Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13])[CH3:8].Cl>CCO>[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([NH:13][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:14]=[CH:15][CH:16]=1)[CH3:8]
Reactant: CCOc1cccc(N)c1
Reactant: Brc1nccs1
Agent: Cl
Solvent: CCO
Product: CCOc1cccc(Nc2nccs2)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(thiazol-2-ylamino)phenol, 2-bromothiazole (0.15 mL, 1.66 mmol), 3-ethoxyaniline (0.11 mL, 0.83 mmol) and 37% HCl solution (0.14 mL, 1.66 mmol) in 10% aqueous EtOH solution (1 mL) was stirred at 90° C. for 24 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 8/2) in 53% yield (97 mg).
Reaction SMILES: C(OC([N:8]1[CH2:22][CH2:21][C:11]2[NH:12][C:13]3[C:14]([C:19]#[N:20])=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH2:9]1[C:10]2[C:18]3[C:13](=[C:14]([C:19]#[N:20])[CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH2:21][CH2:22][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(C#N)cccc3c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc2c3c([nH]c12)CCNC3
Reaction time: 7 h
Yield: 99.5 %

Procedure:
A solution of 6-cyano-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (1.00 g) in CH2Cl2 (10 mL) was treated with TFA (2 mL). The reaction mixture was stirred for 7 h then converted to the free base with K2CO3 to provide 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carbonitrile (0.66 g, 99%) as a white solid: mp 230–235° C.; 1H NMR (300 MHz, CD3OD) δ 7.71–7.69 (m, 1H), 7.50–7.46 (m, 1H), 7.16–7.11 (m, 1H), 4.05–4.04 (m, 2H), 3.26–3.21 (m, 2H), 2.91–2.87 (m, 2H); ESI MS m/z 198 [C12H, N3+H]+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CC1C=CC(S([N:31]=[N+:32]=[N-])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[F:1][C:2]([F:19])([F:20])[C:3]1[CH:4]=[C:5]([C:13](=[N+:31]=[N-:32])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: CCOC(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)C(=[N+]=[N-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
To a solution of ethyl 3,5-bis(trifluoromethyl)phenylacetate (Step M, 26.0 g, 87 mmol) and 4-methylbenzenesulfonyl azide (Step L, 18.0 g, 91 mmol) in dry acetonitrile (150 mL) was added DBU (14.3 mL, 95 mmol) dropwise at −10° C. over 15 min with stirring. The mixture was stirred at −10° C. for a further 0.5 hr. The solvent was removed and the residue was partitioned between ether and water. The organic layer was washed with aqueous NaHCO3, brine, dried over Mg2SO4, and the solvent was removed. The residue was chromatographed (eluted with 9:1 hexane:ethyl acetate) to afforded a yellow solid. 1H-NMR (CDCl3): δ: 8.0 (2H, s), 7.68 (1H, s), 4.41 (2H, d, J=7.1 Hz), 1.40 (3H, t, J=7.1 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1>C(Cl)Cl>[CH3:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][N:3]=[CH:2]2
Reactant: Cc1cccc2c(Cl)ncnc12
Solvent: ClCCl
Product: Cc1cccc2cncnc12
Temperature: 45 °C
Yield: 41.3 %

Procedure:
To a stirred solution of 4-Chloro-8-methylquinazoline (45 g, 0.252 mol) in DCM (700 mL) under N2 was added p-toluenesulfonylhydrazide (65.9 g, 0.353 mol) in portions. The reaction mixture was heated at 45° C. for 12 h. The reaction completion was monitored by LCMS and TLC. After completion, the reaction mixture was cooled to RT, the solvent evaporated to dryness and the resulted residue redissolved in EtOH (500 mL) and added 2N NaOH solution (300 mL) and refluxed for 6 h. After confirming by LCMS, the reaction mixture was cooled to RT and extracted with MTBE (3×600 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate and concentrated under vacuum. The resulted residue was filtered through column chromatography using neutralized silica gel (60-120 mesh) and pet ether/ethyl acetate as an elutent to yield (15 g, 27% yield) of the titled compound as a low melting yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 9.54 (s, 1H), 9.31 (s, 1H), 7.97-7.94 (dd, J=8.8, 8.1 Hz, 1H), 7.87-7.84 (m, 1H), 7.65-7.62 (d, J=15.2 Hz, 1H), 2.67 (s, 3H).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:45])[CH2:18][NH:19][C:20](=[O:44])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:43])[O:28][CH2:29][CH:30]2[C:42]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:36]3[C:31]2=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:12][CH:11]=1)=O)(C)(C)C.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>C(Cl)Cl>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[NH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:45])[CH2:18][NH:19][C:20](=[O:44])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:43])[O:28][CH2:29][CH:30]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=3[C:37]3[C:42]2=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=O)CNC(=O)CCCCCNC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccc(NC(=O)CNC(=O)CCCCCNC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of #B120 (1 g, 1.63 mmol, 1.0 eq) in dry DCM (20 mL) at 0° C. was added trifluoroacetic acid (6 mL, large excess). The mixture was stirred at room temperature for 2 hrs and concentrated in vacuo. The residue was suspended in water (30 mL) and lyophilized to afford #B121 (1.2 g, 100%) as a slight yellow solid. 1H NMR (400 Hz, DMSO-d6): δ10.08 (s, 1H), 8.15 (br, 4H), 7.90 (d, 2H), 7.69 (d, 2H), 7.63 (d, 2H), 7.41 (m, 8H), 4.30 (m, 3H), 3.98 (m, 3H), 3.87 (d, 2H), 2.97 (m, 2H), 2.17 (m, 2H), 1.51 (m, 2H), 1.40 (m, 2H), 1.26 (m, 2H): LCMS (Protocol I): m/z 537.1 (M+Na]+, retention time=1.10 minutes.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH:13]1[CH:14]=[CH:15][C:16]2N(O)N=[N:19][C:17]=2C=1.C(N)CCCC.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:19][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13])=[O:10])=[CH:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCCCCN
Solvent: CC#N
Product: CCCCCNC(=O)c1ccc(N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 127.1 %

Procedure:
4-Azidobenzoic acid (846 mg, 5.08 mmol), HOBt (694 mg, 5.08 mmol, 1.0 eq.) and n-pentylamine (0.783 ml, 6.61 mmol, 1.3 eq.) were dissolved in acetonitrile (6 ml) and DMF (6 ml), WSC (1.19 g, 6.10 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (50 ml), washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated at 30° C. or below to give the title compound as a pale-yellow solid (1.5 g, including residual solvent).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][CH:12]=[C:13]2[C:17]([N+:18]([O-])=O)=[C:16]([CH3:21])[N:15]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38]>CO.O>[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38].[NH2:18][C:17]1[C:13]2[C:14](=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:10]=[N:11][CH:12]=2)[N:15]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:16]=1[CH3:21]
Reactant: Cc1c([N+](=O)[O-])c2cnnc(OCc3ccccc3)c2n1CC(C)C
Agent: O=C(O)/C=C/C(=O)O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1c(N)c2cnnc(OCc3ccccc3)c2n1CC(C)C
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A suspension of 1.0 g (2.94 mmol) of 7-benzyloxy-1-isobutyl-2-methyl-3-nitropyrrolo [2,3-d]pyridazine in 30 ml of methanol is treated with a solution of 2.6 g (14.6 mmol) of sodium dithionite in 30 ml of water and stirred at 70° C. for 30 min. After addition of 100 ml of water, the mixture is extracted with 3×100 ml of ethyl acetate. The organic extracts are washed with 200 ml of water, dried over magnesium sulfate and subsequently treated with a solution of 341 mg (2.94 mmol) of fumaric acid in 10 ml of methanol. The solution is subsequently concentrated to a volume of 30 ml. After filtration, 800 mg (64%) of the title compound are isolated. M.p.: 143° C. (dec.).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[CH2:19][CH2:18][C@:17]4([CH3:22])[C@H:20]([CH3:21])[C@H:13]3[CH2:14][C:15]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([N+:29]([O-])=O)[C:16]=34)=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1>[Pd].CO>[NH2:29][C:23]1[C:16]2[C@@:17]3([CH3:22])[C@H:20]([CH3:21])[C@H:13]([N:12]([C:10]([C:8]4[CH:7]=[CH:6][C:5]5[N:1]=[CH:2][NH:3][C:4]=5[CH:9]=4)=[O:11])[CH2:19][CH2:18]3)[CH2:14][C:15]=2[CH:26]=[CH:25][C:24]=1[O:27][CH3:28]
Reactant: COc1ccc2c(c1[N+](=O)[O-])[C@]1(C)CCN(C(=O)c3ccc4nc[nH]c4c3)[C@H](C2)[C@H]1C
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1N)[C@]1(C)CCN(C(=O)c3ccc4nc[nH]c4c3)[C@H](C2)[C@H]1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 10% palladium on carbon (1.0 g) and (3H-benzoimidazol-5-yl)-[(2R,6R,11S)-8-methoxy-6,11-dimethyl-7-nitro-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone (1.50 g) in methanol (20 mL) is shaken under hydrogen atmosphere at room temperature for 1 d. Then, the mixture is filtered and the filtrate is concentrated under reduced pressure to give the title compound as a foam-like solid.
Reaction SMILES: [CH2:1]([O:3][P:4]([O:21][CH2:22][CH3:23])([CH:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:7]([O:9]CC)=[O:8])=[O:5])[CH3:2].[OH-].[Li+].C1CCC(NC2CCCCC2)CC1>CCOCC.C(OC(=O)C)C>[CH2:22]([O:21][P:4]([O:3][CH2:1][CH3:2])([CH:6]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)[C:7]([OH:9])=[O:8])=[O:5])[CH3:23]
Reactant: CCOC(=O)C(Cc1ccc(OC)cc1)P(=O)(OCC)OCC
Agent: C1CCC(NC2CCCCC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)C(Cc1ccc(OC)cc1)C(=O)O
Temperature: 0 °C

Procedure:
The product of stage (a) (10 g) was stirred for 4 hr with 1 M lithium hydroxide (30.5 ml). The mixture was extracted with ether, the aqueous phase cooled to 0° C. and acidified to pH 1.0 with 2 N.HCl and extracted with ethyl acetate, exhaustively. The extracts were dried after washing with brine to give a solid residue. The solid was dissolved in a mixture of ether (35 ml) and ethylacetate (35 ml) and DCHA (4.37 g) added. After refrigeration, the precipitated DCHA salt (m.p. 136°-140°) was filtered and washed with ether. The salt was partitioned between ethyl acetate and 5% citric acid solution, the ethyl acetate extract washed with brine and evaporated in vacuo to give the desired product as a crystalline solid m.p. 94°-98° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7]C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.[CH:15]1([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][N:32]=[C:31]4[CH:35]=[C:36]([C:38]5[CH:43]=[CH:42][C:41]([CH:44]=O)=[CH:40][N:39]=5)[S:37][C:30]=34)=[C:24]([F:46])[CH:23]=2)=[O:20])[CH2:17][CH2:16]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.CC(O)=O>[NH2:7][CH:4]1[CH2:3][CH2:2][N:1]([CH2:44][C:41]2[CH:42]=[CH:43][C:38]([C:36]3[S:37][C:30]4[C:31](=[N:32][CH:33]=[CH:34][C:29]=4[O:28][C:25]4[CH:26]=[CH:27][C:22]([NH:21][C:19]([NH:18][CH:15]5[CH2:16][CH2:17]5)=[O:20])=[CH:23][C:24]=4[F:46])[CH:35]=3)=[N:39][CH:40]=2)[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: NC1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)CC1
Reaction time: 0.5 h
Yield: 61 %

Procedure:
tert-Butyl piperidin-4-ylcarbamate (1.34 g, 6.69 mmol) was added to a solution of the aldehyde 47 (2.0 g, 4.46 mmol) in a mixture of NMP (20 mL) and glacial AcOH (0.250 mL). The reaction mixture was stirred for 30 min. NaBH(OAc)3 was then added and the reaction mixture was stirred for an additional 2.5 hours. The reaction mixture was then poured into a saturated aqueous NaHCO3 solution. A precipitate was formed which was collected by filtration, washed with water and air-dried. The crude material was purified by column chromatography using a 5 to 20% gradient of MeOH in EtOAc as eluent to afford the title compound 343 (1.45 g, 51.4% yield). MS (m/z): 633.6 (M+1)+.
Reaction SMILES: [NH2:1][C:2]([CH3:16])([CH2:5][N:6]1[CH:15]=[C:9]2[N:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:8]2=[N:7]1)[C:3]#[N:4].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[S:24])=[CH:21][CH:20]=1>>[Cl:14][C:12]1[CH:11]=[N:10][C:9]2=[CH:15][N:6]([CH2:5][C:2]([NH:1][C:23](=[S:24])[C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:27][CH:26]=3)([C:3]#[N:4])[CH3:16])[N:7]=[C:8]2[CH:13]=1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CC(N)(C#N)Cn1cc2ncc(Cl)cc2n1
Product: CC(C#N)(Cn1cc2ncc(Cl)cc2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(6-chloro-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (35 mg, described in Example 180) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (13 mg, 20%). MS (ES): M/Z [M+H]=440. 1H NMR: (400 MHz, CHLOROFORM-0:1.96 (s, 3H), 4.86 (d, J=14.0 Hz, 1H), 5.01 (d, J=14.0 Hz, 1H), 7.71-7.83 (m, 2H), 7.83-7.92 (m, 2H), 8.02 (dd, J=2.1, 0.9 Hz, 1H), 8.12 (s, 1H), 8.43 (d, J=0.7 Hz, 1H) and 8.56 (d, J=2.1 Hz, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −42.2 (s, 3F).
Reaction SMILES: C([N:8]1[CH2:29][CH2:28][C:11]2([O:15][C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:12]2=[CH2:27])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)=[O:31]>[Pd]>[CH2:17]([N:13]1[C:12]([OH:31])([CH3:27])[C:11]2([CH2:28][CH2:29][NH:8][CH2:9][CH2:10]2)[O:15][C:14]1=[O:16])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=CO
Reactant: C=C1N(CCCCCCCCCC)C(=O)OC12CCN(Cc1ccccc1)CC2
Agent: [Pd]
Product: CCCCCCCCCCN1C(=O)OC2(CCNCC2)C1(C)O
Yield: 78 %

Procedure:
4.0 g of 8-benzyl-3-decyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane are stirred together with 4.0 g of 10% by weight palladium-on-carbon catalyst in 40 ml of 50% aqueous formic acid for 2 hours at room temperature. After filtering off the catalyst the solution is evaporated under reduced pressure, the residue is treated with aqueous sodium hydrogen carbonate solution and the solid product is filtered off. After recrystallizing this product from a mixture of chloroform with n-hexane the title substance is obtained in 78.0% yield, m.p. 139°-140° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@:4]([N:15]1[C:20](=[O:21])[N:19]2[CH:22]=[N:23][C:24]([C:25](=[O:27])[NH2:26])=[C:18]2[N:17]=[N:16]1)([CH3:14])[CH2:5][O:6][Si](C(C)(C)C)(C)C>Cl>[CH3:1][O:2][C:3](=[O:28])[C@:4]([N:15]1[C:20](=[O:21])[N:19]2[CH:22]=[N:23][C:24]([C:25](=[O:27])[NH2:26])=[C:18]2[N:17]=[N:16]1)([CH3:14])[CH2:5][OH:6]
Reactant: COC(=O)[C@](C)(CO[Si](C)(C)C(C)(C)C)n1nnc2c(C(N)=O)ncn2c1=O
Agent: Cl
Product: COC(=O)[C@](C)(CO)n1nnc2c(C(N)=O)ncn2c1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 61.1 %

Procedure:
(S)-3-(tert-Butyl-dimethyl-silanyloxy)-2-(8-carbamoyl-4-oxo-imidazo[5,1-d][1,2,3,5]tetrazin-3-yl)-2-methyl-propionic acid methyl ester (80 mg, 0.21 mmol) was diluted in 1 mL of 1.25 M ethanolic HCl solution. The reaction mixture was then stirred at room temperature for 45 minutes, whereupon the mixture concentrated in vacuo. The crude residue was diluted in Et2O which promoted the formation of a precipitate. The solid was removed by vacuum filtration, washed with Et2O (3×1 reaction volumes) and purified by flash chromatography (SiO2) using CH2Cl2: MeOH (9:1) as eluent to give the title compound (38 mg, 61%) as a white solid. 1H NMR (400 MHz, d6-DMSO) δ ppm: 8.94 (1H, s), 7.91 (1H, s), 7.76 (1H, s), 5.70 (1H, dd, J=8.0 Hz, 6.0 Hz), 5.10 (OH, s (br), 1H), 4.11 (2H, multiplet), 3.70 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[O:5].[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>O1CCCC1>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:4](=[O:5])[C:3]2[C:2](=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:1][C:22]1=[O:23]
Reactant: Nc1ccccc1C(=O)NCCCCSc1ccccn1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2c(=O)n1CCCCSc1ccccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.6 %

Procedure:
Under nitrogen atmosphere, to a solution of 452 mg (1.5 mmol) of 2-[4-(2-aminobenzoylamino)butylthio]pyridine in 20 ml of tetrahydrofuran, 486 mg (3.0 mmol) of 1,1'-carbonyldiimidazole was added, and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off and the residue was dissolved in chloroform. The solution was washed with water and dried. The solvent was distilled off and the residue was recrystallized from chloroform/ether to give 337 mg of the desired product (68.8% yield, white crystals).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:5]=[C:6]([C:14]2[S:18][C:17]([NH:19][C:20]3[CH:24]=[CH:23][NH:22][N:21]=3)=[N:16][C:15]=2[CH3:25])[CH:7]=[CH:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11]>C(Cl)(Cl)Cl.CO>[Br:1][C:24]1[C:20]([NH:19][C:17]2[S:18][C:14]([C:6]3[CH:7]=[CH:8][C:9]([S:10]([CH3:13])(=[O:12])=[O:11])=[C:4]([F:3])[CH:5]=3)=[C:15]([CH3:25])[N:16]=2)=[N:21][NH:22][CH:23]=1
Reactant: BrBr
Reactant: Cc1nc(Nc2cc[nH]n2)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1nc(Nc2n[nH]cc2Br)sc1-c1ccc(S(C)(=O)=O)c(F)c1

Procedure:
Bromine (0.012 ml, 0.23 mmol) in chloroform (0.5 ml) is added dropwise to a stirred solution of [5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-(1H-pyrazol-3-yl)-amine (69) (0.10 g, 0.23 mmol) in chloroform (1 ml) and methanol (2 ml). After stirring at room temperature for 1 hour the hydrobromide salt of the titled compound precipitates. This is removed by filtration and washed with ether.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6]1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1>>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH:18]2[CH2:19][CH2:20][N:15]([CH2:2][CH2:3][CH2:4][N:5]3[C:13](=[O:14])[N:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]4=[N:6]3)[CH2:16][CH2:17]2)=[CH:22]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: O=c1n(CCCCl)nc2ccccn12
Product: O=c1n(CCCN2CCC(c3c[nH]c4ccccc34)CC2)nc2ccccn12

Procedure:
2-{3-[4-(1H-Indol-3-yl)-piperidin-1-yl]-propyl}-2H-[1,2,4]triazolo-[4,3-a]pyridin-3-one was prepared in a similar fashion to compound 22, using 2-(3-Chloro-propyl)-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one and 3-Piperidin-4-yl-1H-indole. Yield: 90 mg (48%); mp: 111.7° C. M+: 376.1; (300 MHz, CDCl3): 8.04 (s, 1H, NH), 7.77 (d, 1H), 7.62(d, 1H), 7.35(d, 1H), 7.09(m, 5H), 6.59(m, 1H), 6.49 (m, 1H), 4.08 (m, CH2), 3.10 (d, CH2), 2.70 (t, CH) 2.55(t, CH2), 2.04(m, 4H), 1.82(m, CH2).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:34]=[C:35]([S:40](Cl)(=[O:42])=[O:41])[CH:36]=[CH:37][C:38]=1[CH3:39]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:35]4[CH:36]=[CH:37][C:38]([CH3:39])=[C:33]([Cl:32])[CH:34]=4)(=[O:41])=[O:42])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1Cl
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(C)c(Cl)c4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 3-chloro-4-methyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=610.1)=98%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([O:15][C:14]([CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)=[O:16])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)OCc2ccccc2)CC1
Yield: 104.1 %

Procedure:
A solution of 1-tert-butoxycarbonyl-piperidine-4-carboxylic acid (20 g) in DMF (100 ml) was treated with anhydrous potassium carbonate (60 g) and then benzyl bromide (16.43 g) and the mixture was stirred at room temperature for 72 hours. It was filtered, evaporated to dryness, dissolved in ethyl acetate, washed with sodium carbonate solution and water and dried over sodium sulfate. The product was evaporated to give an oil (29 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C([Li])CCC.[N:14]1[C:27]2[C:18](=[CH:19][CH:20]=[C:21]3[C:26]=2[N:25]=[CH:24][CH:23]=[CH:22]3)[CH:17]=[CH:16][CH:15]=1>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:24]2[CH:23]=[CH:22][C:21]3[C:26](=[C:27]4[C:18](=[CH:19][CH:20]=3)[CH:17]=[CH:16][CH:15]=[N:14]4)[N:25]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: c1cnc2c(c1)ccc1cccnc12
Agent: [Li]CCCC
Solvent: CCOCC
Product: Brc1ccc(-c2ccc3ccc4cccnc4c3n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
A solution of 6.79 g (24 mmol) of 4-bromoiodobenzene in 100 mL of diethyl ether was cooled to −70° C., added with 14 mL (23.4 mmol) of n-butyllithium dropwise, and stirred for 30 min and further for 30 min after elevating the temperature to 0° C. The resulting solution was added dropwise to 100 mL of a diethyl ether solution of 3.60 g (20 mmol) of 1,10-phenanthroline at 0° C., and the mixture was stirred for 3 h. Ice water was added, an organic layer was separated, and an aqueous layer was extracted with dichloromethane (100 mL×2). The obtained organic layers were combined and dried over anhydrous sodium sulfate, followed by filtration. To a filtrate, 20 g of manganese dioxide was added, and the mixture was stirred for 30 min. Thereafter, 20 g of manganese dioxide was further added, and the mixture was stirred for one hour and allowed to stand at room temperature overnight. The reaction solution was filtered, and a filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography to obtain 2.50 g (yield: 37%) of 2-(4′-bromophenyl)-1,10-phenanthroline as a yellow solid.