Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)=[CH:7][C:4]=1[C:5]#[N:6].[OH-].[Na+].O>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: COc1ccc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncccc23)cc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2c[nH]c3ncccc23)cc1C#N
Yield: 45.2 %

Procedure:
The nitrile 37 (95.8 mg, 237 μmol) was dissolved in dioxane (5 ml) and treated with 2N sodium hydroxide in water (250 μl, 500 μmol). The reaction was sealed and heated to reflux for 2 hours. The reaction was concentrated to dryness and extracted with ethyl acetate and water. The organics were washed with brine, dried over sodium sulfate, filtered and concentrated to give crude product (72.3 mg). The crude was purified via flash chromatography and eluted with a gradient from 1:1 ethyl acetate/hexane to 100% ethyl acetate to 4/4/1 ethyl acetate/hexane/7N ammonia in methanol to give 38 (26.7 mg, 45%).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[CH2:8]([C@:15]1([CH2:21][C:22]([OH:24])=[O:23])[CH2:19][CH2:18][C@@H:17]([CH3:20])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1.CO>[CH3:1][O:23][C:22](=[O:24])[CH2:21][C@@:15]1([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:19][CH2:18][C@@H:17]([CH3:20])[CH2:16]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C[C@@H]1CC[C@@](CC(=O)O)(Cc2ccccc2)C1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C[C@@]1(Cc2ccccc2)CC[C@@H](C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Trimethylsilyldiazomethane (31.5 mL of a 2 M solution in hexanes, 63 mmol) was added dropwise to a stirring solution of ((1S,3R)-1-benzyl-3-methyl-cyclopentyl)-acetic acid (10 g, 43 mmol) in toluene (80 mL) and methanol (20 mL) at 0° C. under argon, and the mixture was allowed to warm to room temperature. The mixture was stirred for 1 hour, and then the solvent was evaporated under reduced pressure. The residue was taken up in ethyl acetate (50 mL), washed with saturated sodium hydrogen carbonate solution, dilute hydrochloric acid, dried (MgSO4), and the solvent removed in vacuo to give 10.6 g (100%) of ((1S,3R)-1-benzyl-3-methyl-cyclopentyl)-acetic acid methyl ester;
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=1.Cl>O1CCCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:22][C:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=2)=[O:23])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: CC(=O)c1ccc(C)cc1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)C=Cc2cc(O)c(O)c([N+](=O)[O-])c2)cc1

Procedure:
A solution containing 5.49 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 5.37 g of 4'-methylacetophenone in 50 ml of tetrahydrofuran was added a catalytic amount of gaseous hydrogen chloride and refluxed for 4.5 h. The solvent was evaporated in vacuo and the residue crystallized from ether-petroleum-ether, yield 1.85 g (21%), m.p. 184°-186° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:41][CH2:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)c1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1
Reactant: NCc1ccccc1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4ccnc(NCc5ccccc5)n4)n[nH]c3n2)CC1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
The mixture of {4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 9 supra) (150 mg, 0.32 mmol) and benzylamine (138 mg, 1.3 mmol) was heated at 130° C., with stirring for 2 hours. The residue was purified by chromatography (silica gel, 6 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) and then further purified by prep-HPLC to afford {4-[3-(2-benzylamino-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester. (Yield 30 mg, 18.4%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](Cl)=[O:13])[CH:6]=[CH:5]2.[NH:15]1[C:19]2[CH:20]=[CH:21][C:22]([NH2:24])=[CH:23][C:18]=2[N:17]=[CH:16]1>>[NH:15]1[C:19]2[CH:20]=[CH:21][C:22]([NH:24][C:12]([C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=4)[CH:8]=3)=[O:13])=[CH:23][C:18]=2[N:17]=[CH:16]1
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: O=C(Cl)c1ccc2cc(Br)ccc2c1
Product: O=C(Nc1ccc2[nH]cnc2c1)c1ccc2cc(Br)ccc2c1

Procedure:
This material was prepared analogous to the procedure described for Example 1 (b). 6-Bromo-naphthalene-2-carbonyl chloride, Example 1(a), reacted with 1H-benzoimidazol-5-ylamine (TimTec) to give the title compound as an amorphous solid. MS (ESI, pos. ion.) m/z: 366 (M+1).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][S:39]([CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:41])=[O:40]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:47]3[CH2:46][CH2:45][N:44]([CH2:43][CH2:42][S:39]([CH3:38])(=[O:40])=[O:41])[CH2:49][CH2:48]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCN1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 1-(2-methanesulfonyl-ethyl)-piperazine (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound. HR-MS (ES, m/z) calculated for C36H46Cl2N5O4S [(M+H)+] 714.2642, observed 714.2641.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([NH:19][CH:20]([CH3:25])[CH:21]=[C:22](Cl)Cl)=[O:18])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][O-:27].[Na+]>CN1CCCC1=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:21]([CH2:22][O:27][CH3:26])=[C:20]([CH3:25])[N:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C=C(Cl)Cl)NC(=O)c1nn(Cc2ccccc2)c2ccccc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COCc1oc(-c2nn(Cc3ccccc3)c3ccccc23)nc1C
Yield: 40.3 %

Procedure:
100 mg of 3-(1-benzylindazole-3-carboxamido)-1,1-dichloro-but-1-ene (0.267 mmol) and 29 mg of sodium methylate were stirred in 0.5 ml of N-methylpyrrolidone at 100° C. under argon overnight. The crude mixture was cooled and purified directly by column chromatography (SiO2, cyclohexane:ethyl acetate 3:1). 35.9 mg (40%) of 2-(1-benzylindazol-3-yl)-5-methoxymethyl-4-methyloxazole were isolated as a yellowish oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][C:18]=1[CH3:26].O[N:28]=[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][C:38]([F:41])([F:40])[F:39])[NH2:30].CCN(C(C)C)C(C)C>>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:25][N:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][C:38]([F:39])([F:40])[F:41])[N:28]=2)=[CH:19][C:18]=1[CH3:26]
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2C)c(OC)c1
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2ccc(-c3nc(-c4ccccc4OC(F)(F)F)no3)cc2C)c(OC)c1

Procedure:
Oxalyl chloride (112 μL; 1.32 mmol; 3 eq.), Intermediate 28 (120 mg; 0.44 mmol; 1 eq.), Intermediate 2 (97 mg; 0.44 mmol, 1 eq.) and DIEA (228 μL; 1.32 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 95/5) afforded the title compound as a white solid.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1.CC(C)=O>C(O)C>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: N#Cc1ccc(CBr)cc1
Solvent: CCO
Solvent: CC(C)=O
Product: N#Cc1ccc(CN2CCN(c3ccccc3)CC2)cc1
Yield: 79.3 %

Procedure:
4-phenylpiperazine (41.4 g, 0.26 mol) was added to a solution of 4-(bromomethyl)benzonitrile (25 g, 0.13 mol) in 60 ml ethanol and the mixture was refluxed for one hour. After filtration of the precipitated N-phenylpiperazinium bromide, the filtrate was evaporated and the residue was recrystallized in a chloroform: acetone mixture to afford 28.6 g (79% yield) of 4-(4-phenylpiperazinylmethyl)benzonitrile.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[S:13][C:12]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[N:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C:1]1([C:7]#[C:8][C:9]2[S:13][C:12]([C:14]3[S:15][C:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:17][CH:18]=3)=[N:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C(#Cc1cnc(-c2cccs2)s1)c1ccccc1
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(-c2ncc(C#Cc3ccccc3)s2)s1
Temperature: -78 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
Under a dry nitrogen atmosphere, a stirred solution of 0.80 gram (0.0030 mole) of 1-phenyl-2-[2-(thien-2-yl)thiazol-5-yl]ethyne in 20 ml of tetrahydrofuran was cooled to -78° C. A solution of n-butyllithium (1.4 ml of a 2.1M solution in hexane) was added, and the mixture was stirred at -78° C. for two hours. This mixture was transferred to another reaction flask containing a stirred solution of 0.65 gram (0.0060 mole) of ethyl chloroformate in 10 ml of tetrahydrofuran. This reaction mixture was allowed to warm slowly to room temperature and stir for approximately 18 hours. An aqueous, saturated ammonium chloride solution (20 ml) was added dropwise. The resultant mixture was extracted with diethyl ether. The organic extract was washed with water followed by an aqueous, saturated sodium chloride solution. The washed extract was dried over anhydrous sodium sulfate and was filtered. The filtrate was evaporated under reduced pressure leaving a residue. This residue was purified by column chromatography on silica gel, eluting with methylene chloride:n-hexane (3:2), to yield 0.82 gram of ethyl [5-[5-phenylethynylthiazol-2-yl]thien-2-yl]carboxylate as a solid, m.p. 137°-141° C., Compound 30 of Table 1.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31]C(=O)C(C)(C)C)[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)(O)=O.[CH2:40]([NH:44][CH3:45])[CH2:41][CH2:42][CH3:43]>>[CH2:40]([N:44]([CH3:45])[CH2:1][CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)[CH2:41][CH2:42][CH3:43]
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Reactant: CCCCNC
Product: CCCCN(C)CCc1ccc(CCCNc2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 17.8 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and butylmethylamine (22 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (3.2 mg) was obtained.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9](=[O:23])[CH2:10][C@H:11]2[C@H:16]([O:17]C)[CH2:15][CH2:14][CH2:13][N:12]2C(OC)=O)[CH:6]=[N:5][C:4]2[C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[O:26][C:3]1=2.[BrH:31]>C(O)C>[BrH:31].[BrH:31].[OH:17][C@@H:16]1[CH2:15][CH2:14][CH2:13][NH:12][C@H:11]1[CH2:10][C:9](=[O:23])[CH2:8][N:7]1[C:2](=[O:1])[C:3]2[O:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[C:4]=2[N:5]=[CH:6]1
Reactant: COC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2c(oc3ccccc32)c1=O
Agent: Br
Solvent: CCO
Product: O=C(C[C@@H]1NCCC[C@H]1O)Cn1cnc2c(oc3ccccc32)c1=O
Temperature: 25 °C
Reaction time: 0.2 h

Procedure:
A solution of 0.600 g (0.00145 mole) of methyl trans-2-[3-(3,4-dihydro-4-oxobenzofuro[3,2-d]pyrimidin-3-yl)-2-oxopropyl]-3-methoxy-1-piperidinecarboxylate and 30 ml of 48% hydrobromic acid in a 100 ml round bottom flask was immersed in a bath preheated to 150° C. and held there for 12 minutes. Upon cooling to room temperature, the solution was evaporated under reduced pressure to afford a residue. The residue was heated with ethanol briefly; the mixture was allowed to cool, and the ethanol removed by pipette to furnish the title compound: m.p. 257°-258° C.; yield 0.28 g (41%); 1H-nmr (DMSO-d6) delta 1.4-2.0 ppm (multiplet, 4H, CH3OCHCH2CH2CH2N), 2.8-3.0 (multiplet, 2H, NCH2), 3.1-3.5 (multiplet, includes H2O, CHOH, COCH2CH, and CH2CHNCO), 5.2 (singlet, 2H, NCH2CO), 7.5 (triplet, 1H, aromatic H), 7.7 (triplet, 1H, aromatic H), 7.9 (doublet, 1H, aromatic H), 8.1 (doublet, 1H, aromatic H), 8.4 (singlet, 1H, N=CH--N), 8.7 (broad singlet, 1H, OH).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:22](Cl)=[O:23]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(Cl)c(Cl)c4)cc23)CC1
Yield: 81.9 %

Procedure:
Beginning with 10 mg (0.0437 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 9.6 mg (0.0458 mMol) 3,4-dichlorobenzoyl chloride, 14.4 mg (82%) of the title compound were recovered.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][CH:8]([N:14]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[CH2:7]2)([O-])=O>C(O)(=O)C.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][CH:8]([N:14]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[CH2:7]2
Reactant: CCCN(C(=O)CC)C1COc2ccc([N+](=O)[O-])cc2C1
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCN(C(=O)CC)C1COc2ccc(N)cc2C1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 55.6 %

Procedure:
A solution of 6-nitro-3-(N-propionyl-N-n-propylamino)chroman (17) (700 mg, 2.40 mmol) in glacial acetic acid (50 ml) was treated with zinc dust (1.0 g). The mixture was stirred at 50° C. for 90 minutes. The solution was filtered and acetic acid evaporated at reduced pressure. The product was dissolved in CH2Cl2 and washed with 5%-aqueous Na2CO3. The organic layer was separated, dried (Na2SO4) and the solvent was evaporated. The crude product was chromatographed on silica (60 g), with CH2Cl2CH3OH (19:1) as eluant, yielding 350 mg (56%) of 6-amino-3-(N-propionyl-N-n-propylamino)chroman (18) as an oil.
Reaction SMILES: [C:1](OCC#N)(=[O:5])[CH2:2][CH:3]=[CH2:4].C([N+](CCCC)(CCCC)CCCC)CCC.[P:27]([O:31][CH2:32][C@@H:33]1[C@@H:37]([O:38][P:39]([O:42][CH2:43][C@@H:44]2[C@@H:48]([OH:49])[C@@H:47]([OH:50])[C@H:46]([N:51]3[CH:59]=[N:58][C:57]4[C:52]3=[N:53][CH:54]=[N:55][C:56]=4[NH2:60])[O:45]2)([OH:41])=[O:40])[CH2:36][C@H:35]([N:61]2[CH:66]=[CH:65][C:64]([NH2:67])=[N:63][C:62]2=[O:68])[O:34]1)([OH:30])([OH:29])=[O:28].C(O)(C(F)(F)F)=O>CN(C=O)C>[C:1]([O:49][C@H:48]1[C@@H:47]([OH:50])[C@H:46]([N:51]2[CH:59]=[N:58][C:57]3[C:52]2=[N:53][CH:54]=[N:55][C:56]=3[NH2:60])[O:45][C@@H:44]1[CH2:43][O:42][P:39]([O:38][C@H:37]1[CH2:36][C@H:35]([N:61]2[CH:66]=[CH:65][C:64]([NH2:67])=[N:63][C:62]2=[O:68])[O:34][C@@H:33]1[CH2:32][O:31][P:27]([OH:30])([OH:29])=[O:28])([OH:41])=[O:40])(=[O:5])[CH2:2][CH:3]=[CH2:4]
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: C=CCC(=O)OCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: C=CCC(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyanomethyl but-3-enoate (Compound 86) (0.050 g, 0.400 mmol) was added to a solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate tetrabutylammonium salt (Compound 1h) (0.20 g, 0.150 mmol) in DMF (1.0 ml), and the mixture was stirred at room temperature for 1 hour. A 0.05% aqueous TFA solution was added to the reaction solution, the mixture was lyophilized, and the resulting residue was purified by preparative HPLC (0.05% aqueous TFA solution:acetonitrile) to prepare the title compound 85 (0.010 g, 10%).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[C:24]1([C@H:30]([NH2:32])[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:32][C@@H:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:31])=[O:2])([CH2:11][CH2:10]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: C[C@@H](N)c1ccccc1
Product: C[C@@H](NC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2)c1ccccc1

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and (1R)-1-phenylethylamine (43.4 μL) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-[(1R)-1-phenyl-1-ethyl]amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (22.8 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[C:14]([OH:21])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.[Br:24]Br>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([Br:24])=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[C:14]([OH:21])[C:11]=3[C:12]=2[CH3:13])=[CH:22][CH:23]=1
Reactant: BrBr
Reactant: CCCc1ccc2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Solvent: ClCCl
Product: CCCc1cc(Br)c2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Reaction time: 0.25 h

Procedure:
A solution of 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-benzofuran (1 gm; 3.22 mmoles) in methylene chloride (30 mL) was cooled at 0° C. and bromine (0.52 gm; 3.22 mmoles) in methylene chloride (10 mL) was added dropwise. The reaction mixture was stirred for 15 minutes. The reaction mixture was washed with a saturated sodium bicarbonate solution, dried (Na2SO4), and concentrated in vacuo. The residue was purified by preparative TLC, eluting with 15% ethylacetate in hexane to yield 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-bromo benzofuran, mp. 110°-112° C.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Br[CH2:12][CH2:13][O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:12][CH2:13][O:14][C:15](=[O:23])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(S)nc1
Reactant: O=C(OCCBr)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCCSc1ccc([N+](=O)[O-])cn1)c1cccc(Cl)c1
Temperature: 55 °C
Reaction time: 5 h

Procedure:
A heterogeneous mixture of 2-mercapto-5-nitropyridine (4) (46 mg, 0.29 mmol), 2-bromoethyl-3-chlorobenzoate (3) (77 mg, 0.29 mmol), and K2CO3 (0.160 g, 1.1 mmol) in acetone (1 mL) was stirred at 55° C. for 5 h. The cooled reaction mixture was filtered through Celite®, concentrated, and then purified by silica gel chromatography to give 2-[(5-nitro-2-pyridinyl)thio]ethyl-3-chlorobenzoate (5) as a white solid. 1H NMR (CDCl3): δ 9.22 (d, J=1.8 Hz, 1H), 8.24 (dd, J=2.4 and 9.0 Hz, 1H), 7.95-7.91 (m, 1H), 7.90 (t, J=0.9 Hz, 1H), 7.56-7.51 (m, 1H), 7.39 (d, J=8.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 4.61 (t, J=6.6 Hz, 2H), 3.68 (t, J=6.6 Hz, 2H)
Reaction SMILES: [OH-].C([N+](C)(C)C)C1C=CC=CC=1.[Br:13][C:14](Br)=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][C:17]=1[Cl:24].S(=O)(=O)(O)O>CO.C1(C)C=CC=CC=1>[Br:13][C:14]#[C:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][C:17]=1[Cl:24]
Reactant: CSc1ccc(C=C(Br)Br)c(Cl)c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CSc1ccc(C#CBr)c(Cl)c1
Reaction time: 0.25 h
Yield: 12381.4 %

Procedure:
A suspension of Triton B (Reg Trade Mark, N-benzyltrimethylammonium hydroxide, 40% in methanol, 1.8 g) in toluene was added to a solution of 1,1-dibromo-2-[2-chloro-4-(methylsulphenyl)phenyl]ethene (0.96 g) in toluene. The mixture was stirred for 15 minutes. Sulphuric acid (2 m) was added and the resulting layers were separated. The organic layer was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromotography eluted with a mixture of hexane and dichloromethane to give 1-bromo-2-[2-chloro-4-(methylsulphenyl)phenyl]acetylene 90.78 g) as a yellow oil, NMR (CDCl3) 2.5 (s,3H), 7.05(d,1H), 7.2(s,1H), 7.35(d,1H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18]([NH:25][CH2:26][CH2:27][NH2:28])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1COCC1>[C:21]([O:20][C:18](=[O:19])[NH:25][CH2:26][CH2:27][NH:28][S:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:9])=[O:8])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.8 %

Procedure:
To a stirred solution of commercially available 5-bromo-thiophene-2-sulfonyl chloride (1.0 g, 3.82 mmol) in THF (8 ml) was added at room temperature triethylamine (0.59 ml, 4.21 mmol), the mixture was cooled (ice-water) and a solution of commercially available N-BOC-ethylenediamine (1.82 ml, 11.5 mmol) in THF (8 ml) was added drop wise. The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/heptane) and subsequent crystallization from dichloromethane/hexane to yield the title compound (1.41 g, 96%) as a white solid. MS (ISN) 383.0 [(M−H)−], mp 106° C.