Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]1[C:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=2)=[C:12]([C:23]([F:26])([F:25])[F:24])[N:11]([CH:27]([CH2:30][F:31])[CH2:28][F:29])[N:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:21]([C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:13]2[C:9](=[O:8])[NH:10][N:11]([CH:27]([CH2:30][F:31])[CH2:28][F:29])[C:12]=2[C:23]([F:24])([F:25])[F:26])=[CH:20][CH:19]=1)[CH3:22]
Reactant: CCc1ccc(Cc2c(O[Si](C)(C)C(C)(C)C)nn(C(CF)CF)c2C(F)(F)F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1ccc(Cc2c(C(F)(F)F)n(C(CF)CF)[nH]c2=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
1.95 g (4.22 mmol) of 3-t-butyl dimethylsilyloxy-4-((4-ethylphenyl)methyl)-1-(1,3-difluoro-2-propyl)-5-(trifluoromethyl)pyrazole was added to 30 ml of tetrahydrofuran and cooled to 0° C. To the thus obtained mixture, 6.33 ml (6.33 mmol) of a 1M tetrahydrofuran solution of tetrabutylammonium fluoride was slowly added, and the obtained reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and purified with a silica gel column using a mixed solvent of ethyl acetate and hexane at a ratio of 1:4. Thus, 684 mg (1.96 mmol) of the intended product was obtained. (46% yield)
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[CH:8]1([NH:11][C:12]2[N:13]=[C:14]3[CH2:36][CH2:35][NH:34][CH:33]([CH3:37])[C:15]3=[N:16][C:17]=2[N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[CH2:20][CH2:19]2)[CH2:10][CH2:9]1.C=O.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:8]1([NH:11][C:12]2[N:13]=[C:14]3[CH2:36][CH2:35][N:34]([CH3:2])[CH:33]([CH3:37])[C:15]3=[N:16][C:17]=2[N:18]2[CH2:19][CH2:20][CH:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[CH2:22][CH2:23]2)[CH2:10][CH2:9]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC1NCCc2nc(NC3CC3)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc21
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1c2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NC3CC3)nc2CCN1C

Procedure:
A solution of N-cyclopropyl-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (15 mg, 0.028 mmol), formaldehyde (1.5 μL, 0.057 mmol), and DIPEA (5.0 μL, 0.028 mmol) in DCM (283 μL) was stirred for 10 min. To this was then added sodium triacetoxyborohydride (18.0 mg, 0.085 mmol) and the reaction mixture was stirred overnight. Purification by HPLC Method A afforded the title compound as a TFA salt (4 mg). 1H NMR (400 MHz, methanol-d4) 6 ppm 0.60-0.67 (m, 2H), 0.83-0.92 (m, 2H), 1.64-1.80 (m, 3H), 1.87-2.04 (m, 2H), 2.05-2.21 (m, 2H), 2.74 (tt, J=7.0, 3.6 Hz, 1H), 2.98-3.21 (m, 7H), 3.35-3.51 (m, 2H), 3.59 (d, J=6.6 Hz, 1H), 3.78 (br s, 1H), 4.42 (br s, 1H), 4.49 (td, J=7.4, 3.7 Hz, 1H), 6.86-6.93 (m, 1H), 6.96-7.05 (m, 1H), 7.18 (td, J=9.2, 5.3 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3][CH:2]=1.Cl[C:11]1[C:16]([CH2:17][NH:18][C:19]2[N:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[C:26]([Cl:31])[C:25]=3[Cl:32])[N:22]=[N:21][N:20]=2)=[CH:15][CH:14]=[CH:13][N:12]=1>>[Cl:32][C:25]1[C:26]([Cl:31])=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[N:23]1[C:19]([NH:18][CH2:17][C:16]2[C:11]([C:5]3[CH:6]=[N:1][CH:2]=[N:3][CH:4]=3)=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:20][N:21]=[N:22]1
Reactant: OB(O)c1cncnc1
Reactant: Fc1ccc(-n2nnnc2NCc2cccnc2Cl)c(Cl)c1Cl
Product: Fc1ccc(-n2nnnc2NCc2cccnc2-c2cncnc2)c(Cl)c1Cl

Procedure:
The title compound was prepared from pyrimidine-5-boronic acid and the product of Example 285B using General Procedure 6. MS (ESI+) m/z 417.2 (M+H)+; Rt=1.50 min. 1H-NMR (400 MHz DMSO-d6) δ 5.80 (s, 2H), 7.45 (t, J=8.9 Hz, 1H), 7.54 (m, 2H), 7.63 (m, 1H), 8.71 (dd, J=2.6 Hz, J=3.8 Hz, 1H), 9.02 (s, 3H), 9.27 (s, 1H).
Reaction SMILES: [FH:1].[C:2]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C:22](=[CH:23][CH2:24][C@:7]12[CH3:8])[C@:20]1([CH3:21])[C:15](=[CH:16][C:17](=[O:25])[CH2:18][CH2:19]1)[CH2:14][CH2:13]3)(=[O:4])[CH3:3].[Br:26]N1C(=O)CCC1=O.N>CN(C)C=O>[C:2]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@:22]([Br:26])([C@@H:23]([F:1])[CH2:24][C@:7]12[CH3:8])[C@:20]1([CH3:21])[C:15](=[CH:16][C:17](=[O:25])[CH2:18][CH2:19]1)[CH2:14][CH2:13]3)(=[O:4])[CH3:3]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]12C
Reactant: F
Reactant: O=C1CCC(=O)N1Br
Agent: N
Solvent: CN(C)C=O
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(Br)[C@@H](F)C[C@]12C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
At -78°, 80 ml. of hydrogen fluoride is combined with 32 ml. of dimethylformamide, 22 g. of 17β-acetoxy-4,9(11)-androstadien-3-one, and 16 g. of N-bromosuccinimide. The mixture is allowed to stand for 1.5 hours at -30° and then introduced into a mixture of ice/water and a 25% ammonia solution. The precipitate is filtered off, dissolved in a mixture of ethyl acetate and methylene chloride, washed with water, and dried over sodium sulfate. After chromatography with acetone/hexane, 9.1 g of 17β-acetoxy-9-bromo-11β-fluoro-4-androsten-3-one is obtained; m.p. 172°-174° UV: ε239 = 16,300 (methanol).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]([CH3:39])([CH3:38])[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=O)[CH2:31][CH2:30]1.[NH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([N:50]2[CH2:59][CH2:58][C:57]3[N:56]=[C:55]([CH3:60])[N:54]([CH2:61][C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)[C:53]=3[C:52]3[CH:68]=[CH:69][CH:70]=[CH:71][C:51]2=3)=[O:49])=[CH:44][C:43]=1[CH3:72].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:61]([N:54]1[C:53]2[C:52]3[CH:68]=[CH:69][CH:70]=[CH:71][C:51]=3[N:50]([C:48]([C:45]3[CH:46]=[CH:47][C:42]([CH2:41][NH:40][C:35]([CH:32]4[CH2:31][CH2:30][N:29]([CH2:28][CH2:27][C:26]([CH3:25])([CH3:39])[CH3:38])[CH2:34][CH2:33]4)=[O:37])=[C:43]([CH3:72])[CH:44]=3)=[O:49])[CH2:59][CH2:58][C:57]=2[N:56]=[C:55]1[CH3:60])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: Cc1cc(C(=O)N2CCc3nc(C)n(Cc4ccccc4)c3-c3ccccc32)ccc1CN
Reactant: CC(C)(C)CCN1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2CCc3nc(C)n(Cc4ccccc4)c3-c3ccccc32)ccc1CNC(=O)C1CCN(CCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
HBTU (175 mg, 0.46 mmol) was added to a solution of 1-(3,3-dimethyl-butyl)-piperidine-4-carboxylic acid (86 mg, 0.34 mmol) in DMF (5 ml). The mixture was stirred at room temperature for 2 h then (4-aminomethyl-3-methyl-phenyl)-(1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone from Example E121.2 (100 mg, 0.23 mmol) and DIEA (0.12 ml, 0.69 mmol) were added. The mixture was stirred at room temperature for 18 h then solvents were removed in vacuo and azeotroped with toluene. The residue was purified by flash chromatography on silica gel through an isolute (eluant; 5% methanol:95% dichloromethane then 10% methanol:90% dichloromethane) to give a yellow foam identified as the title compound (114 mg, 79%).
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CS(C)=O>CCOCC>[Br:19][CH2:10][CH2:9][CH2:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCC(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: CCOCC
Product: BrCCCC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
4,4-Diphenyl-1-butanol (22.41 g, 0.099 mol) was dissolved in ether (250 mL). CBr4 (41.07 g, 0.123 mol) was added and the reaction cooled to 0° C. Triphenylphosphine (38.96 g, 0.148 mol) in ether (400 mL) was added dropwise to the reaction. The reaction was then allowed to warm to room temperature overnight. DMSO (3.51 mL) was added, and the reaction allowed to stir for 8 hours. The white precipitate was filtered and washed with ether (100 mL). The ether was removed in vacuo, and the residue washed with hexanes and filter. The hexanes were removed in vacuo, and the residue chromatographed on silica gel eluting with hexanes to give 20.72 g (72%) of desired product as an oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21].[CH3:22][NH:23][CH3:24]>O1CCCC1>[ClH:21].[CH3:22][N:23]([CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21]
Reactant: CNC
Reactant: Clc1ccccc1CCc1ccccc1OCCCCBr
Solvent: C1CCOC1
Product: CN(C)CCCCOc1ccccc1CCc1ccccc1Cl
Product: Cl
Yield: 93 %

Procedure:
A solution of 3.0 g of 2-(4-bromobutoxy)-2'-chlorobibenzyl in 15 ml of 50% aqueous dimethylamine solution and 15 ml of tetrahydrofuran was stirred at room temperature for 5 hours. The reaction mixture was concentrated and to the concentrate was added 2 N-NaOH solution. The product was extracted with ether, washed well with saturated sodium chloride solution and then dried over anhydrous sodium sulfate. To the ether solution was added 20% ethanolic hydrogen chloride to yield white crystals. Recrystallization from ethanol-ether gave 2.8 g (93% yield) of 2-(4-dimethylaminobutoxy)-2'-chlorobibenzyl hydrochloride, m.p. 122°-123° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14]CCN1C(=O)C3C(=CC=CC=3)C1=O)[C:7]([CH3:28])=[C:6]2[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[C:35]([NH:42][CH2:43]CBr)([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14][CH2:43][NH:42][C:35](=[O:36])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:7]([CH3:28])=[C:6]2[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1ccc2c(=O)n(CCCN3C(=O)c4ccccc4C3=O)c(C)c(-c3ccccc3)c2c1
Reactant: CC(C)(C)OC(=O)NCCBr
Product: COc1ccc2c(=O)n(CCNC(=O)OC(C)(C)C)c(C)c(-c3ccccc3)c2c1

Procedure:
Following the procedure for 2-[3-(6-methoxy-3-methyl-1-oxo-4-phenylisoquinolin-2(1H)-yl)propyl]-1H-isoindole-1,3(2H)-dione, using 2-(Boc-amino)ethyl bromide in place of 3-phthalimido-1-bromopropane, tert-butyl 2-(6-methoxy-3-methyl-1-oxo-4-phenylisoquinolin-2(1H)-yl)ethylcarbamate was obtained.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38]CC1C=CC=CC=1)=[O:37]>[Pd].C(OCC)(=O)C.CO>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:10][CH2:11]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37]
Reactant: O=C(CCCCCN1CN(c2ccccc2)C2(CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)C1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)CCCCCN1CN(c2ccccc2)C2(CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
To a solution of benzyl 6-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)hexanoate (0.25 g, 0.41 mmol) in 4:1 ratio of ethyl acetate/methanol (4 mL), was added 10 wt % palladium on carbon (0.1 g). After stirring under hydrogen at room temperature and atmospheric pressure for 2 hours, the reaction mixture was filtered, washed with 1% acetic acid in methanol, concentrated in vacuo and isolated by reverse phase HPLC to obtain the title compound (0.09 g, 42%); 1H NMR (DMSO-d6): δ 1.21-1.26 (m, 2H), 1.47-1.57 (m, 6H), 1.77-1.82 (m, 2H), 2.18 (t, 2H, J=7.2 Hz), 2.32 (t, 2H, J=6.4 Hz), 2.59-2.67 (m, 6H), 2.91 (d, 2H, J=11.2 Hz), 3.84 (t, 2H, J=6.4 Hz), 4.64 (s, 2H), 6.76 (t, 1H, J=7.2 Hz), 6.88 (d, 2H, J=8.4 Hz), 6.96 (d, 3H, J=3.6 Hz), 7.18-7.20 (m, 1H), 7.24 (t, 2H, J=8.8 Hz), 10.82 (s, 1H); MS for C29H37N5O4 m/z 520.08 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:6]2[C:11]=1[C:10](=[O:12])[NH:9][C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N:7]2)[CH3:2].[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:25]([N:22]1[CH2:23][CH2:24][CH:19]([C:5]2[N:6]3[C:11]([C:10](=[O:12])[NH:9][C:8]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:7]3)=[C:3]([CH2:1][CH3:2])[N:4]=2)[CH2:20][CH2:21]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCc1nc(C2CCNCC2)n2nc(-c3ccccc3)[nH]c(=O)c12
Reactant: O=C(Cl)c1ccccc1
Product: CCc1nc(C2CCN(C(=O)c3ccccc3)CC2)n2nc(-c3ccccc3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 103 Step (b), 30 mg (0.09 mmol) 5-ethyl-2-phenyl-7-(4-piperidinyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one, 14 mg (0.10 mmol) benzoyl chloride are stirred at room temperature overnight, proportionate amounts of the solvents are used.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[C:6]2[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15][C:7]=2[N:8]=[C:9](S(C)(=O)=O)[N:10]=1.[NH2:31][C:32]1[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][CH:35]=[C:34]([NH:41][CH2:42][CH2:43][NH2:44])[N:33]=1>>[NH2:31][C:32]1[N:33]=[C:34]([NH:41][CH2:42][CH2:43][NH:44][C:9]2[N:10]=[C:5]([O:4][C:3]3[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:2]=3[Cl:1])[C:6]3[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15][C:7]=3[N:8]=2)[CH:35]=[CH:36][C:37]=1[N+:38]([O-:40])=[O:39]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(S(C)(=O)=O)nc(Oc3ccc(Cl)cc3Cl)c2C1
Reactant: NCCNc1ccc([N+](=O)[O-])c(N)n1
Product: CC(C)(C)OC(=O)N1CCc2nc(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc(Oc3ccc(Cl)cc3Cl)c2C1

Procedure:
Following Example 7, treatment of tert-butyl 4-(2,4-dichlorophenoxy)-2-(methylsulfonyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate with 2-amino-3-nitro-6-(2-aminoethylamino)pyridine gave tert-butyl 2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-(2,4-dichlorophenoxy)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]([O:13][CH3:14])=[O:12])=[N:4][C:5]([O:8][CH2:9][CH3:10])=[CH:6][CH:7]=1.[Cl:15]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[C:3]([C:11]([O:13][CH3:14])=[O:12])=[N:4][C:5]([O:8][CH2:9][CH3:10])=[CH:6][C:7]=1[Cl:15]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOc1ccc(N)c(C(=O)OC)n1
Solvent: CN(C)C=O
Product: CCOc1cc(Cl)c(N)c(C(=O)OC)n1
Temperature: 80 °C
Yield: 5.3 %

Procedure:
To a stirred solution of the compound prepared in Example 426 (0.048 g) in N,N-dimethylformamide (1.2 mL) was added N-chlorosuccinimide (0.0343 g). The resulting mixture was heated at 80° C. for 18 hours. The solvent was evaporated and the residue dissolved in dichloromethane and purified by column chromatography on silica gel (20% ethyl acetate in hexanes) to obtain the title compound (0.003 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2.[N-:22]=[N+:23]=[N-:24].[Na+].O.C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[C:3]([N:22]=[N+:23]=[N-:24])=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2c(ccc(Cl)c2F)OC1C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1=Cc2c(ccc(Cl)c2N=[N+]=[N-])OC1C(F)(F)F
Temperature: 85 °C
Yield: 74.2 %

Procedure:
To the solution of ethyl 6-chloro-5-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (1.0 g, 3.1 mmol) in 20 mL of DMSO was added a solution of sodium azide (1.0 g, 5 mmol) in minimum amount of water. The reaction was then heated to 85° C. for 15 hrs. After cooling to room temperature, to the reaction was added 200 mL of ethyl acetate. The resulting suspension was then washed with brine, and dried over anhydrous magnesium sulfate. After removing the solvents, the residue was purified on silica gel column with ethyl acetate/hexane, it gave 0.8 g of a yellow oil. Part of the product was purified on reverse phase HPLC for further analytical characterization. It gave a pink solid. LC-MS(ES+) 348.3(M+1, 70), 320.2(M−27, 100). 1H NMR(CDCl3/400 MHz) 7.99(s, 1H), 7.24(d, J=8.8 Hz, 1H), 6.75(d, J=8.8 Hz, 1H), 5.67(q, J=6.8 Hz, 1H), 4.32(m, 2H), 1.35(t, J=7.2 Hz, 3H). 19F NMR(CDCl3/400 Hz) −78.71(d, J=6.8 Hz). 13C NMR(CDCl3/400 Hz) 163.7, 152.7, 134.4, 133.9, 131.9,123.3(q, J=287.3 Hz), 122.6, 117.7, 114.6, 114.2, 70.6(q, J=33.3 Hz), 61.9, 14.4. HRSM(EI+) m/e calc. for (C13H9ClF3N3O3) 347.0285(M+), found: 347.0294(M+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].N[C:15](N)=[S:16].BrC[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].ICCCCCCCCCCCCSCCC(OC)=O>CS(C)=O>[OH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:16][CH2:15][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]
Reactant: OCCCCCCCCCCCBr
Reactant: NC(N)=S
Reactant: COC(=O)CCCCBr
Agent: COC(=O)CCSCCCCCCCCCCCCI
Solvent: CS(C)=O
Product: COC(=O)CCCCSCCCCCCCCCCCO
Temperature: 80 °C
Yield: 48 %

Procedure:
To a solution of 11-bromo-1-undecanol (10 g, 40 mmol) in DMSO (80 mL) was added thiourea (3.64 g, 48 mmol), and the mixture was allowed to react at room temperature for 21 hr. The mixture was extracted twice with hexane (20 mL) to remove the unreacted bromo alcohol. To the DMSO fraction was added 2N KOH (50 mL) and the mixture was heated at 80° C. for 5 min, releasing the thiol 11-mercapto-undecanol. The mixture was acidified (HCl) and extracted twice with ether (40 ml). The combined ether phases were washed successively with water and brine, dried over MgSO4, and evaporated under reduced pressure. The resulting thiol (≅7.2 g) was caused to react with methyl 5-bromo-pentanoate (7 g, 37 mmol) according to the procedure for compound 1. Crystallization of the product in hexane yielded 5.5 g (18 mmol 48% yield from the thiol) of methyl 17-hydroxy-6-thia-heptadecanoate. TLC (hexane/ether 1:1) showed a single product at Rf=0.3. Without further characterization, the hydroxy-ester (4 g, 12 mmol) was caused to react with Ts-Cl (2.7 g, 12 mmol) and pyridine (14 mmol) in CHCl2(40 mL) at 5° C. for 4 hr. The mixture was acidified with ice-diluted HCl, and the organic layer separated, dried (MgSo4) and evaporated under reduced pressure. The product 3 (2.4 g, 34% yield) was isolated by column chromatography (hexane/ethyl acetate 7:3) and recrystallized in hexane. TLC (hexane/ethyl acetate 7:3) Rf=0.6. Melting point=54° C. 1H-NMR δ1.3 (m, 22H, CH2), 2.38 (t. 2H, C(2)H2), 2.5 (m, 7H, C(5)H2, C(7)H2, (tosyl) CH3), 3.7 (s, 3H, —COO—CH3), 4.0 (t, 2H, C(17)H2), 7.6 (m, 4H, aryl).
Reaction SMILES: [SH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6](=[NH:10])OCC)=[CH:4][CH:3]=1.[CH3:13][C:14]1[N:15]=[CH:16][NH:17][C:18]=1[CH2:19][S:20][CH2:21][CH2:22][NH2:23]>C(O)C>[CH3:13][C:14]1[NH:15][CH:16]=[N:17][C:18]=1[CH2:19][S:20][CH2:21][CH2:22][NH:23][C:6](=[NH:10])[C:5]1[CH:4]=[CH:3][C:2]([SH:1])=[CH:12][CH:11]=1
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CCOC(=N)c1ccc(S)cc1
Solvent: CCO
Product: Cc1[nH]cnc1CSCCNC(=N)c1ccc(S)cc1

Procedure:
4-Cyanothiophenol was treated with hydrogen chloride in ether at 0° and the hydrochloride salt produced was treated with potassium carbonate to give ethyl 4-mercaptobenzimidate. Ethyl 4-mercaptobenzimidate was treated with 4-methyl-5-[(2-aminoethyl)-thiomethyl]imidazole in dry ethanol at room temperature to give the title product.
Reaction SMILES: [CH2:1]1[C@H:5]2[CH2:6][CH2:7][C@@H:8]([OH:9])[C@H:4]2[CH2:3][NH:2]1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]=1.C(N(CC)CC)C>C(O)C>[F:18][C:17]([F:20])([F:19])[C:13]1[N:12]=[C:11]([N:2]2[CH2:3][C@@H:4]3[C@H:8]([OH:9])[CH2:7][CH2:6][C@@H:5]3[CH2:1]2)[CH:16]=[CH:15][CH:14]=1
Reactant: FC(F)(F)c1cccc(Br)n1
Reactant: O[C@@H]1CC[C@@H]2CNC[C@@H]21
Solvent: CCO
Solvent: CCN(CC)CC
Product: O[C@@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Temperature: 80 °C

Procedure:
(3aR,4R,6aS)-Octahydrocyclopenta[c]pyrrol-4-ol (1.65 g, 12.97 mmol) from Example 29, 2-bromo-6-(trifluoromethyl)pyridine (3.66 g, 16.22 mmol) and triethylamine (7.23 mL, 51.9 mmol) were combined in ethanol (7.23 mL). The reaction was heated at 80° C. for 24 hours and the solvent was concentrated in vacuo. The resulting residue was purified by silica gel chromatography using 0-40% ethyl acetate/hexane as eluent to give the title compound and the title compound of Example 31: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.47 (t, J=7.9, 1H), 6.94 (d, J=7.2, 1H), 6.53 (d, J=8.6, 1H), 6.38 (d, J=4.1, 1H), 4.47-4.38 (m, 1H), 4.12 (dd, J=11.0, 4.3, 1H), 3.70-3.63 (m, 1H), 3.53 (t, J=10.0, 1H), 3.38 (dd, J=10.4, 4.6, 1H), 2.80-2.73 (m, 1H), 2.72-2.64 (m, 1H), 1.97-1.74 (m, 3H), 1.64-1.56 (m, 1H); MS (ESI+) m/z 273 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][NH2:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1)[CH2:10][NH:11][C:15]1[C:16]([Cl:20])=[CH:17][N:18]=[C:13]([Cl:12])[N:14]=1
Reactant: COc1cc(Br)cc(CN)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Br)cc(CNc2nc(Cl)ncc2Cl)c1
Yield: 85.6 %

Procedure:
To a solution of 1-(3-bromo-5-methoxyphenyl)methanamine (2.57 g, 11.9 mmol) and 2,4,5-trichloropyrimidine (2.4 g, 13 mmol) in N,N-dimethylformamide (30 mL) was added potassium carbonate (3.3 g, 24 mmol). The resultant mixture was stirred overnight at room temperature. The reaction mixture was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and brine successively, then dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography to give the desired product (3.7 g, 87%). LCMS for C12H10BrCl2N3O (M+H)+: m/z=361.9, 363.9.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[N:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:13]=3[N:14]=2)=[CH:22][CH:21]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: CCc1cc2c(NCc3ccc(F)cc3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-4-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(4-fluorobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.