Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:7]=1[CH3:20].[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.C(=O)([O-])[O-].[K+].[K+]>>[N:21]1([CH2:2][CH2:3][CH2:4][S:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[C:7]=2[CH3:20])[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: Cc1c(SCCCCl)ccnc1CSc1ccncc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1c(SCCCn2ccnc2)ccnc1CSc1ccncc1
Yield: 32 %

Procedure:
According to the procedure indicated in Example 7, reaction of 4-(3-chloropropylthio)-3-methyl-2-[(4-pyridinylthio)methyl]pyridine with imidazole (2.0 equivalents) and potassium carbonate and subsequent chromatography on silica gel (dichloromethane/acetone/NH3 aq) gives, after crystallization from diisopropyl ether, the title compound; m.p. 117-119° C.; yield 32% of theory.
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[NH2:14])(=[O:7])=[O:6])([CH3:3])[CH3:2].[CH2:15]=O.Cl>C(O)(C)C.C(OCC)(=O)C>[CH:1]([N:4]1[CH2:15][NH:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[S:5]1(=[O:7])=[O:6])([CH3:3])[CH3:2]
Reactant: C=O
Reactant: CC(C)NS(=O)(=O)c1cnccc1N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(C)N1CNc2ccncc2S1(=O)=O
Reaction time: 2 h

Procedure:
A mixture of 0.5 g of N-isopropyl-4-aminopyridine-3-sulfonamide (Preparation 7) and 0.5 g of paraformaldehyde in 15 cm3 of isopropanol to which 50 drops of ethyl acetate saturated with gaseous HCl have been added is brought to reflux for 24 hours. After this lapse of time, the solvent is removed under partial vacuum. The residue is redissolved in 20 cm3 of methanol. The possible insoluble material is removed by filtration. The filtrate, treated with 40 cm3 of water and stored for 2 hours at +4° C., produces a precipitate of the isopropoxymethylenated derivative of Preparation 7. It is collected on a filter, washed with water, dried and recrystallized from a CHCl3 /petroleum ether (40°-60° C.) (1/2) mixture. The dry product is introduced into an open round-bottomed flask and brought to a temperature of 180°-190° C. After 15 to 30 minutes, the molten mass solidifies. It is then cooled and then dissolved in a small volume of chloroform. The addition of 1 volume of petroleum ether (40°-60° C.) causes precipitation of crystals of the title compound. They are collected on a filter, washed with petroleum ether (40°-60° C.) and dried.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[C:14]([F:16])[C:13]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[C:12]([F:22])[CH:11]=2)=[CH:6][N:5]=[C:4]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:27])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]I>[CH:19]1([CH2:18][O:17][C:13]2[C:14]([F:16])=[CH:15][C:10]([C:9]3[O:23][C:2]4[CH:3]=[C:4]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:27])[N:5]=[CH:6][C:7]=4[N:8]=3)=[CH:11][C:12]=2[F:22])[CH2:21][CH2:20]1
Reactant: C[C@@H](COc1cc(Cl)c(NC(=O)c2cc(F)c(OCC3CC3)c(F)c2)cn1)NC(=O)OC(C)(C)C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](COc1cc2oc(-c3cc(F)c(OCC4CC4)c(F)c3)nc2cn1)NC(=O)OC(C)(C)C
Temperature: 160 °C
Reaction time: 4 h
Yield: 34.7 %

Procedure:
A suspension of tert-butyl ((2S)-1-((4-chloro-5-((4-(cyclopropylmethoxy)-3,5-difluorobenzoyl)amino)pyridin-2-yl)oxy)propan-2-yl)carbamate (4.40 g), potassium carbonate (2.38 g) and copper(I) iodide (164 mg) in DMF (20 mL) was stirred at 160° C. for 4 hr under microwave irradiation. To the reaction mixture was added water, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and subjected to silica gel column chromatography (NH, ethyl acetate). The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.42 g).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1([CH2:13][S:14](Cl)(=[O:16])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br.[Br:19][CH2:20][CH2:21][NH2:22].O>C(Cl)Cl>[Br:19][CH2:20][CH2:21][NH:22][S:14]([CH2:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: NCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(Cc1ccccc1)NCCBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.2 %

Procedure:
K2CO3 (8.7 g, 62 mmol) was added into a mixture of phenylmethanesulfonyl chloride (6 g, 31 mmol) and 2-bromoethanamine hydrobromide (6.4 g, 31 mmol) in DCM (100 mL) at 0° C. And the resulting mixture was stirred at r.t. for 4 hours and left standing overnight. Upon the completion of reaction, water (100 mL) was added in and DCM phase was separated. The aqueous phase was extracted with DCM. The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuo to provide a crude which was separated with column chromatography (silica gel with 200-300 mesh, 0 to 50% of EtOAc in petroleum ether) to provide compound N-(2-bromoethyl)(phenyl)methanesulfonamide (7.0 g, 80%) as a pale yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.40 (m, 5H), 4.58 (m, 1H), 4.29 (s, 2H), 3.34-3.29 (m, 4H). LCMS (ESI), 300, 302 [M+Na]+, Br pattern found.
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([O:22][CH:23]([CH3:25])[CH3:24])[CH:14]=1>CO.[Pd]>[CH3:5][O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([O:22][CH:23]([CH3:25])[CH3:24])[CH:14]=1
Reactant: COc1cnccc1-c1ccc([N+](=O)[O-])c(OC(C)C)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1cnccc1-c1ccc(N)c(OC(C)C)c1
Temperature: 80 °C
Yield: 103.8 %

Procedure:
7.55 g of ammonium formate and 1.5 g of Pd/C (10%) are added to a solution of 5.75 g of 3-methoxy-4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridine in 100 ml of methanol. The reaction medium is microwave-heated at 80° C. for 5 minutes. The mixture is filtered on Clarcel, and the Clarcel is rinsed with methanol. The filtrate is concentrated under reduced pressure. The residue is taken up with 60 ml of ethyl acetate and 20 ml of water. The 2 phases are separated, and the aqueous phase is extracted with twice 20 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and evaporated, so as to give 5.35 g of 4-(3-methoxypyridin-4-yl)-2-(propan-2-yloxy)aniline in the form of a brown gum.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:21]1([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[CH:25]=[CH:24][CH:23]=[N:22]1>>[N:21]1([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH2:29][N:1]2[CH:2]([C:11]3[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:3][CH:4]([CH3:10])[C:5]2=[O:7])[CH:25]=[CH:24][CH:23]=[N:22]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-n2cccn2)c1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-n2cccn2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 3-(1H-pyrazol-1-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.81 min.; [M+H]+: 392.18 g/mol.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[O:7][CH2:6][C@@H:5]1[NH:12][C:13](=[O:21])[O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[N+]=[N-].[H][H]>[Pd].CO>[NH2:1][C@@H:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[O:7][CH2:6][C@@H:5]1[NH:12][C:13](=[O:21])[O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:20])[CH3:19]
Reactant: [H][H]
Reactant: CC1(C)C[C@@H](N=[N+]=[N-])[C@@H](NC(=O)OCC[Si](C)(C)C)CO1
Agent: [Pd]
Solvent: CO
Product: CC1(C)C[C@@H](N)[C@@H](NC(=O)OCC[Si](C)(C)C)CO1
Yield: 118.9 %

Procedure:
A mixture of 2-(trimethylsilyl)ethyl (3R,4R)-4-azido-6,6-dimethyl-tetrahydro-2H-pyran-3-ylcarbamate (1.3 g, 3.5 mmol) and 10% palladium on carbon (200 mg) in methanol (10 mL) was stirred at room temperature under 1 atm hydrogen atmosphere (hydrogen balloon) overnight. After that, the mixture was filtered through a pad of celite. The filtrate was concentrated to get the title compound (1.2 g, crude) as a yellow oil, which was used directly for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][C:10]1([CH3:24])[C:15]2[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][C:14]=2[NH:13][C:12](=[O:23])[O:11]1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:17]2[CH:18]=[CH:19][C:14]3[NH:13][C:12](=[O:23])[O:11][C:10]([CH3:24])([CH3:9])[C:15]=3[CH:16]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: Nc1ccc(Br)cn1
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(N)nc3)cc21

Procedure:
Prepared according to procedure B from 2-amino-5-bromopyridine and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. White crystals, mp 257-259° C. 1H-NMR (DMSO-d6) δ 10.20 (s, 1H), 8.22 (d, 1H, J=2.38 Hz) 7.69, 7.66 (dd, 1H, J=2.5, 2.5 Hz), 7.42 (m, 2H), 6.89 (d, 1H, J=8.8 Hz), 6.49 (d, 1H, J=8.64 Hz), 6.02 (s, 2H), 1.64 (s, 6H), MS m/z 269 M+. Anal. Calcd. For C15H15N3O2.17H2O: C, 66.15; H, 5.68; N, 15.43. Found: C, 66.10; H, 5.81; N, 15.02.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH3:12])[C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:11]=1.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:12][N:4]1[C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:11]=[C:3]1[CH2:2][O:1][C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1c(CO)nc2cnccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cnccc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 1.94 g of 2-hydroxymethyl-1-methyl-1H-imidazo[4,5-c]pyridine (prepared as described in Preparation 73), 5.71 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 3.1 ml of tributylphosphine, 3.09 g of 1,1'-(azodicarbonyl)dipiperidine and 50 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1:0 to 10:1 by volume as the eluent, to give 3.55 g of the title compound having Rf=0.08 (on silica gel thin layer chromatography using ethyl acetate as the developing solvent).
Reaction SMILES: [CH2:1]1[O:13][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:14]([NH2:17])[CH2:15][NH2:16]>CO>[CH2:14]([NH:17][CH2:1][CH:2]([OH:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:15][NH:16][CH2:1][CH:2]([OH:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NCCN
Reactant: CCCCCCCCCCC1CO1
Solvent: CO
Product: CCCCCCCCCCC(O)CNCCNCC(O)CCCCCCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-dodecene oxide (100 g.) and ethylenediamine (16.3 g.) and recrystallization of part (20 g.) of the resulting product (55.3 g.) from methanol gave N,N'-ethylenebis[2-hydroxydodecylamine] (I: R= CH3 (CH2)9, R' = H, X= (CH2)2, Z= H) (13.4 g., m.p. 137.0°-142.0° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:30])[N:15]([CH2:17][C:18]4[C:19]([CH3:29])=[N+:20]([O-])[C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:4][CH:3]=1.C([O-])([O-])=[O:38].[K+].[K+]>FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:30])[N:15]([CH2:17][C:18]4[C:19]([CH2:29][OH:38])=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:4][CH:3]=1
Reactant: Cc1c(Cn2nc3c(-c4ccncc4)c(-c4ccc(Cl)cc4)ccn3c2=O)ccc(C(F)(F)F)[n+]1[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2CO)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The title compound was also prepared as follows: A solution of 3-((7-(4-chlorophenyl)-3-oxo-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)methyl)-2-methyl-6-(trifluoromethyl)pyridine 1-oxide (770 mg, 1.50 mmol) in trifluoroacetic anhydride (7 mL) and CH2Cl2 (7 mL) in a sealed tube was stirred at 50° C. for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The crude product was dissolved in methanol (14 mL), and 1.0 M aqueous K2CO3 solution (7 mL, 7 mmol) was added. The resulting mixture was stirred at room temperature for 30 min, then concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc (50 mL×2). The combined EtOAc extracts were washed with saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated under reduced pressure. The product was purified using a silica gel cartridge (80 g) eluted with a gradient of ethyl acetate (50-100%) in hexanes to afford 660 mg (86%, 2 steps) of the title compound as a yellow foam. HPLC/MS: retention time=2.68 min, [M+H]+=512.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH3:13][N:14]([CH3:18])[C:15](Cl)=[O:16].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:13][N:14]([CH3:18])[C:15](=[O:16])[NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: CN(C)C(=O)Cl
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN(C)C(=O)Nc1ccc2c(c1)CCC(=O)N2

Procedure:
6-Amino-3,4-dihydrocarbostyril (1 g) is suspended in benzene (20 ml), and thereto is added dropwise a solution of N,N-dimethylcarbamoyl chloride (0.86 ml) in benzene (10 ml) at room temperature. The mixture is reacted at 50° C. for 3 hours, and thereto is added triethylamine (0.86 ml), and the mixture is further reacted at 50° to 60° C. for 5 hours. After the reaction, benzene is distilled off under reduced pressure, and water is added to the residue. The resulting precipitate is separated by filtration and washed with water. The crystal thus obtained is purified by silica gel column chromatography (solvent; chloroform:methanol=100:1) and then recrystallized from methanol-diethyl ether to give 6-(3,3-dimethylureido)-3,4-dihydrocarbostyril (0.6 g), as colorless prisms, m.p. 181°-183° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15])([O-:11])=[O:10].O>N1C=CC=CC=1>[Cl:8][C:3]1[C:2]([NH:1][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Nc1cccnc1Cl
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cccnc1Cl)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 3-amino-2-chloropyridine (3.85 g, 29.95 mmol) and 2-nitrobenzoyl chloride (5.56 g, 29.95 mmol) in pyridine (50 mL) was stirred at 0° C. for 1 h and then at room temperature overnight. Water was added and the precipitate formed was collected by filtration and dried to give N-(2-chloropyridin-3-yl)-2-nitrobenzamide as a white solid (8.52 g, crude yield: >100%).
Reaction SMILES: B(F)(F)F.[C:5](O)(=[O:7])[CH3:6].[O:9]([C@H:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])(=O)C.[Na+]>>[C:5]([C:13]1[CH:14]=[CH:15][C:10]([O:9][C@H:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:12]=1)(=[O:7])[CH3:6]
Reactant: COC(=O)[C@@H](C)Oc1ccccc1
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Product: COC(=O)[C@@H](C)Oc1ccc(C(C)=O)cc1
Temperature: 80 °C
Reaction time: 7 h
Yield: 83.7 %

Procedure:
67 g (1 mol) of boron trifluoride were passed into 60 g (1 mol) of acetic acid. The mixture was heated to 45°-50° C., and 36 g (0.2 mol) of methyl (R)-2-phenoxypropionate were added. After stirring at 45°-50° C. for 7 hours, the temperature was raised to 80° C. for 1 h and the mixture was then stirred into 800 ml of 25% by weight aqueous sodium acetate solution. The product was extracted with 200 ml of ethyl acetate and, after concentration of the organic phase, purified by vacuum distillation. Yield: 83.7% (94-95% enantiomeric excess).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].O.O.[C:16](O)(=[O:20])[C:17](O)=[O:18]>Cl.[OH-].[Na+]>[F:9][C:5]1[CH:6]=[C:7]2[C:2]([NH:1][C:16](=[O:20])[C:17](=[O:18])[NH:8]2)=[C:3]([C:10]([F:13])([F:11])[F:12])[CH:4]=1
Reactant: Nc1cc(F)cc(C(F)(F)F)c1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c2cc(F)cc(C(F)(F)F)c2[nH]c1=O
Temperature: 25 °C
Yield: 58.3 %

Procedure:
A mixture of 2,3-diamino-5-fluorobenzotrifluoride (148 mg, 0.76 mmol) and oxalic acid dihydrate (96 mg, 0.76 mmol, used as received) in 4N HCl (2 mL) was refluxed at 120°-5° C. for 3 h, then cooled to room temperature. The mixture was centrifuged and the liquid layer was removed. The yellow solid was washed by cold water (2×2 mL), collected by filtration, and dried at 60° C. for 2 h, affording 120 mg of crude title compound (64%) as a yellow powder. The crude product was dissolved in 1N NaOH (5 mL) and filtered. The filtrate was acidified to pH=6, affording 110 mg of pure title compound as a yellow powder. Mp: 300°-2° C. IR (KBr, cm-1): 3408, 3122, 1754, 1721, 1621, 1492. 1H NMR (DMSO-d6): δ 7.178 (dd, 1H, J1 =2.7 Hz, J2 =8.7 Hz), 7.359 (dd, 1H, J1 =2.7 Hz, J2 =8.7 Hz); 11.270 (s, 1H); 12.237 (s, 1H). HRMS: calcd for C9H4N2O2 (M+) m/z: 248.0208; found: 248.0220.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[CH2:9]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)C>ClC(Cl)C>[NH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:1][CH:19]1[CH2:18][CH2:17][N:16]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:21][CH2:20]1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Nc1ccncc1N
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Nc1ccncc1NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 144 h
Yield: 98.2 %

Procedure:
A mixture of 3,4-diaminopyridine (1.1 g, 10.1 mmol), 1-benzyl-4-piperidone (3.2 g, 16.9 mmol) sodium triacetoxyborohydride (4.0 g, 18.9 mmol), and acetic acid (10.7 mL) in dichloroethane (10 mL) was stirred for about 6 days at room temperature. The reaction was concentrated to near dryness, and partitioned between chloroform (5×50 mL) and 1N sodium hydroxide (50 mL). The organic phase was dried over magnesium sufate and concentrated to give the title compound (2.8 g). MS 283 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:31]([OH:35])[CH2:32][C:33]#[CH:34]>C(NCC)C.[Pd](Cl)Cl.[Cu](I)I>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([C:34]#[C:33][CH2:32][CH2:31][OH:35])=[CH:3][CH:4]=1
Reactant: C#CCCO
Reactant: COC(=O)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: COC(=O)c1ccc(C#CCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a stirring solution of methyl 4-bromobenzoate (13.4 g, 0.62 mmol) in diethyl amine (200 mL) was added palladium chloride (0.55 g, 3.06 mmol), and triphenylphosphine (0.16 g, 0.62 mmol). The solution was degassed and copper iodide (0.12 g, 0.62 mmol) and 3-butyn-1-ol (4.34 g, 62 mmol) were added. The reaction mixture continued to stir at room temperature overnight. Over the next two days, an additional 0.5 mol % palladium chloride, 1.0 mol % triphenylphosphine, and 12 mol % 3-butyn-1-ol were added. Once the reaction was complete according to LCMS, the reaction mixture was concentrated and the crude material was taken up in a slurry of silica gel and ethyl acetate. The organic solvent was removed and the remaining dried silica gel was packed in a fritted funnel. Extensive washes with a hexane:ethyl acetate mixture (1:4) followed by ethyl acetate (100%) washes yielded the desired 4-(4-hydroxy-but-1-ynyl)-benzoic acid methyl ester (11.9 g, 0.58 mmol) as the desired product (94% yield). 1H(CDCl3, 600 MHz): δ 7.95 (2H, d, J=8.4 Hz), 7.45 (2H, d, J=8.4 Hz), 3.9 (s, 3H), 3.83 (2H, t, J=6.6 Hz), 2.71 (2H, t, J=6.0 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1.Br[C:17]1[CH:25]=[C:24]2[C:20]([C:21]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:22]=3[N:23]2[CH3:26])=[CH:19][CH:18]=1>>[CH3:26][N:23]1[C:24]2[C:20](=[CH:19][CH:18]=[C:17]([N:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:10][C:11]3=[O:15])[CH:25]=2)[C:21]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:22]1=2
Reactant: O=c1cc(OCc2ccccn2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccn5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Yield: 51.4 %

Procedure:
4-(Pyridin-2-ylmethoxy)pyridin-2(1H)-one (138 mg, 0.682 mmol) and tert-butyl 7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (250 mg, 0.68 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (170 mg, 51%) as a white foam: 1H NMR (300 MHz, CDCl3) δ 8.63 (d, J=4.1 Hz, 1H), 7.76 (overlapping ddd, J=7.7, 1.7 Hz, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.33 (d, J=7.4 Hz, 1H), 7.29-7.26 (m overlapping with solvent, 2H), 7.01 (dd, J=8.2, 1.8 Hz, 1H), 6.12-6.07 (m, 2H), 5.19 (s, 2H), 4.63 (s, 2H), 3.74 (br s, 2H), 3.62 (s, 3H), 2.79 (s, 2H), 1.51 (s, 9H).
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[C:10]([O:14][C:15]([O:17][CH2:18][C@@:19]1([C:32]#[CH:33])[O:23][C@@H:22](OC(OC(C)(C)C)=O)[CH:21]=[CH:20]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:10]([O:14][C:15]([O:17][CH2:18][C@@:19]1([C:32]#[CH:33])[O:23][C@@H:22]([N:1]2[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]2=[O:3])[CH:21]=[CH:20]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: C#C[C@@]1(COC(=O)OC(C)(C)C)C=C[C@H](OC(=O)OC(C)(C)C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C#C[C@@]1(COC(=O)OC(C)(C)C)C=C[C@H](n2cc(C)c(=O)[nH]c2=O)O1
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
Thymine (16.7 g), N,N′-dimethylformamide (162 g), and tetrakis(triphenylphosphine)palladium(0) (917 mg) were added to a glass reactor under nitrogen, and the mixture was heated to 55° C. Then, a solution of (2S,5R)-5-t-butoxycarbonyloxymethyl-5-ethynyl-2-t-butoxycarbonyloxy-2,5-dihydrofuran (β/α=>99/1) (9.0 g) in N,N′-dimethylformamide was added dropwise thereto, and the mixture was stirred for 30 minutes. The reaction mixture was filtered, and water was added to the filtrate, followed by stirring for phase separation. The thus-separated organic layer was concentrated. The residue was purified through recrystallization from acetonitrile and toluene, to thereby yield 6.5 g of (2R,5R)-5-t-butoxycarbonyloxymethyl-5-ethynyl-2-(thymin-1-yl)-2,5-dihydrofuran (yield: 72%, β/α=>99/1). The 1H-NMR data of the compound are as follows.