Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]([NH2:6])=[CH:4][CH:3]=[N:2]1.[Br:7][CH:8]([CH:11]=O)[CH:9]=O>C(O)(=O)C.CO>[Br:7][C:8]1[CH:9]=[C:4]2[CH:3]=[N:2][NH:1][C:5]2=[N:6][CH:11]=1
Reactant: Nc1ccn[nH]1
Reactant: O=CC(Br)C=O
Solvent: CC(=O)O
Solvent: CO
Product: Brc1cnc2[nH]ncc2c1
Temperature: 25 °C
Yield: 24.5 %

Procedure:
1H-Pyrazol-5-amine (5.3 g, 64 mmol) and 2-bromomalonaldehyde (9.9 g, 64 mmol) were suspended in acetic acid (100 mL). The reaction mixture was heated to reflux under N2 for 6 hours. The reaction mixture was cooled to room temperature and concentrated to give a solid. The crude solids were suspended in MeOH (200 mL) and absorbed onto silica gel (200 g). The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (4:1), hexanes/ethyl acetate (2:1) to give 5-bromo-1H-pyrazolo[3,4-b]pyridine as a solid (3.1 g, 25%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O>CN(C)C=O>[C:16]1([C:14]2[N:1]=[C:2]3[N:6]([CH:13]=2)[C:5]2[CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[S:3]3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1nc2c(s1)C(=O)CCC2
Solvent: CN(C)C=O
Product: O=C1CCCc2c1sc1nc(-c3ccccc3)cn21
Temperature: 25 °C
Yield: 74 %

Procedure:
2-Amino-4,5-dihydrobenzothiazole-7(6H)-one (18 g) prepared in the above (A) was dissolved into dimethylformamide (250 ml), and 2-bromoacetophenone (21,83 g) was added thereto followed by heating to reflux for 12-15 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and placed into distilled water. The resulting precipitates were filtered, neutralized with sodium hydroxide solution, filtered, washed with ethyl acetate (100 ml), and dried to give the titled compound (21.25 g, 76%).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:29]1[C:30]([CH3:60])=[C:31]([C:38]([C:40]2[CH:49]=[C:48]3[C:43]([C:44](=[O:59])[N:45]([CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:46](=[O:50])[NH:47]3)=[CH:42][CH:41]=2)=[O:39])[N:32]2[C:37]=1[CH:36]=[CH:35][CH:34]=[CH:33]2.OS([O-])(=O)=O.[K+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:55]([O:54][C:52](=[O:53])[CH2:51][N:45]1[C:44](=[O:59])[C:43]2[C:48](=[CH:49][C:40]([C:38]([C:31]3[N:32]4[C:37]([CH:36]=[CH:35][CH:34]=[CH:33]4)=[C:29]([C:14]4[CH:15]=[CH:16][C:11]([C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[O:10])=[CH:12][CH:13]=4)[C:30]=3[CH3:60])=[O:39])=[CH:41][CH:42]=2)[NH:47][C:46]1=[O:50])([CH3:58])([CH3:56])[CH3:57]
Reactant: O=C(OCc1ccccc1)c1ccc(B(O)O)cc1
Reactant: Cc1c(Br)c2ccccn2c1C(=O)c1ccc2c(=O)n(CC(=O)OC(C)(C)C)c(=O)[nH]c2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc(C(=O)OCc3ccccc3)cc2)c2ccccn2c1C(=O)c1ccc2c(=O)n(CC(=O)OC(C)(C)C)c(=O)[nH]c2c1
Temperature: 80 °C
Yield: 0.1 %

Procedure:
{4-[(Benzyloxy)carbonyl]phenyl}boronic acid (0.7 g, 2.73 mmol), 5.5 mL of a molar solution of potassium phosphate and the catalyst PdCl2(dppf) (192 mg, 0.27 mmol) are added to a solution of tert-butyl {7-[(1-bromo-2-methylindolizin-3-yl)carbonyl]-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl}acetate [described in Step 3.2.] (1 g, 1.82 mmol) in 20 mL of DMF placed in a microwave reactor under nitrogen. The reactor is sealed and the solution is heated for 30 min at 80° C. in a microwave. The reaction medium is cooled and run into a molar solution of KHSO4, and extracted with EtOAc. The organic phase is washed with a saturated aqueous solution of NaCl, dried over Na2SO4, and concentrated to dryness. The residue obtained is purified by flash chromatography on silica (DCM/EtOH: 100/0 to 80/20] to give 1.08 mg (92%) of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH:17]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:7]=1.[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH:17]2[CH2:23][CH2:22][CH2:21][N:20]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:19][CH2:18]2)[N:7]=1
Reactant: ClCc1ccccc1
Reactant: O=c1c2ccccc2c(Cc2ccc(Cl)c(Cl)c2)nn1C1CCCNCC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=c1c2ccccc2c(Cc2ccc(Cl)c(Cl)c2)nn1C1CCCN(Cc2ccccc2)CC1

Procedure:
A solution of 3.28 grams (8.15 mmoles) of 4-(3,4-dichlorobenzyl)-2-(hexahydro-1H-azepin-4-yl)-1-(2H)-phthalazinone, 3.4 ml (29.5 mmol) of benzyl chloride and 9 ml (64.6 mmol) of triethylamine in 20 ml of dioxane were heated for 12 hours at 200° C.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([O:15]C)=[O:14])[C:8]2=[O:17])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([OH:15])=[O:14])[C:8]2=[O:17])=[CH:18][CH:19]=1
Reactant: COC(=O)c1cccn(Cc2ccc(F)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccn(Cc2ccc(F)cc2)c1=O
Temperature: 0 °C
Reaction time: 15 h
Yield: 70.3 %

Procedure:
A solution of methyl 1-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (2.4 g, 9.2 mmol, 1.0 eq) in MeOH (25 ml) was treated with 5 N aqueous sodium hydroxide (4.6 mL, 24 mmol, 2.6 eq) at room temperature and the reaction mixture was stirred for 15 h. The reaction mixture was concentrated in vacuo, diluted with water and the solution was extracted with ethyl acetate (discarding the organic fraction). The aqueous fraction was cooled to 0° C. and acidified with concentrated HCl. The resulting solid was filtered, washed with water and the solid dried in vacuo to afford the product (1.6 g, 70%) which was sufficiently pure to use in the subsequent step without further purification. 1H NMR (DMSO-d6) δ 8.44-8.39 (m, 2H), 7.46-7.42 (m, 2H), 7.24-7.18 (m, 2H), 6.78 (d, 1H, J=6.98 Hz), 5.31 (s, 2H); HRMS(ESI), calcd.: 248.0723, found: 248.0718.
Reaction SMILES: C[O:2][C:3](=[O:42])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:21]=[C:20]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][CH:25]=3)[N:19]=[C:18]([C:32]#[C:33][C:34]3[CH:39]=[CH:38][C:37]([CH2:40][OH:41])=[CH:36][CH:35]=3)[CH:17]=2)=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.Cl.O.C(OCC)(=O)C>C1COCC1.C(O)C.[OH-].[Na+]>[OH:31][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]#[C:22][C:20]2[CH:21]=[C:16]([S:15][C:12]3[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:42])=[O:2])=[C:7]4[C:11]=3[CH2:10][CH2:9][CH2:8]4)[CH:17]=[C:18]([C:32]#[C:33][C:34]3[CH:35]=[CH:36][C:37]([CH2:40][OH:41])=[CH:38][CH:39]=3)[N:19]=2)=[CH:25][CH:26]=1
Reactant: COC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)nc(C#Cc3ccc(CO)cc3)c2)c2c1CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)nc(C#Cc3ccc(CO)cc3)c2)c2c1CCC2
Reaction time: 16 h

Procedure:
{7-[2,6-Bis-(4-hydroxymethyl-phenylethynyl)-pyridine-4-ylsulfanyl]-indan-4-yloxy}-acetic acid methyl ester (70 mg; 0.12 mmol) was dissolved in a mixture of THF and ethanol (1:2) (30 ml) and 1N sodium hydroxide (1 ml) was added. The reaction mixture was stirred for about 16 h and 1N aqueous hydrogen chloride (2 ml), water (10 ml) and ethyl acetate (20 ml) were added. The organic phase was separated from the aqueous phase and the aqueous phase was extracted with ethyl acetate (10 ml). The pooled organic phases were washed with water (10 ml), dried and evaporated to dryness to give {7-[2,6-bis-(4-hydroxymethyl-phenylethynyl)-pyridin-4-ylsulfanyl]-indan-4-yloxy}-acetic acid. Yield: 64 mg LC-MS (system 1): Rt: 2.09; Mw: 562.5.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:23]([C:24](=[O:28])[NH:25][CH2:26]C)=[C:22]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[O:21][C:12]2=[N:13][C:14]=1[N:15]([S:17]([CH3:20])(=[O:19])=[O:18])[CH3:16])C.[Li+].[OH-]>CO>[F:35][C:32]1[CH:33]=[CH:34][C:29]([C:22]2[O:21][C:12]3=[N:13][C:14]([N:15]([CH3:16])[S:17]([CH3:20])(=[O:18])=[O:19])=[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:36])=[O:3])[CH:10]=[C:11]3[C:23]=2[C:24](=[O:28])[NH:25][CH3:26])=[CH:30][CH:31]=1
Reactant: CCNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(CCCCC(=O)OCC)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(CCCCC(=O)O)cc12
Temperature: 25 °C

Procedure:
To a solution of 5-[2-(4-Fluoro-phenyl)-6-(methanesulfonyl-methyl-amino)-3-ethylcarbamoyl-furo[2,3-b]pyridin-5-yl]-pentanoic acid ethyl ester (3.0 mg) in MeOH (0.5 ml) is added LiOH (1 M in water, 0.25 ml) and the mixture is refluxed for 1 h, cooled to rt and purified by preparative HPLC to afford the title compound (M+H)+=478.1; Retention time=1.03 min, Method A.
Reaction SMILES: [Cl:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([N+:15]([O-:17])=[O:16])[CH:8]=1)[C:3]([OH:5])=[O:4].[C:18]1(C)C(S(O)(=O)=O)=CC=C[CH:23]=1>C(O)C>[Cl:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([N+:15]([O-:17])=[O:16])[CH:8]=1)[C:3]([O:5][CH2:18][CH3:23])=[O:4]
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: COc1ccc(C[C@H](Cl)C(=O)O)cc1[N+](=O)[O-]
Solvent: CCO
Product: CCOC(=O)[C@@H](Cl)Cc1ccc(OC)c([N+](=O)[O-])c1
Yield: 710.4 %

Procedure:
To a ethanol solution of (S)-2-chloro-3-(4-methoxy-3-nitrophenyl)propionicacid (4.46 g) was added p toluenesulfonicacid (0.38 g) and heated under reflux for 5 hours.After cooled it down, the solvent was evaporated in vacuo. Theresultant suspension solution was extracted by ethyl acetate (50 ml×3).After the ethyl acetate layer was washed with saturated brine,dried over anhydrous sodium sulfate. The solvent was evaporated invacuo, the resultant crude product was purified by silica gel columnchromatography, and eluted with mixture of hexane or ethylacetate (4:1, v/v). The fractions containing the desired productwere combined and evaporated in vacuo to obtain ethyl (S)-2-chloro-3-(4-methoxy-3-nitrophenyl)propionate(4.51 g)
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[C:7]([C:10]1[O:14][C:13]([CH2:15][CH3:16])=[N:12][C:11]=1[CH3:17])(=[O:9])[CH3:8]>>[CH2:15]([C:13]1[O:14][C:10]([C:7]([C:2]2[CH:6]=[CH:5][S:4][CH:3]=2)([OH:9])[CH3:8])=[C:11]([CH3:17])[N:12]=1)[CH3:16]
Reactant: Brc1ccsc1
Reactant: CCc1nc(C)c(C(C)=O)o1
Product: CCc1nc(C)c(C(C)(O)c2ccsc2)o1

Procedure:
Starting with 3-bromothiophene and 5-acetyl-2-ethyl-4-methyloxazole and following the general method of Example 4 the title compound was prepared. M.p. 77.5°-79° C.
Reaction SMILES: [ClH:1].C([O:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[NH:16])C1C=CC=CC=1>CO.[Pd]>[ClH:1].[NH:16]=[C:11]1[CH2:12][CH2:13][CH2:14][CH2:15][N:10]1[OH:9]
Reactant: N=C1CCCCN1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: N=C1CCCCN1O
Reaction time: 3 h

Procedure:
A solution of 1-(benzyloxy)piperidin-2-imine hydrochloride in methanol, containing palladium on charcoal (10%, w/w) was stirred under hydrogen at atmospheric pressure for 3 h. The catalyst was filtered off and the solution was concentrated to dryness under reduced pressure. The residue was triturated with diethyl ether, filtered and dried under high vacuum to afford 2-iminopiperidin-1-ol hydrochloride as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.C([O:11][C:12](=[O:17])[CH2:13][N:14]=[C:15]=[O:16])C>C1COCC1>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:15](=[O:16])[NH:14][CH2:13][C:12]([OH:17])=[O:11])[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)CN=C=O
Reactant: Cc1cc(N)ccn1
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)NCC(=O)O)ccn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2-Methyl-pyridin-4-ylamine (1.08 g, 10 mmol) is dissolved in dry THF (30 mL) and isocyanatoacetic acid ethyl ester (1.29 g, 10 mmol) is added. The mixture is stirred at r.t. for 15 h. The mixture is evaporated and 6N aq. HCl (20 mL) is added. The mixture is stirred at 50° C. for 6 h, evaporated and the residue purified by reversed phase MPLC to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.O=[C:8]([CH:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1)[CH2:9][C:10]#[N:11]>C(O)(=O)C>[S:15]1[CH2:16][CH2:17][CH:12]([C:8]2[CH:9]=[C:10]([NH2:11])[N:3]3[N:4]=[CH:5][CH:6]=[C:2]3[N:1]=2)[CH2:13][CH2:14]1
Reactant: N#CCC(=O)C1CCSCC1
Reactant: Nc1cc[nH]n1
Solvent: CC(=O)O
Product: Nc1cc(C2CCSCC2)nc2ccnn12
Temperature: 100 °C

Procedure:
A mixture of 3-aminopyrazole (19.3 mmol, 1.61 g) and 3-oxo-3-(tetrahydro-2H-thiopyran-4-yl)propanenitrile (21.3 mmol, 3.60 g) in acetic acid (40 mL) was heated at 100° C. in a sealed tube overnight. After cooling to rt, all the volatiles were removed under reduced pressure to afford 5-(tetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine as a light brownish oil. LCMS tR=0.59 Min. Mass calculated for, M+ 234.1, observed LC/MS m/z 235.1 (M+H).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.[C:11]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17])#[CH:12].N>>[N:5]1[CH:6]=[CH:7][N:8]=[CH:9][C:4]=1[C:3]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[O:1][N:2]=1
Reactant: C#Cc1cccc(C#N)c1
Reactant: ON=C(Cl)c1cnccn1
Agent: N
Product: N#Cc1cccc(-c2cc(-c3cnccn3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 83D (79 mg, 0.5 mmol) and the product of Example 19A (64 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.59 (s, 1H), 7.75 (t, J=8.1 Hz, 1H), 7.88 (dt, J=8.0, 1.4, 1.2 Hz, 1H), 8.21-8.30 (m, 1H), 8.31-8.37 (m, 1H), 8.71 (d, J=2.7 Hz, 1H), 8.77 (dd, J=2.5, 1.5 Hz, 1H), 9.31 (d, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 249 (M+H)+.
Reaction SMILES: [ClH:1].C([S:5][CH:6]1[CH2:11][CH2:10][N:9]([CH:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:13]([CH:15]2[CH2:17][CH2:16]2)=[O:14])[CH2:8]/[C:7]/1=[CH:25]/[C:26]1[CH:30]=[CH:29][N:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:27]=1)(=O)C.Cl>>[ClH:1].[CH:15]1([C:13](=[O:14])[CH:12]([N:9]2[CH2:10][CH2:11][CH:6]([SH:5])/[C:7](=[CH:25]\[C:26]3[CH:30]=[CH:29][N:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:27]=3)/[CH2:8]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[CH2:17][CH2:16]1
Reactant: CCOC(=O)Cn1ccc(/C=C2/CN(C(C(=O)C3CC3)c3ccccc3F)CCC2SC(C)=O)n1
Agent: Cl
Product: CCOC(=O)Cn1ccc(/C=C2/CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S)n1
Yield: 42 %

Procedure:
(Z)-4-(Acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-{[1-(ethoxycarbonylmethyl)-1H-pyrazol-3-yl]methylidene}piperidine hydrochloride (0.80 g) was treated with hydrogen chloride in a similar manner to that described in Example 133, and the product was purified by preparative HPLC to afford the free base of the title compound (0.31 g) as a pale yellow foam, which was treated with 4N hydrogen chloride dioxane solution to afford the title compound (0.38 g, yield: 51%) as a pale yellow foam.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:9])=[CH:5][C:6]=1[C:7]#[N:8].F[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].O.[OH-].[Li+].Cl>O.CS(C)=O>[F:17][C:15]1[CH:14]=[CH:13][C:12]([N+:18]([O-:20])=[O:19])=[C:11]([NH:1][C:2]2[S:3][C:4]([CH3:9])=[CH:5][C:6]=2[C:7]#[N:8])[CH:16]=1
Reactant: Cc1cc(C#N)c(N)s1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C#N)c(Nc2cc(F)ccc2[N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.3 %

Procedure:
Add 2-amino-5-methyl-thiophene-3-carbonitrile (10.0 g, 72.4 mmol) and 2,4-difluoro-1-nitro-benzene (8.00 mL, 73.0 mmol) to DMSO (130 mL) and stir under nitrogen at ambient temperature. Add lithium hydroxide monohydrate (6.10 g, 145 mmol) in one portion and stir at ambient temperature. After 18 hours, add deionized water (390 mL) dropwise at 10-20° C. Adjust the pH to 7-8 with concentrated HCl (˜6 mL) and stir for 4 hours. Filter the crude product and rinse with 3:1/water: DMSO, then water. Dry at 50° C. to constant weight. Purify by flash chromatography, eluting with methylene chloride to give the title compound 10.3 g (62%): 1H NMR (400 MHz, DMSO-d6) δ 9.83 (bs, 1H), 8.28 (m, 1H), 7.12 (s, 1H), 6.91 (m, 1H), 6.73 (m, 1H), 2.53 (s, 3H). HRMS (ES) exact mass M+H calcd for C12H8FN3O2S 300.0219; found 300.0219.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH2:24]([O:31][C:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:24]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]3)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=2)[CH2:36][CH2:35]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC1CCN(c2nc(Cl)ccc2[N+](=O)[O-])CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CCN(c2nc(N3CCN(C(=O)OCc4ccccc4)CC3)ccc2[N+](=O)[O-])CC1
Temperature: 40 °C
Yield: 94 %

Procedure:
A solution of 6′-chloro-4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl (as prepared in the previous step, 2.0 g, 7.8 mmol) in DMF (40 mL) was treated with solid Na2CO3 (0.99 g, 9.4 mmol) and piperazine-1-carboxylic acid benzyl ester (1.5 mL, 7.8 mmol), then heated to 90° C. for 1 h and to 40° C. for 15 h. The reaction was concentrated to 20 mL volume, diluted with EtOAc, and washed well with water. The combined aqueous layers were further extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Silica gel chromatography (25% EtOAc in hexane) afforded the title compound (3.2 g, 94%) as a yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 8.19 (d, 1H, J=9.2 Hz), 7.39-7.31 (m, 5H), 6.01 (d, 1H, J=9.2 Hz), 5.16 (s, 2H), 3.84-3.76 (m, 2H), 3.71-3.65 (m, 4H), 3.64-3.58 (m, 4H), 3.02-2.93 (m, 2H), 1.74-1.65 (m, 2H), 1.66-1.60 (m, 1H), 1.38-1.26 (m, 2H), 0.97 (d, 3H, J=6.4 Hz). LC-MS (ESI, m/z): Calcd. for C23H29N5O4, 440.2 (M+H), found 439.9.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:16])=[O:29])=[CH:23][CH:22]=1)(=[O:19])=[O:20]
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Product: CS(=O)(=O)c1ccc(CC(=O)Nn2nc(C(F)(F)F)c3ccccc3c2=O)cc1

Procedure:
The product from Example 11B and 2-[4-(methylsulfonyl)phenyl]acetic acid were treated as in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.40-8.45 (m, 1H), 8.13-8.17 (m, 1H), 8.02-8.09 (m, 2H), 7.92-7.94 (m, 2H), 7.65-7.68 (m, 2H), 3.90 (s, 2H), 3.21 (s, 3H); MS (ESI−) M/Z 424 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[CH:5]=[N:4][C:3]=1[C:16]([NH2:18])=[O:17].C1(N=[C:26]=[S:27])C=CC=CC=1>N1C=CC=CC=1>[SH:27][C:26]1[N:18]=[C:16]([OH:17])[C:3]2[N:4]=[CH:5][N:6]([C:2]=2[N:1]=1)[C@@H:7]1[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]1[OH:9]
Reactant: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1N
Reactant: S=C=Nc1ccccc1
Solvent: c1ccncc1
Product: OC[C@H]1O[C@@H](n2cnc3c(O)nc(S)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Yield: 79.9 %

Procedure:
The 5-Amino-1-β-ribofuranosylimidazole-4-carboxamide (1.3 g, 5 mmol) was dissolved in pyridine and 18 ml (15 mmol) phenyl-isothiocyanate were added slowly. The reaction mixture was refluxed for 2 hours under argon atmosphere. The solution was cooled to room temperature, the precipitate collected by filtration and washed with diethyl ether. The obtained pyridinium salt of the product was dissolved in aqueous sodium hydroxide (15%, 40 ml). The solution was heated 30 minutes at 60° C. and concentrated under vacuum. Methanol was then added and the solution was kept in the refrigerator overnight. After 20 hours the precipitated colourless prisms were collected by filtration to give 1.2 g (80%) 2-Mercaptoinosine.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[S:10]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)(=[O:13])(=[O:12])[NH2:11]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:18][C:17]2[CH:19]=[CH:20][C:14]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: O=Cc1ccc(F)cc1
Product: NS(=O)(=O)c1ccc(N=Cc2ccc(F)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-fluorobenzaldehyde and 4-sulfamoylaniline as starting materials, the title compound was obtained as a white powder (yield 63%).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[I:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[CH:14]2.C([O-])([O-])=O.[Cs+].[Cs+].O>CS(C)=O>[I:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)[N:15]=[CH:14]2
Reactant: ClCCN1CCCC1
Reactant: Ic1ccc2[nH]ncc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Ic1ccc2c(cnn2CCN2CCCC2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 52.3 %

Procedure:
1-(2-Chloroethyl)pyrrolidine hydrochloride (9.88 g, 58.1 mmol) was added to a suspension of 5-iodo-1H-indazole (8.86 g, 36.3 mmol) and Cs2CO3 (50.8 g, 456 mmol) in anhydrous DMSO (100 mL) and the resulting suspension was stirred at 25° C. for 14 h. H2O (100 mL) was added and the aqueous solution was extracted with EtOAc (3×200 mL). The combined organic extracts were washed with brine (2×200 mL), dried over MgSO4 and concentrated under reduced pressure. Flash chromatography on silica gel (9:1 Et2O/Et3N) afforded 6.473 g (52%) of the title compound as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.08 (br d, J=13 Hz, 1H), 7.91 (d, J=0.9 Hz, 1H), 7.60 (dd, J=87, 1.3 Hz, 1H), 7.25 (d, J=8.7 Hz, 1H), 4.50 (t, J=7.4 Hz, 2H), 2.98 (t, J=7.4 Hz, 2H), 2.59-2.50 (m, 4H), 1.82-1.70 (m, 4H).
Reaction SMILES: C([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])(=O)C1C=CC=CC=1.[C:28]([O-:33])(=O)[CH:29]([CH3:31])[OH:30].C([O-])(=O)C(C)(C)C.C([O-])(=O)CCCCCCC.C([O-])(=O)CCCCCCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCCCC>>[CH2:31]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH:29]([CH2:28][OH:33])[OH:30]
Reactant: CC(O)C(=O)[O-]
Reactant: CC(C)CCCCCCCCCCCCCCCOC(=O)c1ccccc1
Agent: CC(C)(C)C(=O)[O-]
Agent: CCCCCCCC(=O)[O-]
Agent: CCCCCCCCCCCCCC(=O)[O-]
Product: CC(C)CCCCCCCCCCCCCCCOCC(O)CO

Procedure:
Isostearyl Benzoate, Lactate, Neopentanoate, Octanoate, Palmitate or Myristate