=[CH:55][C:54](F)=[C:53]([F:58])[CH:52]=1)[CH3:48].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:47]([N:49]([C:60]1[CH:65]=[C:64]([O:66][CH3:67])[CH:63]=[CH:62][C:61]=1[CH:68]1[CH2:77][CH2:76][C:75]2[C:70](=[CH:71][CH:72]=[C:73]([O:78][CH3:79])[CH:74]=2)[CH2:69]1)[C:50](=[O:59])[C:51]1[CH:56]=[CH:55][C:54]([O:12][CH:10]2[CH2:11][CH:5]3[N:4]([CH3:3])[CH:8]([CH2:7][CH2:6]3)[CH2:9]2)=[C:53]([F:58])[CH:52]=1)[CH3:48]
Reactant: CCN(C(=O)c1ccc(F)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Reactant: CN1C2CCC1CC(O)C2
Agent: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: O=C(Cl)c1ccc(F)c(F)c1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CCN(C(=O)c1ccc(OC2CC3CCC(C2)N3C)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.4 %

Procedure:
To a suspension of 60% sodium hydride (187 mg) in N,N-dimethylformamide (2 ml) was added tropine (599 mg) on an ice bath. The solution was stirred for 30 minutes while warming to room temperature. Synthesized from ethyl [5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine and 3,4-difluorobenzoyl chloride according to an analogous synthetic method to Preparation Example 87, a solution of N-ethyl-3,4-difluoro-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]benzamide (383 mg) in N,N-dimethylformamide (5 ml) was added the above solution followed by stirring overnight at 80° C. The reaction mixture was let to cool, then a saturated aqueous solution of sodium bicarbonate was added thereto, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous potassium carbonate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (chloroform-methanol system) to provide the title compound (143 mg).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]2=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[CH:19]=[C:20]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:22][CH:23]=1)CCC>>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:22]3[CH:23]=[CH:18][CH:19]=[C:20]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[CH:21]=3)=[CH:3][N:4]=[C:5]2[CH:10]=1
Reactant: COc1ccn2c(Br)cnc2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2cccnc2)c1
Product: COc1ccn2c(-c3cccc(-c4cccnc4)c3)cnc2c1

Procedure:
The title compound was prepared in a similar manner to that described in Example 11 from 3-bromo-7-methoxyimidazo[1,2-α]pyridine and 3-[3-(tri-n-butylstannanyl)phenyl]pyridine to furnish a white crystalline solid, m.p. 153-154° C. 1H NMR (360 MHz, CDCl3) δH 3.89 (3H, s), 6.57 (1H, dd, J 2 and 8), 6.94 (1H, d, J 2), 7.37-7.43 (1H, m), 7.55-763 (4H, m), 7.72 (1H, s), 7.89-7.94 (1H, m), 8.19 (1H, d, J 7), 8.62-8.65 (1H, m), 8.90 (1H, s); m/z (ES+) 302 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([N+:14]([O-])=O)[CH:4]=1.[H][H]>[Pd].COCCOC.CO>[NH2:14][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: [H][H]
Reactant: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OC
Agent: [Pd]
Solvent: COCCOC
Solvent: CO
Product: COc1cc(N)c(C(N)=O)cc1OC
Reaction time: 16 h

Procedure:
A suspension of 4,5-dimethoxy-2-nitrobenzamide (5.8 g, 25.6 mmol) in a 1:1 mixture of DME/MeOH (total volume 200 ml) and 10% Pd/C (0.7 g) was hydrogenated at RT using a balloon filled with hydrogen gas. The reaction was stirred for 16 h and the reaction mixture filtered through Celite®. The pad of Celite® was washed with a 1:1 mixture of MeOH/CH2Cl2 (200 mL). The filtrate was then concentrated in vacuo and dried under high vacuum overnight to give 2-amino-4,5-dimethoxybenzamide. (5.0 g, 25.5 mmol, 99%). HPLC retention time 2.303 mins.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>CN1CCCC1.CCOCC>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[C:10]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2]
Reactant: C1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2c(F)c(F)c(F)c(F)c21
Agent: CN1CCCC1
Solvent: CCOCC
Product: CCn1cc(C(=O)O)c(=O)c2c(F)c(F)c(N3CCCC3)c(F)c21
Reaction time: 1 h

Procedure:
A 200 mg portion of 1-ethyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was dissolved in 1 ml of 1-methylpyrrolidine with warming. A 130 mg portion of pyrrolidine was added dropwise, the reaction was allowed to stand one hour and then diluted with ether. The solid was collected, washed with ether and hexane, dried and recrystallized from a mixture of dichloromethane-acetone, giving 140 mg of the desired product as white crystals, mp >320° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[C:5]2[CH2:19][CH2:20][C:21](O)=[O:22].Cl.[F:25][C:26]([F:41])([F:40])[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)=[C:5]2[CH2:19][CH2:20][C:21]([N:37]1[CH2:36][CH2:35][N:34]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[O:27][C:26]([F:40])([F:25])[F:41])[CH2:39][CH2:38]1)=[O:22]
Reactant: Cn1c(-c2ccc(Cl)cc2)c(CCC(=O)O)c2cc(Cl)ccc21
Reactant: FC(F)(F)Oc1ccccc1N1CCNCC1
Agent: Cl
Product: Cn1c(-c2ccc(Cl)cc2)c(CCC(=O)N2CCN(c3ccccc3OC(F)(F)F)CC2)c2cc(Cl)ccc21

Procedure:
Prepared from 5-chloro-2-(4-chlorophenyl)-1-methyl-1H-indole-3-propanoic acid (Description 12) and 1-[2-(trifluoromethoxy)phenyl]piperazine hydrochloride (Description 19) according to the method of Description 25. 1H NMR (360 MHz, CDCl3) δ7.60 (1H, d, J 1.7 Hz), 7.49 (2H, m), 7.32 (2H, m), 7.24-7.18 (4H, m), 7.04-7.00 (1H, m), 6.93 (1H, dd, J 1.3, 8.0 Hz), 3.71 (2H, t, J 5.0 Hz), 3.54 (3H, s), 3.37 (2H, t, J 5.0 Hz), 3.02 (2H, m), 2.95 (2H, t, J 5.0 Hz), 2.80 (2H, t, J 5.0 Hz), and 2.54 (2H, m). m/z (ES+) 576, 578 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=4[O:31][CH3:32])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12](O)=[O:13])=[CH:4][CH:3]=1.C(OC(=O)[NH:39][CH2:40][CH2:41][NH2:42])(C)(C)C.Cl>>[NH2:39][CH2:40][CH2:41][NH:42][C:12](=[O:13])[CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:15]([N:17]2[CH2:18][CH2:19][CH:20]([C:23]3[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=3[O:31][CH3:32])[CH2:21][CH2:22]2)=[O:16])=[CH:7]1
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2cn(CC(=O)O)c3cc(Cl)ccc23)CC1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: Cl
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cn(CC(=O)NCCN)c3cc(Cl)ccc23)CC1

Procedure:
Analogous to general procedure I, the coupling of {6-chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetic acid (prepared herein) with (commercially available) (2-amino-ethyl)-carbamic acid tert-butyl ester gave, after treatment with HCl and neutralisation, the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]1([CH2:15][C:16](Cl)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:16](=[O:17])[CH2:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
1.0 g (9.3 mmol) of 4-methylaniline is dissolved in toluene (10 ml) at 0° C., under a nitrogen atmosphere. A solution of phenylacetyl chloride (1.25 ml, 9.4 mmol) in 20 ml of toluene is added dropwise to the medium. The reaction mixture is stirred at room temperature for 2 h and the medium is then hydrolyzed with cold sodium hydrogen carbonate solution. The two-phase system is stirred vigorously for 30 min and the organic phase is then collected. The aqueous phase is extracted with ethyl acetate (twice). The organic phase is dried over MgSO4 and then evaporated. The residue obtained is purified by chromatography on a column of silica (3/7 EtOAc/PE) to give 1.9 g (92%) of compound 47.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH3:32])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29](O)=[O:30])[CH2:24]2)[O:12]1.[O:33]1[CH2:36][CH:35]([C:37]2[CH:38]=[C:39]([NH2:44])[C:40]([NH2:43])=[CH:41][CH:42]=2)[CH2:34]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>C(Cl)Cl>[NH2:43][C:40]1[CH:41]=[CH:42][C:37]([CH:35]2[CH2:34][O:33][CH2:36]2)=[CH:38][C:39]=1[NH:44][C:29](=[O:30])[CH2:28][CH2:27][CH:25]1[CH2:26][CH:23]([N:22]([CH2:21][C@@H:13]2[C@@H:14]3[C@@H:15]([O:16][C:17]([CH3:20])([CH3:19])[O:18]3)[C@H:11]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[NH2:1])[O:12]2)[CH3:32])[CH2:24]1
Reactant: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)O)C1
Reactant: Nc1ccc(C2COC2)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)Nc2cc(C3COC3)ccc2N)C1
Temperature: 15 °C
Reaction time: 5.25 h
Yield: 82 %

Procedure:
A suspension of the above crude 3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanoic acid and 4-(oxetan-3-yl)benzene-1,2-diamine (0.135 g, 0.822 mmol) in methylene chloride (8.0 mL) was treated with N,N-diisopropylethylamine (0.716 mL, 4.11 mmol) and cooled to −5° C. (ice/brine). N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate [HATU] (0.469 g, 1.23 mmol) was added and the reaction mixture was stirred for 5.25 h, warming to 15° C.; HPLC/LC MS indicated complete conversion. The reaction mixture was concentrated in vacuo and diluted with CH2Cl2 (15 mL) and water (7.5 mL). The separated aqueous layer was extracted with CH2Cl2 (2×10 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford a brown-purple semi-opaque oil/foam. Purification by column chromatography (2×8 cm silica; 0-5% 7 N methanolic NH3/CH2Cl2) afforded both amide regioisomers of the title compound (0.45 g, 82%) as a semi-opaque pink foam: MS (ESI+) for C30H40N8O5 m/z 593.3 (M+H)+; MS (ESI−) for C30H40N8O5 m/z 591.3 (M−H)− and 637.4 (M+HCO2)−; HPLC purity 90% (ret. time, 2.097 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH:14]([NH:17][CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15]>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([N:17]([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])=[O:6]
Reactant: CC(C)NC(C)C
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Solvent: ClCCl
Product: COc1ccc(C(=O)N(C(C)C)C(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of 2,4-dimethoxybenzoyl chloride (10.0 g, 50 mmol) in 10 mL of dichloromethane at 0° C. is treated with 30 mL of diisopropylamine. This solution is stirred at room temperature for 1 hour and the resulting solution is partitioned between ethyl acetate and water. The organic layer is washed with 1N hydrochloride solution, 1N sodium hydroxide solution, water and brine, dried over sodium sulfate and concentrated in vacuo to give 2,4-dimethoxy-N,N-bis(1-methylethyl)benzamide.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]2[S:5](=[O:7])(=[O:6])[NH:4][CH2:3][CH2:2][C:13]=2[CH:12]=1
Reactant: O=S(=O)(NCCBr)c1ccc(Cl)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: O=S1(=O)NCCc2cc(Cl)ccc21
Yield: 4.2 %

Procedure:
A two-necked flask equipped with a condenser and a rubber septum was charged with N-(2-bromoethyl)-4-chlorobenzenesulfonamide (2.80 g, 9.4 mmol) and anhydrous benzene (50 mL). The reaction vessel was degassed and backfilled with argon and then heated to reflux. Under reflux, a solution of tributyltin hydride (5.05 mL, 18.8 mmol) and 2,2′-azobis(2-methylpropionitrile) (0.77 g, 4.7 mmol) in anhydrous benzene (25 mL) was added slowly over 8 hours using a syringe pump, and the mixture was refluxed for a further 12 hours. After cooling, the reaction mixture was concentrated and the residue purified by silica gel column chromatography (0-40% ethyl acetate in methylene chloride) followed by preparative TLC (1:2 ethyl acetate in hexanes) to afford the pure product as a white foam (0.085 g, 4%). 1H NMR (300 MHz, CDCl3) δ 7.77 (d, 1H, J=8.4 Hz), 7.37 (dd, 1H, J=8.1, 2.1 Hz), 7.26 (s, 1H), 4.47 (t, 1H, J=7.5 Hz), 3.83 (dt, 2H, J=7.5, 6.0 Hz), 3.00 (t, 2H, J=6.0 Hz).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]1([CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH3:45])[C:23]2[CH:22]=[C:21]([C:24]#[C:25]C(C)(O)C)[CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][C:14]([C:30]#[C:31]C(C)(O)C)=[CH:15][CH:16]=2.[OH-].[Na+]>C1(C)C=CC=CC=1.CC(O)C>[C:30]([C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[C:23](=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=3)[C:11]([CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])([CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH3:45])[C:12]=2[CH:13]=1)#[CH:31]
Reactant: COCCOCCOCCC1(CCOCCOCCOC)c2cc(C#CC(C)(C)O)ccc2-c2ccc(C#CC(C)(C)O)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: C#Cc1ccc2c(c1)C(CCOCCOCCOC)(CCOCCOCCOC)c1cc(C#C)ccc1-2
Yield: 58.2 %

Procedure:
To a solution of 4,4′-[9,9-bis[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-9H-fluorene-2,7-diyl]bis(2-methyl-3-butyn-2-ol) (0.363 g, 0.58 mmol) in 9 mL of toluene and 2 mL of i-PrOH, was added solid NaOH (0.15 g, 3.75 mmol). The mixture was heated under reflux for 1.5 h. After cooling, NaOH was filtered off and the solvents were evaporated and the residue was purified by column chromatography on silica gel (CH2Cl2/AcOEt 60:40) to yield 0.171 g (58%) of 2,7-diethynyl-9,9-bis[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-9H-fluorene, mp 68° C.; 1H NMR (CDCl3) δ 2.37 (t, 4H, J=7.8 Hz), 2.74 (t, 4H, J=7.2 Hz), 3.17 (s, 2H), 3.20 (m, 4H), 3.35 (s, 6H), 3.39 (m, 4H), 3.54-3.47 (m, 8H), 7.50 (dd, 2H, J=7.8 Hz, J=1.3 Hz), 7.55 (d, 2H, J=1.3 Hz). 7.63 (d, 2H, J=7.8 Hz); 13C NMR (CDCl3) δ 39.5, 51.3, 59.1, 65.9, 66.8, 70.0, 70.4, 71.8, 77.9, 84.1, 120.1, 121.2, 127.0, 131.7, 140.2, 149.3. Anal. Calcd for C31H38O6 (506.63): C, 73.49; H, 7.56. Found: C, 73.59; H, 7.64.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].Cl[C:11](OC(Cl)(Cl)Cl)=[O:12]>O1CCCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][C:11](=[O:12])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc(F)ccc1O
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(F)ccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
To a solution of 2-amino-4-fluorophenol (40.5 g, 0.32 mole) in 400 ml tetrahydrofuran, at 0° C., was added dropwise trichloromethyl chloroformate (44.8 ml, 0.32 mole). The reaction mixture was allowed to warm up to room temperature Stirring was continued for 2 hours. Then, the reaction mixture was poured onto ice and the organic substance was extracted with ethyl acetate (500 ml×3). The combined extracts were washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated to yield 44.3 g of the title compound as brown solids.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]1(=O)[O:13][CH2:12][CH2:11][CH2:10]1>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[N:4]1[CH2:9][CH2:10][CH2:11][C:12]1=[O:13]
Reactant: Nc1ccccc1Cl
Reactant: O=C1CCCO1
Product: O=C1CCCN1c1ccccc1Cl
Yield: 25.4 %

Procedure:
Following example 19, 12.57 g (0.1 M) of 2-chloroaniline and 9.5 g (0.11 M) of γ-butyrolactone were heated for 48 hours. The excess starging materials were removed at 50°-80°/0.3 mm. Distillation of the residue gave 4.9 g (25%) of product (45% based on recovered 2-chloroaniline); b.p. 150°-155°/0.3-0.4 mm.