Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:13]2[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@H](Oc2cc(Cl)ncn2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1CC[C@H](Oc2ccncn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an argon purged solution of cis/trans-4-(6-chloro-pyrimidin-4-yloxy)-cyclohexanecarboxylic acid ethyl ester (1:1) (1.05 g, 3.69 mmol) and triethylamine (0.52 ml, 3.69 mmol) in ethyl acetate (37 ml) was added palladium on charcoal 10% (0.078 g). The reaction mixture was purged with hydrogen gas and stirred under an atmosphere of hydrogen gas for 16 h at room temperature. The catalyst and the ammonium salts were removed by filtration over Decalite. The filtrate was concentrated in vacuo to give the title compound (0.92 g) as light yellow oil in quantitative yield. MS m/e: 251 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:13]([O:14][CH3:15])=[CH:12][C:5]2[CH2:6][C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)=[CH:26][C:25]=2[O:37][CH3:38])[C:20]([Cl:39])=[CH:19][N:18]=1>>[Cl:39][C:20]1[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)=[CH:26][C:25]=2[O:37][CH3:38])=[N:22][C:17]([NH:1][C:2]2[C:13]([O:14][CH3:15])=[CH:12][C:5]3[CH2:6][C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:18][CH:19]=1
Reactant: COc1cc2c(cc1N)CCNC(=O)C2
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCN(C)CC4)cc3OC)n1)CCNC(=O)C2

Procedure:
The title compound was prepared from 7-Amino-8-methoxy-1,3,4,5-tetrahydro-benzo[d]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white solid (0.012 g, 15%). MP: 208-213° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 8.14-8.10 (m, 2H), 8.03-8.02 (m, 1H), 7.44 (s, 2H), 6.64-6.62 (m, 1H), 6.58-6.56 (m, 1H), 6.54-6.49 (m, 1H), 5.70 (br s, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.78 (s, 3H), 3.56-3.50 (m, 2H), 3.23-3.18 (m, 4H), 3.00-2.96 (m, 2H), 2.64-2.59 (m, 4H), 2.38 (s, 3H). MS: 538 (MH)+.
Reaction SMILES: [CH3:1][N+:2]([CH2:5][CH:6]([OH:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].Cl.O[C@@H](CC(=O)[O-])C[N+](C)(C)C.[Cl-]>>[OH:11][C@H:6]([CH2:7][C:8](=[O:9])[O-:10])[CH2:5][N+:2]([CH3:4])([CH3:1])[CH3:3]
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Agent: C[N+](C)(C)CC(O)CC(=O)O
Agent: C[N+](C)(C)C[C@@H](O)CC(=O)[O-]
Agent: Cl
Product: C[N+](C)(C)C[C@H](O)CC(=O)[O-]
Reaction time: 69 h
Yield: 23 %

Procedure:
The procedure of Example 2c was followed except that the concentration of DL-carnitine chloride for the F-2 stage was 50 g/l, which consisted of 3 parts of L-carnitine chloride and 7 parts D-carnitine chloride in 250 ml of medium B held in a two liter Erlenmeyer flask. After incubation with A. calcoaceticus ATCC 39647 for 69 hours (F-2 stage), 50 ml of the broth was centrifuged (9000×6 for 20 minutes) to remove the cells. The supernatant was evaporated to dryness in vacuo and the residue was extracted with anhydrous ethanol. The ethanolic extract was concentrated to dryness and the residue was dissolved in distilled water and chromatographed over a Dowex 1-X-4 OH column (5×22 cm) to obtain L-carnitine [140 mg (23% yield), [α]D25 -29.2°, c, 1.5 H2O].
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([O:15][C:16]([CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)=[O:17])[CH3:14].Cl[CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Cl-].[NH4+]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH2:13]([O:15][C:16]([C:18]1([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:20][CH2:19]1)=[O:17])[CH3:14]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: ClCOCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1(COCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (15% solution in n-hexane; 9.5 mL, 0.022 mol) is added to a stirred solution of diisopropyl amine (3.1 mL, 0.022 mol) in tetrahydrofuran (15 mL) at −70° C. under an atmosphere of nitrogen and stirred for 30 minutes. A solution of piperidine-1,4-dicarboxylic acid-1-tert-butyl ester-4-ethyl ester (3 g, 0.012 mol) in tetrahydrofuran (10 mL) is introduced at −70° C. Hexamethyl phosphoramide (4.8 mL) is added and reaction mixture is allowed to stir till the temperature reaches at −45° C. Reaction mixture again cooled to −70° C., benzyl chloromethyl ether (5 mL, 0.035 mol) is added and stirred for 1 hour. Saturated aqueous solution of ammonium chloride (30 mL) is added slowly into the reaction mixture at −30° C. and stirred for 10 minutes. It is extracted with ethyl acetate (2×20 mL). Combined organic layer is dried over sodium sulfate. Removal of solvent under reduced pressure gives a viscous liquid which is purified by column chromatography (silica gel 230-400, toluene:ethyl acetate, 23:2 to furnish 4-benzyloxymethylpiperidine-1,4-dicarboxylic acid-1-tert-butyl ester-4-ethyl ester.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:32][CH2:33][CH2:34][CH2:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[Cl:32][CH2:33][CH2:34][CH2:35][S:36]([N:22]1[CH2:23][CH2:24][CH:19]([C:10]2[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[NH:12][CH:11]=2)[CH2:20][CH2:21]1)(=[O:38])=[O:37]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Reactant: O=S(=O)(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
To a solution of 5-phenyl-3-(4-piperidinyl)-1H-indole-7-carboxamide (404 mg, 1.26 mmol) in CH2Cl2 at 0° C., triethylamine (0.7 mL, 5.04 mmol) and 3-chloropropanesulfonyl chloride (0.23 mL, 1.89 mmol) were added. The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was partitioned between CH2Cl2 (100 mL) and water (50 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×100 mL). The combined organic phase washed with brine (50 mL), dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure and purified via filtration through an SPE Cartridge (Aminopropyl NH2, 500 mg/6 mL) to give the title compound (370 mg, 64%).
Reaction SMILES: [CH:1]1([N:5]([CH3:28])[C:6](=[O:27])[C:7]2[CH:12]=[C:11]([O:13][C:14]3[C:19]([Cl:20])=[CH:18][C:17]([CH2:21]OC)=[CH:16][C:15]=3[Cl:24])[CH:10]=[CH:9][C:8]=2[O:25]C)[CH2:4][CH2:3][CH2:2]1.B(Br)(Br)[Br:30]>ClCCl>[Br:30][CH2:21][C:17]1[CH:18]=[C:19]([Cl:20])[C:14]([O:13][C:11]2[CH:10]=[CH:9][C:8]([OH:25])=[C:7]([CH:12]=2)[C:6]([N:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)[CH3:28])=[O:27])=[C:15]([Cl:24])[CH:16]=1
Reactant: BrB(Br)Br
Reactant: COCc1cc(Cl)c(Oc2ccc(OC)c(C(=O)N(C)C3CCC3)c2)c(Cl)c1
Solvent: ClCCl
Product: CN(C(=O)c1cc(Oc2c(Cl)cc(CBr)cc2Cl)ccc1O)C1CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the title compound of Step F in dichloromethane (2.2 ml) at room temperature was added boron tribromide (1M in dichloromethane, 1.5 ml, 1.5 mmol). The reaction mixture was stirred at room temperature for about two hours, and quenched with water (20 ml). After stirring for about 15 minutes, the solution was extracted with dichloromethane (3×15 ml). The combined organic extracts were washed with brine (50 ml), treated with activated carbon, filtered through diatomaceous earth, dried and concentrated to give the title compound (163 mg) as an off-white solid which was used in the next step without further purification. MS (APCl−) Calc: 457.0, found: 456.0 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8](=[O:19])[C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[OH:18])=[C:4]([F:22])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].Cl>CC(C)=O>[C:34]([O:33][C:31](=[O:32])[CH2:30][O:18][C:10]1[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:9]=1[C:8](=[O:19])[NH:7][CH2:6][C:5]1[CH:20]=[CH:21][C:2]([Br:1])=[CH:3][C:4]=1[F:22])([CH3:37])([CH3:36])[CH3:35]
Reactant: O=C(NCc1ccc(Br)cc1F)c1cc([N+](=O)[O-])ccc1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc([N+](=O)[O-])cc1C(=O)NCc1ccc(Br)cc1F
Temperature: 50 °C
Yield: 96.3 %

Procedure:
A solution of N-(4-bromo-2-fluoro-benzyl)-2-hydroxy-5-nitro-benzamide (0.95 g, 2.6 mmol) in acetone (15 mL, 0.2 M) was treated with aq K2CO3 (2 M, 1.9 mL, 3.8 mmol) and t-butyl bromoacetate (2.2 mL, 8.4 mmol). After heating to 50° C. for 30 h, the reaction was acidified to pH 1–2 with 2 N HCl and extracted with ethyl acetate (3×). The combined organic extracts were washed With saturated aq NaCl, dried over Na2SO4, filtered and concentrated. The crude oil was crystallized from heptane and ethyl acetate to give [2-(4-bromo-2-fluoro-benzylcarbamoyl)-4-nitro-phenoxy]-acetic acid tert-butyl ester as a white crystalline solid (1.21 g, 97%): 1H NMR (DMSO-d6, 300 MHz) δ 9.01 (br t, J=5.7 Hz, 1 H), 8.58 (d, J=3.0 Hz, 1 H), 8.33 (dd, J1=9.0 Hz, J2=3.0 Hz, 1 H), 7.51 (br d, J=9.6 Hz, 1 H), 7.42–7.34 (m, 2 H)., 7.32 (d, J=9.3 Hz, 1 H), 4.99 (s, 2 H), 4.52 (d, J=5.7 Hz, 2 H), 1.40 (s, 9 H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16]C)=[O:14].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[C:21]([C:38]([F:41])([F:40])[F:39])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(O)(C)(C)C>[C:34]([O:33][C:31]([N:28]1[CH2:27][CH2:26][N:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=4)[N:5]=[CH:4][C:3]=3[C:13]([O:15][CH3:16])=[O:14])=[CH:20][C:21]=2[C:38]([F:40])([F:41])[F:39])[CH2:30][CH2:29]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CCOC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: COC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.1 %

Procedure:
Ethyl 4,6-dichloro-1,5-naphthyridine-3-carboxylate (0.5 g, 1.84 mmol) and tert-butyl 4-(4-amino-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (0.766 g, 2.22 mmol) were dissolved in a mixture of dichloromethane (5 mL) and tert-butanol (5 mL), to the system added potassium carbonate (0.612 g, 4.43 mmol). The reaction mixture was stirred at room temperature for 24 h, suction filtrated, the solid was washed with 30 mL of dichloromethane, and the resulting wash solution and the filtrate were combined, concentrated under reduced pressure, and the resulting residue was recrystallized from diethyl ether to give 0.73 g of a pale yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[O:12][C:13]([CH:15]=O)=[CH:14][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:4]=2[NH:3]1.[NH3:23]>C(O)(C)C.O=[Mn]=O>[O:1]=[C:2]1[C:11]2[O:12][C:13]([C:15]#[N:23])=[CH:14][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:4]=2[NH:3]1
Reactant: O=Cc1cc2c(o1)c(=O)[nH]c1c(N3CCCCC3)cccc12
Reactant: N
Agent: O=[Mn]=O
Solvent: CC(C)O
Product: N#Cc1cc2c(o1)c(=O)[nH]c1c(N3CCCCC3)cccc12
Reaction time: 1.5 h

Procedure:
A solution of 4-oxo-6-piperidin-1-yl-4,5-dihydro-furo[2,3-c]quinoline-2-carbaldehyde (v) in isopropanol (“iPrOH”) is treated with ammonia gas at room temperature. After 90 min, the reaction is treated with MnO2 and stirred for an additional 16 h. The reaction is filtered and evaporated onto celite. Chromatography on silica gel affords 4-oxo-6-piperidin-1-yl-4,5-dihydro-furo[2,3-c]quinoline-2-carbonitrile. IV. Results
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CO[CH:11](OC)[CH2:12]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH:12]=[CH:11][C:4]=2[CH:3]=1
Reactant: COC(CBr)OC
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2occc2c1
Temperature: 150 °C
Yield: 30.5 %

Procedure:
A solution of 4-bromophenol (17.3 g, 100 mmol) in dimethylformamide (40 ml) was treated with bromoacetaldehyde dimethyl acetal (16.9 g, 100 mmol) and potassium carbonate (13.8 g, 100 mmol) and heated at 150° C. for 16 h. The mixture was cooled, poured into water (500 ml) and extracted with diethyl ether (3×100 ml). The combined organic extracts were dried (MgSO4), concentrated, and filtered through a plug of silica gel eluting with 10% diethyl ether in hexane. The resulting oil (15 g) was added to a solution of polyphosphoric acid (~12 g) in toluene (100 mL) and heated at 80° C. for 16 h. The mixture was cooled and the toluene layer was decanted off and washed with saturated aqueous sodium hydrogen carbonate, dried (MgSO4), concentrated and the residue distilled to give 5-bromobenzofuran (6 g) as a colourless oil, bp. 98° C./1 mmHg; δH (DMSO-d6) 6.96 (1H, m, ArH), 7.45 (1H, m, ArH), 7.59 (1H, m, ArH), 7.91 (1H, m, ArH), and 8.05 (1H, m, ArH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([C:17]3[CH:18]=[N:19][C:20]([CH3:26])=[C:21]([N+:23]([O-])=O)[CH:22]=3)[N:16]=2)[N:13]=1.CC(O)=O.N1C=CC=CC=1.[CH3:37][C:38]([CH3:43])([CH3:42])[C:39](Cl)=[O:40]>C(O)C.O.[Fe]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([C:17]3[CH:22]=[C:21]([NH:23][C:39](=[O:40])[C:38]([CH3:43])([CH3:42])[CH3:37])[C:20]([CH3:26])=[N:19][CH:18]=3)[N:16]=2)[N:13]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ncc(-c2cn3nc(-c4ccccc4F)ccc3n2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ncc(-c2cn3nc(-c4ccccc4F)ccc3n2)cc1NC(=O)C(C)(C)C
Temperature: 80 °C
Reaction time: 4 h
Yield: 43.3 %

Procedure:
To a solution of 6-(2-fluorophenyl)-2-(6-methyl-5-nitropyridin-3-yl)imidazo[1,2-b]pyridazine (0.016 g, 0.0458 mmol) in ethanol (3 mL) and water (1 mL) containing AcOH (0.274 mmol) is added iron (0.013 g, 0.229 mmol). The mixture is heated at 80° C. for 2 hours. The mixture is concentrated under reduced pressure and sat. aqueous NaHCO3 (10 mL) is added. The mixture is extracted with EtOAc (20 mL). Organic layer is collected and concentrated to dryness. Crude amine is taken up in acetonitrile (3 mL) containing pyridine (0.137 mmol). To this solution is added trimethylacetylchloride (0.0503 mmol). The mixture is stirred at room temperature for 4 hours, concentrated to dryness and then purified via silica chromatography using a gradient CH2Cl2 to CH2Cl2:EtOAc:methanol (1:1:0.1) to afford the title compound (0.008 g, 44%) as a light yellow solid: Rf 0.34 (1:1:0.1 CH2Cl2:EtOAc:methanol); LCMS (m/z)=404.4 [M+H]+, tR=2.11 min. (compound same as Example 390)
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:10]([C:12](O)=[O:13])=[CH:9][C:8]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([F:22])[CH:16]=3)=[N:7][C:6]=2[NH:5][N:4]=1)[CH3:2].[N:23]1([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C(=O)C>[C:32]([O:31][C:29]([N:23]1[CH2:28][CH2:27][N:26]([C:12]([C:10]2[C:11]3[C:3]([CH2:1][CH3:2])=[N:4][NH:5][C:6]=3[N:7]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([F:22])[CH:16]=3)[CH:9]=2)=[O:13])[CH2:25][CH2:24]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCc1n[nH]c2nc(-c3ccc(O)c(F)c3)cc(C(=O)O)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CCc1n[nH]c2nc(-c3ccc(O)c(F)c3)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
To a suspension of 3-ethyl-6-(3-fluoro-4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (0.25 g, 0.83 mmol), tert-butyl piperazine-1-carboxylate (0.17 g, 0.91 mmol), 1-hydroxybenzotriazole (0.11 g, 0.83 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.16 g, 0.83 mmol) in anhydrous tetrahydrofurane (5 ml) was added dry N,N-dimethylacetamide (2 ml). The reaction mixture was stirred at room temperature under nitrogen overnight. A solution of saturated sodium hydrogen carbonate was then added, the resulting precipitate was filtered off to afford the title compound (0.25 g, 66%) as a beige solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:11]([OH:13])=[O:12].[I:14]I.[OH-].[K+].S([O-])(O)=O.[Na+].Cl>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:14])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: II
Reactant: O=C(O)c1cc2cc[nH]c2cc1F
Agent: Cl
Agent: O=S([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cc2c(I)c[nH]c2cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.9 %

Procedure:
To a solution of 6-fluoro-1H-indole-5-carboxylic acid (2.32 g, 12.95 mmol) in DMF (15 mL) was added iodine (3.45 g, 13.60 mmol) and potassium hydroxide (1.60 g, 28.5 mmol). After stirring 20 min at RT, the reaction mixture was poured into ice water (40 mL) containing sodium hydrogensulfite (1.35 g, 12.95 mmol). The reaction mixture was stirred for 5 min, treated with 2 N HCl to adjust the pH to about pH=6 and filtered. The resulting orange solid was washed with water (2×25 mL) and transferred to a 250 mL round bottomed flask and dried overnight using a lyophilizer to afford 6-fluoro-3-iodo-1H-indole-5-carboxylic acid (3.63 g, 11.90 mmol, 92% yield) as an orange amorphous solid. MS (ESI, pos. ion) m/z: 305.9 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[C:16](I)=[CH:15][C:14]([S:18][CH3:19])=[CH:13][N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1)#[CH:21].O>C(N(CC)CC)C>[C:1]1([S:7]([N:10]2[C:11]3=[N:12][CH:13]=[C:14]([S:18][CH3:19])[CH:15]=[C:16]3[CH:21]=[C:20]2[C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ncccn1
Reactant: CSc1cnc(NS(=O)(=O)c2ccccc2)c(I)c1
Solvent: O
Solvent: CCN(CC)CC
Product: CSc1cnc2c(c1)cc(-c1ncccn1)n2S(=O)(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
A suspension of 2-benzenesulfonylamino-5-methylthio-3-iodo-pyridine (1.53 g), 2-ethynylpyrimidine (768 mg), bistriphenylphosphine palladium dichloride (259 mg) and cuprous iodide (70.3 mg) in triethylamine (37 ml) was stirred in a sealed tube at 100° C. for 1.5 hours. After cooling, the reaction solution was poured into water, extracted with chloroform, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 1.21 g of the desired product as a white crystal.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[CH:30]=[CH:31][N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:41])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[C:30]([Br:41])=[CH:31][N:32]=[C:20]4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nccn4cc3-c3ccccc3)cc2)CCC1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ncc(Br)n4cc3-c3ccccc3)cc2)CCC1
Yield: 127.2 %

Procedure:
To a solution of compound 4-1 (100 mg, 0.227 mmol) in CHCl3 (5 mL) was added NBS (40 mg 0.227 mmol.) and the mixture was heated to reflux for 2 hrs. After cooling, the mixture was diluted with 15 mL of DCM, the combined organic phase was washed with 0.1N HCl(aq) and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.TLC to give 150 mg of 4-3.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=3)[CH2:18][CH2:17][CH2:16][N:15]3[C:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]5[O:32][C:31]([CH3:33])=[N:30][CH:29]=5)=[C:24]([O:34][CH3:35])[CH:23]=4)=[N:20][N:21]=[C:14]23)(=O)=O)=CC=1.[N-:44]=[N+]=[N-].[Na+].O>CS(C)=O>[Cl:43][C:38]1[CH:37]=[C:36]([C:13]2([CH2:12][NH2:44])[CH2:18][CH2:17][CH2:16][N:15]3[C:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]5[O:32][C:31]([CH3:33])=[N:30][CH:29]=5)=[C:24]([O:34][CH3:35])[CH:23]=4)=[N:20][N:21]=[C:14]23)[CH:41]=[CH:40][C:39]=1[Cl:42]
Reactant: COc1cc(-c2nnc3n2CCCC3(COS(=O)(=O)c2ccc(C)cc2)c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(-c2nnc3n2CCCC3(CN)c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Temperature: 100 °C
Reaction time: 48 h
Yield: 48.9 %

Procedure:
A mixture of {8-(3,4-dichlorophenyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl}methyl 4-methylbenzenesulfonate (150 mg) and sodium azide (45.8 mg) in DMSO (2 mL) was stirred at 100° C. for 2 days. Water was added to the reaction mixture, and the precipitated solid was collected by filtration. The solid was dissolved in THF (2 mL)/water (2 mL), diphenylphosphino-polystyrene (1.99 mmol/g, 236 mg) was added, and the mixture was stirred at 60° C. overnight. The reaction mixture was filtered, and the solvent in the filtrate was evaporated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give the title compound (55.5 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[CH3:13][O:14][C:15](=[O:36])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24](Cl)[C:25]3[C:30]4[CH2:31][CH2:32][CH2:33][CH2:34][C:29]=4[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1>>[CH3:13][O:14][C:15](=[O:36])[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:23]=[C:24]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:25]3[C:30]4[CH2:31][CH2:32][CH2:33][CH2:34][C:29]=4[S:28][C:26]=3[N:27]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c4c(sc3n2)CCCC4)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(OC)c(OC)c3)c3c4c(sc3n2)CCCC4)cc1

Procedure:
The reaction procedure as above wherein 3,4-dimethoxy-benzylamine is reacted with 4-(4-chloro-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dimethoxybenzylamino)-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester